This report contains the collective views of an international group of experts and does not

necessarily represent the decisions or the stated policy of the United Nations Environment
Programme, the International Labour Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 20

MONONITROPHENOLS

First draft prepared by Dr A. Boehncke, Dr G. Koennecker, Dr I. Mangelsdorf, and

Dr A. Wibbertmann, Fraunhofer Institute for Toxicology and Aerosol Research,
Hanover, Germany

Please note that the layout andpagination of this pdf file are not identicalto those of
theprinted CICAD

Published under the joint sponsorship of the United Nations Environment Programme, the
International Labour Organisation, and the World Health Organization, and produced within the
framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization

Geneva, 2000
 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture
of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO),
and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the
scientific basis for assessment of the risk to human health and the environment from exposure to
chemicals, through international peer review processes, as a prerequisite for the promotion of chemical
safety, and to provide technical assistance in strengthening national capacities for the sound management
of chemicals.
The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was
established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,
the United Nations Industrial Development Organization, the United Nations Institute for Training and
Research, and the Organisation for Economic Co-operation and Development (Participating
Organizations), following recommendations made by the 1992 UN Conference on Environment and
Development to strengthen cooperation and increase coordination in the field of chemical safety. The
purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating
Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human
health and the environment.

WHO Library Cataloguing-in-Publication Data

Mononitrophenols.

(Concise international chemical assessment document ; 20)

1.Nitrophenols - toxicity 2.Risk assessment 3.Environmental exposure

I.International Programme on Chemical Safety II.Series

ISBN 92 4 153020 0 (NLM classification: QD 341.P5)

ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate its
publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications,
World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on
any changes made to the text, plans for new editions, and reprints and translations already available.

©World Health Organization 2000

Publications of the World Health Organization enjoy copyright protection in accordance with the
provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization
concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the
delimitation of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers’ products does not imply that they are
endorsed or recommended by the World Health Organization in preference to others of a similar nature
that are not mentioned. Errors and omissions excepted, the names of proprietary products are
distinguished by initial capital letters.
The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany,
provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

 TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . . 8

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND

HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

7.1 2-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7.2 4-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
8.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
8.3.1 Oral exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
8.3.2 Inhalation exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.3.2.1 2-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.3.2.2 4-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.3.3 Dermal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.4 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.4.1 Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.4.2 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
8.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
8.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
8.6.1 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
8.6.2 Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.6.2.1 2-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.6.2.2 4-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.8 Methaemoglobin formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

iii
Concise International Chemical Assessment Document 20

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
11.1.2 Criteria for setting guidance values for 2- and 4-nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
11.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

APPENDIX 1 — 3-NITROPHENOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

APPENDIX 2 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

APPENDIX 3 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

APPENDIX 4 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

iv

FOREWORD
Concise International Chemical Assessment
Documents (CICADs) are the latest in a family of
publications from the International Programme on
Chemical Safety (IPCS) — a cooperative programme of
the World Health Organization (WHO), the International
Labour Organisation (ILO), and the United Nations
Environment Programme (UNEP). CICADs join the
Environmental Health Criteria documents (EHCs) as
authoritative documents on the risk assessment of
chemicals.
CICADs are concise documents that provide
summaries of the relevant scientific information
concerning the potential effects of chemicals upon
human health and/or the environment. They are based
on selected national or regional evaluation documents or
on existing EHCs. Before acceptance for publication as
CICADs by IPCS, these documents undergo extensive
peer review by internationally selected experts to ensure
their completeness, accuracy in the way in which the
original data are represented, and the validity of the
conclusions drawn.
The primary objective of CICADs is
characterization of hazard and dose–response from
exposure to a chemical. CICADs are not a summary of all
available data on a particular chemical; rather, they
include only that information considered critical for
characterization of the risk posed by the chemical. The
critical studies are, however, presented in sufficient
detail to support the conclusions drawn. For additional
information, the reader should consult the identified
source documents upon which the CICAD has been
based.
Risks to human health and the environment will
vary considerably depending upon the type and extent
of exposure. Responsible authorities are strongly
encouraged to characterize risk on the basis of locally
measured or predicted exposure scenarios. To assist the
reader, examples of exposure estimation and risk
characterization are provided in CICADs, whenever
possible. These examples cannot be considered as
representing all possible exposure situations, but are
provided as guidance only. The reader is referred to EHC
1701 for advice on the derivation of health-based
guidance values.
1
International Programme on Chemical Safety (1994)
Assessing human health risks of chemicals: derivation
of guidance values for health-based exposure limits.
Geneva, World Health Organization (Environmental
Health Criteria 170).
1
Mononitrophenols
While every effort is made to ensure that CICADs
represent the current status of knowledge, new
information is being developed constantly. Unless
otherwise stated, CICADs are based on a search of the
scientific literature to the date shown in the executive
summary. In the event that a reader becomes aware of
new information that would change the conclusions
drawn in a CICAD, the reader is requested to contact
IPCS to inform it of the new information.
Procedures
The flow chart shows the procedures followed to
produce a CICAD. These procedures are designed to
take advantage of the expertise that exists around the
world — expertise that is required to produce the high-
quality evaluations of toxicological, exposure, and other
data that are necessary for assessing risks to human
health and/or the environment.
The first draft is based on an existing national,
regional, or international review. Authors of the first
draft are usually, but not necessarily, from the institution
that developed the original review. A standard outline
has been developed to encourage consistency in form.
The first draft undergoes primary review by IPCS to
ensure that it meets the specified criteria for CICADs.
The second stage involves international peer
review by scientists known for their particular expertise
and by scientists selected from an international roster
compiled by IPCS through recommendations from IPCS
national Contact Points and from IPCS Participating
Institutions. Adequate time is allowed for the selected
experts to undertake a thorough review. Authors are
required to take reviewers’ comments into account and
revise their draft, if necessary. The resulting second draft
is submitted to a Final Review Board together with the
reviewers’ comments.
The CICAD Final Review Board has several
important functions:
– to ensure that each CICAD has been subjected to
an appropriate and thorough peer review;
– to verify that the peer reviewers’ comments have
been addressed appropriately;
– to provide guidance to those responsible for the
preparation of CICADs on how to resolve any
remaining issues if, in the opinion of the Board, the
author has not adequately addressed all comments
of the reviewers; and
– to approve CICADs as international assessments.
Board members serve in their personal capacity, not as
representatives of any organization, government, or
 Concise International Chemical Assessment Document 20

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY

NATIONAL/REGIONAL
ASSESSMENT DOCUMENT(S)

FIRST DRAFT
PREPARED

PRIMARY REVIEW BY IPCS

( REVISIONS AS NECESSARY)

REVIEW BY IPCS CONTACT POINTS/

SPECIALIZED EXPERTS

R E V I E W O F C O M M E N T S ( PRODUCER/RESPONSIBLE OFFICER),
PREPARATION
OF SECOND DRAFT 1

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

1 Taking into account the comments from reviewers.

2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments.
3 Includes any revisions requested by the Final Review Board.

2
 Mononitrophenols

industry. They are selected because of their expertise in

human and environmental toxicology or because of their
experience in the regulation of chemicals. Boards are
chosen according to the range of expertise required for a
meeting and the need for balanced geographic
representation.

Board members, authors, reviewers, consultants,

and advisers who participate in the preparation of a
CICAD are required to declare any real or potential
conflict of interest in relation to the subjects under
discussion at any stage of the process. Representatives
of nongovernmental organizations may be invited to
observe the proceedings of the Final Review Board.
Observers may participate in Board discussions only at
the invitation of the Chairperson, and they may not
participate in the final decision-making process.

3
Concise International Chemical Assessment Document 20
1. EXECUTIVE SUMMARY
This CICAD on the isomers 2-, 3-, and 4-nitro-
phenol was prepared by the Fraunhofer Institute for
Toxicology and Aerosol Research, Hanover, Germany. It
was based on reviews compiled by the German Advisory
Committee on Existing Chemicals of Environmental
Relevance (BUA, 1992) and the US Agency for Toxic
Substances and Disease Registry (ATSDR, 1992) to
assess the potential effects of 2- and 4-nitrophenol on
the environment and on human health. Data identified up
to 1992 were considered in these reviews. A compre-
hensive literature search of several databases was con-
ducted in 1998 to identify any relevant references on 2-
and 4-nitrophenol published subsequent to those in the
source documents and to identify all references contain-
ing relevant data on the isomer 3-nitrophenol. Informa-
tion found on 3-nitrophenol was very scarce, precluding
a meaningful assessment. As a result, data on this
isomer are summarized in Appendix 1. Information on the
nature of the peer review and the availability of the
source documents is presented in Appendix 2. Informa-
tion on the peer review of this CICAD is presented in
Appendix 3. This CICAD was approved as an interna-
tional assessment at a meeting of the Final Review
Board, held in Washington, DC, USA, on 8–11 December
1998. Participants at the Final Review Board meeting are
listed in Appendix 4. The International Chemical Safety
Card (ICSC 1342) for mononitrophenols, produced by the
International Programme on Chemical Safety (IPCS,
1998), has also been reproduced in this document.
The nitrophenol isomers are water-soluble solids
that are moderately acidic in water as a result of dissoci-
ation. 2-Nitrophenol and 4-nitrophenol are used as inter-
mediates in the synthesis of a number of organophos-
phorus pesticides and some medical products. Releases
into the environment are primarily emissions into air,
water, and soil from diffuse sources, such as vehicle
traffic and hydrolytic and photolytic degradation of the
respective pesticides. Further releases into the hydro-
sphere and the geosphere are caused by the dry and wet
deposition of airborne nitrophenols from the atmos-
phere. The photo-oxidative formation of 2- and 4-nitro-
phenol in the atmosphere is still under discussion.
From the available data, only a slow rate of volati-
lization of 2-nitrophenol and no significant volatilization
of 4-nitrophenol from water to air are to be expected.
2-Nitrophenol is enriched in the liquid phase of clouds,
whereas more 4-nitrophenol than expected from physico-
chemical data can be found in the gas phase owing to
extensive binding to particles. In view of the water
solubilities and the expected occurrence in the vapour
4
phase, wet deposition of nitrophenols from air to surface
waters and soil is to be expected. The major
transformation pathway for 2-nitrophenol emitted to the
troposphere should be rapid nitration to 2,4-dinitro-
phenol, whereas the major portion of airborne 4-nitro-
phenol is expected to be particle bound and therefore
only to a minor extent available for photochemical
reactions. Most of the 4-nitrophenol should be washed
out from air by wet and dry deposition. Nitrophenols are
not considered to contribute directly to the depletion of
the stratospheric ozone layer or to global warming.
Measured half-lives for the photochemical decomposi-
tion of 4-nitrophenol in water ranged from 2.8 to
13.7 days. Numerous studies on the biodegradation of
2- and 4-nitrophenol indicate the isomers to be inher-
ently biodegradable in water under aerobic conditions.
Mineralization of nitrophenols under anaerobic condi-
tions requires extended adaptation of microbial commu-
nities.
Measured coefficients of soil sorption (K oc) in the
range of 44–530 indicate a low to moderate potential for
soil sorption. Nitrophenols released to soil should be
biodecomposed under aerobic conditions. Infiltration
into groundwater is expected only under conditions
unfavourable to biodegradation. For 2- and 4-nitrophe-
nol, measured bioconcentration factors ranging from 11
to 76 indicate a low potential for bioaccumulation.
There is only limited information concerning the
toxicological profiles of 2- and 4-nitrophenol. In experi-
mental animals given 4-nitrophenol orally, intravenously,
or intraperitoneally, most of the applied dose was
excreted via the urine within 24–48 h as glucuronide and
sulfate conjugates, while only very small amounts were
excreted via faeces or as unchanged 4-nitrophenol. The
percentages of glucuronide and sulfate conjugates were
shown to be species and dose dependent. After oral
dosing in rabbits, 4-nitrophenol undergoes reduction to
p-aminophenol as well as glucuronidation and sulfation.
The available data from in vivo and in vitro studies give
an indication for dermal uptake of 4-nitrophenol. The
data for 2-nitrophenol are very limited. However, based
on the available data, a comparable metabolic transfor-
mation is assumed. Bioaccumulation of 2- and 4-nitro-
phenol in organisms is not to be expected owing to their
rapid metabolism and excretion.
In acute studies, 4-nitrophenol is harmful after oral
uptake and was found to be more toxic than 2-nitrophe-
nol. A dose-dependent increase in the formation of
methaemoglobin was seen in cats after oral exposure to
2-nitrophenol and in rats after exposure by inhalation to
4-nitrophenol. After repeated exposure to 4-nitrophenol,
the formation of methaemoglobin was shown to be the

most critical end-point for exposure by inhalation and is
assumed to be relevant for oral exposure too. Other
noted effects included decreases in body weight gain,
differences in organ weights, focal fatty degeneration of
the liver, and haematological changes. For these effects,
it was not possible to identify a clear dose–response or
reliable no-observed-(adverse-)effect levels (NO(A)ELs).
2-Nitrophenol is slightly irritating to the skin but
non-irritating to the eye. The substance proved to have
no sensitizing effects in a Buehler test. Based on valid
studies with experimental animals, irritating effects on
skin and eye are assumed for 4-nitrophenol. In a guinea-
pig maximization test, 4-nitrophenol was considered as
slightly sensitizing. In humans, a possible sensitization
after contact with 4-nitrophenol cannot be excluded,
especially as skin sensitization has been found in patch
tests on factory workers who may have been exposed to
4-nitrophenol.
Neither of the two isomers of nitrophenol has been
fully tested for genotoxicity. Insufficient data are avail-
able on 2-nitrophenol to allow any conclusions to be
made about its possible mutagenicity. More mutageni-
city studies are available for 4-nitrophenol, although
some were inadequately reported. There is evidence to
suggest that 4-nitrophenol can cause chromosomal
aberrations in vitro . In the absence of any in vivo
mutagenicity studies in mammals, it is not possible to
conclude whether or not the mutagenic potential of 4-
nitrophenol is expressed in vivo.
In mice, the dermal application of 4-nitrophenol for
78 weeks gave no indication of carcinogenic effects. In
another study with mice, which has several limitations,
no skin tumours were noted after dermal application of 2-
or 4-nitrophenol over 12 weeks. Carcinogenicity studies
using the oral or inhalation routes were not available for
either of the isomers.
For 4-nitrophenol, the available data gave no
evidence of specific or statistically significant reproduc-
tive or developmental toxicity effects after dermal or oral
application to rats and mice. In an oral study with rats, 2-
nitrophenol induced developmental effects in the
offspring only at doses that also produced maternal
toxicity. However, in these studies, the fetuses were not
examined for internal malformations.
The database for 2-nitrophenol is extremely limited,
and the database for 4-nitrophenol is insufficient for
deriving reliable NO(A)EL values. Therefore, at present,
no tolerable daily intakes (TDIs) or tolerable con-
centrations (TCs) can be derived for either 2- or 4-nitro-
phenol.
5
Mononitrophenols
From valid test results available on the toxicity of
2- and 4-nitrophenol to various aquatic organisms,
nitrophenols can be classified as substances exhibiting
moderate to high toxicity in the aquatic compartment.
The lowest effect concentrations found in chronic
studies with freshwater organisms (Scenedesmus
subspicatus, 96-h EC50: 0.39 mg 2-nitrophenol/litre;
Entosiphon sulcatum, 72-h minimum inhibitory concen-
tration, or MIC: 0.83 mg 4-nitrophenol/litre) were 40–
50 times higher than maximum levels determined in a
densely populated and highly industrialized Asian river
basin (0.0072 mg 2-nitrophenol/litre and 0.019 mg 4-
nitrophenol/litre). Therefore, despite biotic and photo-
chemical decomposition, nitrophenols emitted to water
could pose some risk to sensitive aquatic organisms,
particularly under surface water conditions not favour-
ing both elimination pathways. Because of their use
patterns and release scenarios, it is likely that nitrophe-
nols pose only a minor risk to aquatic organisms.
The available data indicate only a moderate toxicity
potential of nitrophenols in the terrestrial environment.
From calculations of the toxicity exposure ratio (TER) of
nitrophenols from the degradation of pesticides, only a
minor risk for organisms in this compartment is to be
expected, even under a worst-case scenario.
2. IDENTITY AND PHYSICAL/CHEMICAL
PROPERTIES
2-Nitrophenol (CAS No. 88-75-5; 2-hydroxy-1-
nitrobenzene, o-nitrophenol) and 4-nitrophenol (CAS
No. 100-02-7; 4-hydroxy-1-nitrobenzene, p-nitrophenol)
share the empirical formula C6H5NO3. Their structural
formulas are shown below.
OH OH
NO2
NO2
2-nitrophenol 4-nitrophenol
Technical-grade 2- and 4-nitrophenol from the
German producer have a typical purity of >99%. Named
impurities are the corresponding isomer for each product
(0.3%) and traces of 3-nitrochlorobenzene (<0.05%).
Polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/
Concise International Chemical Assessment Document 20

PCDF) and tetrachlorodibenzo-p-dioxin/dibenzofuran 1994; Luettke & Levsen, 1994; Mussmann et al., 1994).
(TCDD/TCDF) isomers were not detected at detection For liquid samples (water, urine, blood), high-
limits between 0.1 and 0.4 :g/kg product (BUA, 1992). performance liquid chromatography in combination with
concentration-gradient elution (acetonitrile/methanol or
The pure nitrophenol isomers form pale yellow to ammonium acetate, acetic acid with potassium chloride/
yellow crystals at room temperature. The substances are methanol) and ultraviolet or electrochemical detection,
characterized by the physicochemical properties given in which can be carried out without derivatization, is also
Table 1 (Sax & Lewis, 1987). used (BUA, 1992; Nasseredine-Sebaei et al., 1993; Ruana
et al., 1993; Paterson et al., 1996; Pocurull et al., 1996;
Thompson et al., 1996). The separation of the different
Table 1: Physicochemical properties of 2- and 4-nitrophenol. isomers is carried out either by steam distillation (BUA,
1992) or by the formation and subsequent extraction of
Parameter 2-Nitrophenol 4-Nitrophenol different ion pairs (León-González et al., 1992).
Molecular mass 139.11 139.11
(g/mol) The following enrichment techniques are used
Melting point (°C) 44–45 (1)(2)(3) 113–114 (1)(2)(3) (BUA, 1992; see also review by Puig & Barcelo, 1996):
Boiling point (°C) 214–217 (1) 279
(decomposition) (3) # solid-phase adsorption with thermal or liquid
extraction for air and water samples (Luettke &
Vapour pressure 6.8 × 10 –3 3.2 × 10 –6
(kPa) (19.8 °C) (4) (20 °C) (5)
Levsen, 1994; Mussmann et al., 1994)

Water solubility 1.26 12.4

# liquid/liquid extraction after derivatization for water
(g/litre) (20 °C) (4) (20 °C) (6)
samples (initial purification by acid/base
n-Octanol/water 1.77–1.89 (7) 1.85–2.04 (7) fractionation of highly polluted samples, increased
partition coefficient
(log K ow)
recovery rates with continuous extraction
methods) (León-González et al., 1992; Nick &
Dissociation constant 7.23 7.08
Schoeler, 1992; Geissler & Schoeler, 1994; Harrison
(pK a) (21.5 °C) (8) (21.5 °C) (8)
et al., 1994)
Ultraviolet spectrum 8max (water): 8max (methanol):
230; 276 nm; no absorption
log ,max: 3.57; maxima #290 nm(9) # liquid extraction with acid/base fractionation or
3.80 (9) solid-phase enrichment and subsequent
desorption following aqueous extraction for soil
Conversion factors 1 mg/m 3 = 0.173 ppmv
1 ppmv = 5.78 mg/m 3 samples (Vozñáková et al., 1996)

References: (1) Budavari et al. (1996); (2) Booth (1991);
(3) Verschueren (1983); (4) Koerdel et al. (1981);
(5) Sewekow (1983); (6) Andrae et al. (1981); (7) BUA (1992);
(8) Schwarzenbach et al. (1988); (9) Weast (1979)
# acid hydrolysis of the glucuronide with
subsequent derivatization for blood and urine
samples or denaturation (Nasseredine-Sebaei et al.,
1993; Thompson et al., 1996).

Additional physicochemical properties for
mononitrophenols are presented in the International
Chemical Safety Card (ICSC 1342) reproduced in this
document.
The detection limits are <10 ng/m3 for air, 0.03–
10 :g/litre for water, and 200–1600 :g/kg for soil. A
detection limit for the determination of the nitrophenol
isomers in biological materials was given only for rat
liver perfusate (0.5–1 mg/litre; Thompson et al., 1996).

3. ANALYTICAL METHODS
4. SOURCES OF HUMAN AND

The nitrophenol isomers are usually determined by

gas chromatography combined with mass spectrometric
detection, flame ionization detection, electron capture There are no known natural sources of the nitro-
detection, or nitrogen-sensitive detection, which are phenol isomers.
generally applied after derivatization (BUA, 1992; Nick &
Schoeler, 1992; Geissler & Schoeler, 1994; Harrison et al.,

6

Within the European Union, 2- and 4-nitrophenol
are produced mainly by three companies. Six other large
manufacturers are known in the USA and Japan (as of
1989). In 1983, the production volume for Western
Europe was estimated at about 6400 t 2-nitrophenol and
about 20 500 t 4-nitrophenol. In 1988–89, the German
production volumes originating from one manufacturer
were approximately 500 t 2-nitrophenol and about 2000 t
4-nitrophenol, with about 20 t of each being exported.
Both 2- and 4-nitrophenol are intermediates in the
synthesis of azo dyes and a number of pesticides, mainly
insecticides (2-nitrophenol: carbofuran, phosalon; 4-
nitrophenol: parathion, parathion-methyl, fluorodifen)
and, to a lesser extent, herbicides (4-nitrophenol:
nitrofen, bifenox). The corresponding aminophenols that
are gained by reduction are used as a photographic
developer (2-aminophenol) and as an intermediate in the
synthesis of the tuberculostatic 4-aminosalicylic acid
and the analgesic 4-acetaminophenol (paracetamol) (4-
aminophenol) (see also Booth, 1991). In the 1980s, the
production volumes for 2- and 4-nitrophenol showed a
decreasing tendency in Germany as a result of changes
in and termination of the production of some organo-
phosphorus pesticides.
The releases of 2- and 4-nitrophenol during pro-
duction and processing at the only German manufacturer
appear to be of minor importance. In 1988–89, about
2.5 kg 2-nitrophenol and 10 kg 4-nitrophenol were
emitted to air, and #93 kg 2-nitrophenol and <64 kg 4-
nitrophenol were emitted to surface water.
For 1996, the following releases of 2- and 4-nitro-
phenol to the environment were reported by manufac-
turers in the USA (TRI, 1998):
# 2-nitrophenol: from three manufacturers (one
production site each) with production volumes
between 450 and 45 000 kg/year, total releases of 15
kg to air and 23 kg into water were reported.
# 4-nitrophenol: from three manufacturers (six
production sites) with production volumes of
45–450 kg/year up to 45 000–450 000 kg/year, a
total release of 420 kg to air was reported. Data on
releases into water were not given.
2-Nitrophenol and 4-nitrophenol have been
detected in the exhaust gases of light-duty gasoline and
diesel vehicles. Depending on the motor load, the
exhaust concentrations of the isomers were <50 :g/m3
exhaust gas (idle) and about 1000 :g 4-nitrophenol/m3
and 2000 :g 2-nitrophenol/m3 (driving at constant
velocity) (Nojima et al., 1983; Tremp et al., 1993). A
regulated three-way catalytic converter reduced the
nitrophenol emissions to about 8% at high motor load
7
Mononitrophenols
and to about 2% at normal motor load (Tremp et al.,
1993). A rough estimation combining the above-
mentioned exhaust gas concentrations with estimations
of the total exhaust gas volumes from vehicle traffic for
Germany resulted in an airborne nitrophenol load of at
least several tonnes per year from this source (BUA,
1992). Data concerning nitrophenol releases from other
combustion processes (heating, burning of refuse) were
not identified.
From laboratory experiments, there is some
evidence that 2- and 4-nitrophenol are generated in the
atmosphere during the photochemical degradation of
aromatic compounds such as benzene and toluene in the
presence of nitric oxide or hydroxyl radicals and nitrous
dioxide. These results were at least partly obtained in
model experiments with unrealistically high nitric oxide
concentrations, and there are competing reactions with-
out nitrophenol formation for which the rate constant is
not known (BUA, 1992). However, smog chamber
experiments confirmed the formation of nitrophenol
isomers during irradiation (Leone & Seinfeld, 1985;
Leone et al., 1985). Recent cloud water model experi-
ments showed that 2- and 4-nitrophenol are also formed
from the reaction of phenol with nitrogen pentoxide or
monochloronitrogen dioxide, especially under alkaline
conditions (Scheer et al., 1996). Estimations of the
contribution of photochemically formed nitrophenols to
total emissions into the atmosphere are not possible with
the available data.
Significant releases of 4-nitrophenol into the
hydrosphere may occur from the hydrolytic degradation
of the insecticides parathion and parathion-methyl and
— although to a lesser extent — from the photolytic
degradation of the herbicides nitrofen and bifenox.
Quantification of releases is not possible with the avail-
able data. Furthermore, a considerable portion of air-
borne nitrophenols, especially 4-nitrophenol, can be
released to the hydrosphere and the geosphere by wet
and dry deposition (see section 5) (Herterich & Herr-
mann, 1990; Luettke et al., 1997). Numerous studies
concerning the concentrations of 2- and 4-nitrophenol in
wet deposition samples are available (see section 6.1).
From precipitation data (average 746 mm rain per year for
land masses, according to Baumgartner & Liebscher,
1990) and the measured concentrations of 2- and 4-
nitrophenol in rainwater, the release of nitrophenols via
rain can be estimated to be at least in the order of several
thousand tonnes per year on a global basis.
The application of the herbicides nitrofen and
bifenox, which are photolytically degraded to 4-nitro-
phenol in aqueous solutions, may especially lead to
emissions into the geosphere and the biosphere. Further,
nitrophenol-contaminated rain, snow, and other wet and
Concise International Chemical Assessment Document 20
dry deposition may contribute to nitrophenol levels in
soils. Data concerning the release of nitrophenols into
the biosphere are not available.
5. ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, AND TRANSFORMATION
Environmental releases of nitrophenols are mostly
to ambient air, surface waters, and — to a smaller extent
— soil. Using a non-steady-state equilibrium model, the
following distribution of 4-nitrophenol in different envi-
ronmental compartments was predicted: air, 0.0006%;
water, 94.6%; sediment, 4.44%; soil, 0.95%; biota,
0.000 09% (Yoshida et al., 1983). The distribution pat-
terns of 2- and 4-nitrophenol sprayed on a natural soil in
a standardized terrestrial ecosystem were determined via
radiotracer technique (14C). Of the applied radioactivity
(2-nitrophenol/4-nitrophenol), 49.45%/20.01% was
recovered in air, 27.38%/40.21% in soil (including
animals), 12.73%/7.57% in plants, and 0.05%/0.02% in
leachate (Figge et al., 1985). Distribution of 4-nitrophenol
in a terrestrial microcosm chamber with artificial soil
largely corresponded to this result (Gile & Gillett, 1981).
Owing to the expected decomposition within the incuba-
tion periods of 30 and 28 days, respectively, it can be
assumed that most of the recovered radioactivity referred
to breakdown products of the applied nitrophenols.
In volatility experiments conducted according to
Organisation for Economic Co-operation and Develop-
ment (OECD) guidelines, half-lives of 2-nitrophenol in
water ranged from 14.5 to 27.3 days, indicating a slow
rate of volatilization (Koerdel et al., 1981; Rippen et al.,
1984; Scheunert, 1984; Schoene & Steinhanses, 1984).
Measurements concerning the partitioning between the
gas and liquid phases of clouds during different rain
events showed that 2-nitrophenol is enriched in the
liquid phase to a larger extent than would be predicted
from its water solubility and vapour pressure. On the
other hand, 4-nitrophenol is extensively adsorbed to
particles. Therefore, elevated levels of this isomer are
detected in the gaseous phase of clouds (Luettke et al.,
1997). From the available data, a significant volatilization
of 4-nitrophenol from water to air is not expected. Since
nitrophenols dissociate in aqueous solution, volatiliza-
tion may further decrease with increasing pH in surface
waters. This leads to the conclusion that dry and wet
deposition of nitrophenols from air to surface waters and
soil are to be expected. The occurrence of this partition
mechanism is supported by the detection of 2- and 4-
nitrophenol in rainwater and wet deposition samples (see
section 6.1).
8
From experimental results on direct photodegrada-
tion (Koerdel et al., 1981) and the atmospheric photo-
oxidation by hydroxyl radicals (Zetzsch et al., 1984), both
pathways were found to be of minor importance for the
removal of 2-nitrophenol emitted to the troposphere.
Thus, the major degradation pathway for airborne 2-
nitrophenol should be rapid nitration to 2,4-dinitrophe-
nol (Herterich & Herrmann, 1990; Luettke et al., 1997).
The major portion of airborne 4-nitrophenol is expected
to be particle bound and therefore only to a minor extent
available for photochemical reactions. Thus, most of the
4-nitrophenol can be washed out from air by wet and dry
deposition. Measured half-lives for the photochemical
decomposition of 4-nitrophenol in water exposed to
sunlight ranged from 2.8 to 13.7 days (Hustert et al.,
1981; Mansour, 1996), being longer with increasing pH
(Hustert et al., 1981). Traces of 4-aminophenol were
found as a photoproduct in river water (Mansour, 1996).
In experiments conducted according to OECD guide-
lines, Andrae et al. (1981) and Koerdel et al. (1981) found
no hydrolysis of 2- or 4-nitrophenol under environmental
conditions.
Numerous studies on the biodegradation of 2- and
4-nitrophenol have been conducted. Standardized tests
on ready or inherent biodegradability provide data of
large variability, indicating 2- and 4-nitrophenol to be
inherently biodegradable under aerobic conditions
(depending on origin and density of inoculum and the
applied test method) (see Table 2). Results from different
tests point to a possible bacteriotoxic effect of 4-
nitrophenol at concentrations above 300 mg/litre (Gerike
& Fischer, 1979; Nyholm et al., 1984; Kayser et al., 1994).
Non-standardized experiments with different
inocula (e.g., natural water, soil, sediment) showed that
microbial decomposition of nitrophenols can occur in
different environmental compartments after adaptation of
the microflora (Rubin et al., 1982; Subba-Rao et al., 1982;
Van Veld & Spain, 1983; Spain et al., 1984; Ou, 1985;
Hoover et al., 1986; Aelion et al., 1987; Wiggins et al.,
1987). Time for acclimation and degree of removal
depended mostly on substance concentration, microbial
population, climate, and additional substrates.
Biotic degradation of nitrophenols under anaerobic
conditions requires extended acclimatization of microbial
communities. In tests with sewage sludge and sludge
from the primary anaerobic stage of a municipal sewage
treatment plant, respectively, initial 2- and 4-nitrophenol
concentrations in the range of 96.5–579 mg/litre were not
degraded at all within 7–60 days (Wagner & Braeutigam,
1981; Battersby & Wilson, 1989). Boyd et al. (1983)
found complete anaerobic removal of 50 mg/litre for all
nitrophenol isomers within 1 week, but complete
 Mononitrophenols

Table 2: Biotic degradation of nitrophenols under aerobic conditions.

Concentration Additional Test duration Removal

Test Substance (mg/litre) carbon source (days) (%) Reference

Tests on ready biodegradability

AFNOR test 2-NP 40 OC no 14 16 Gerike & Fischer (1979)

Sturm test 2-NP 10 no 28 32 Gerike & Fischer (1979)

MITI I 2-NP 100 no 14 0 Urano & Kato (1986)

50 no 14 7 Gerike & Fischer (1979)

Closed bottle test 4-NP 2 no 28 55 Rott et al. (1982)

Modified OECD 4-NP 20 DOC no 28 1 Rott et al. (1982)

screening test

Shake flask test 4-NP 20 OC no 21 50 Means & Anderson

(1981)

AFNOR test 4-NP 40 OC no 14 97 Gerike & Fischer (1979)

Sturm test 4-NP 10 no 28 90 Gerike & Fischer (1979)

MITI I 4-NP 50 no 14 1 Gerike & Fischer (1979)

100 no 14 0 Urano & Kato (1986)
100 no 14 4.3 CITI (1992)

Tests on inherent biodegradability

Zahn-Wellens test 2-NP 400 no 14 80 Gerike & Fischer (1979)

SCAS test 2-NP 20 TOC yes 24 107 Broecker et al. (1984)

13.3 TOC yes 24 110

Bunch & Chambers 2-NP 5–10 yes 28 100 Tabak et al. (1981)

Coupled units test 2-NP 12 OC yes 7 61 Gerike & Fischer (1979)

Batch test, aerated 2-NP 200 COD no 5 97 Pitter (1976)

Zahn-Wellens test 4-NP 300 no 14 8 Andrae et al. (1981)

100 DOC no 28 100 Pagga et al. (1982)

Activated sludge test 4-NP 50 no 19 100 Means & Anderson

100 no 19 90 (1981)

SCAS test 4-NP 20 TOC yes 33 >90 Marquart et al. (1984)

27 >97 Scheubel (1984)
25/39 100 Ballhorn et al. (1984)
12–15 100 Koerdel et al. (1984)

Coupled units test 4-NP 12 OC yes 7 100 Gerike & Fischer (1979)

Batch test, aerated 4-NP 200 COD no 5 95 Pitter (1976)

Abbreviations used: 2-NP = 2-nitrophenol; 4-NP = 4-nitrophenol; OC = organic carbon; DOC = dissolved organic carbon; TOC = total
organic carbon; COD = chemical oxygen demand.

mineralization was demonstrated only if the incubation
period was extended to 10 weeks. Anaerobic degradation
even of high initial nitrophenol concentrations was
found by Tseng & Lin (1994), who observed >90%
removal of 2- and 4-nitrophenol (350–650 mg/litre) in a
biological fluidized bed reactor with three different kinds
of wastewater. From the available results, a slow
degradation of nitrophenols under anaerobic conditions
by adapted microorganisms can be expected.
and from 56 to 530 (4-nitrophenol) (Boyd, 1982; Broecker
et al., 1984; Koerdel et al., 1984; Løkke, 1984; Marquart et
al., 1984). Nitrophenols emitted to soil are expected to be
biodecomposed under aerobic conditions. Infiltration
into groundwater is expected only under conditions
unfavourable for biodegradation (e.g., anaerobic
conditions). From the available experimental results,
nitrophenols have to be classified as substances with a
low to moderate potential for soil sorption.

Soil sorption coefficients (K oc) were found to A low potential for bioaccumulation is to be
increase with increasing organic carbon content. Mea- expected from the available valid test results for 2- and 4-
sured K oc values ranged from 44 to 230 (2-nitrophenol) nitrophenol. Bioconcentration factors ranging from 14.6

9
Concise International Chemical Assessment Document 20
to 24.4 were determined for 2-nitrophenol in a semistatic
test system with zebra fish (Brachydanio rerio) (Koerdel
et al., 1984); in a flow-through experiment,
bioconcentration factors ranged from 30 to 76 for
common carp (Cyprinus carpio), including possible
conjugates (Broecker et al., 1984). In static tests,
accumulation factors for 4-nitrophenol of 11 for the
green alga Chlorella fusca after 1 day (Geyer et al., 1981)
and 57 for the freshwater golden orfe (Leuciscus idus
melanotus) after 3 days of exposure were determined
(Freitag et al., 1982). Zebra fish exposed in tap and river
water nearly completely eliminated the accumulated 14C-
4-nitrophenol within 48 h (Ensenbach & Nagel, 1991).
Star fish (Pisaster ochraceus) and sea urchin
(Strongylocentrotus purpuratus) eliminated 89% and
36%, respectively, of injected 14C-4-nitrophenol (3.48 and
3.70 mg/kg body weight, respectively) within 8 h
(Landrum & Crosby, 1981).
6. ENVIRONMENTAL LEVELS AND
HUMAN EXPOSURE
6.1 Environmental levels
From the concentrations in rainwater, the total
atmospheric nitrophenol pollution in Switzerland is
estimated at about 1 :g/m3 (Leuenberger et al., 1988).
Recent measurements in the air of remote areas in Europe
(German Alps, Fichtelgebirge, Germany; Mount Brocken,
Germany; Great Dun Fell summit, United Kingdom) gave
2-nitrophenol concentrations between 0.8 and 25 ng/m3
and 4-nitrophenol levels between 1.2 and 360 ng/m3
(Herterich & Herrmann, 1990; Luettke et al., 1997). The
higher atmospheric 4-nitrophenol levels are apparently
due to the higher photochemical stability of this isomer
(see section 5). 2-Nitrophenol was found in 22 out of 27
samples of air (range 1–140 ng/m3; detection limit 1
ng/m3) in Japan in 1994, and 4-nitrophenol was detected
in 27 out of 27 air samples (range 1–71 ng/m3; detection
limit 1 ng/m3) (Japan Environment Agency, 1995). In
street dust samples from a Japanese city, up to 3.9 mg 2-
nitrophenol/kg and up to 42 mg 4-nitrophenol/kg were
detected (Nojima et al., 1983).
Numerous studies deal with the distribution, depo-
sition, and degradation behaviour of airborne 2- and 4-
nitrophenol in clouds and rainwater. 2-Nitrophenol levels
in rainwater and snow between 0.03 and 5.7 :g/litre and
4-nitrophenol concentrations from <0.5 to 19 :g/litre are
given in reports mainly from Germany and the USA
(BUA, 1992). The recent measurements in rainwater,
cloud water, and “fog” (water vapour; not further char-
acterized) from rural and urban areas in Europe confirm
10
these concentration ranges (Herterich & Herrmann, 1990;
Levsen et al., 1990; Richartz et al., 1990; Capel et al., 1991;
Geissler & Schoeler, 1993; Levsen et al., 1993; Luettke et
al., 1997). The 2-nitrophenol levels are mostly below or
slightly above the detection limit (i.e., <0.1 :g/litre),
whereas mean 4-nitrophenol concentrations of about 5
:g/litre rainwater and cloud water and 20 :g/litre fog
water were detected. The nitrophenol concentrations in
fog are significantly higher than those in rainwater or
cloud water owing to the higher droplet surface and
longer residence times of the droplets in air compared
with rain. The lower concentrations of 2-nitrophenol in
the deposition samples compared with 4-nitrophenol are
presumably due to the lower photochemical stability of
this compound (see section 5).
In the 1970s and early 1980s, the 2- and 4-nitro-
phenol concentrations in the German and Dutch parts of
the river Rhine and some of its tributaries were between
0.1 and 1 :g/litre (BUA, 1992). 2-Nitrophenol and 4-
nitrophenol were not detected in 177 samples of Japa-
nese surface waters (detection limits 0.04–10 :g/litre) or
in 177 sediment samples (detection limits between 0.002
and 0.8 :g/kg) in 1978, 1979, and 1994 (Japan Environ-
ment Agency, 1979, 1980, 1995). Whereas 4-nitrophenol
was not detected in 129 fish samples (detection limits
0.005–0.2 :g/kg) in Japan in 1979 and 1994, 2-nitro-
phenol was detected in 1 out of 129 saltwater fish
samples (detection limits 0.005–0.3 :g/kg) in 1994 (Japan
Environment Agency, 1980, 1995). 2-Nitrophenol
concentrations between <0.15 :g/litre (detection limit)
and 7.2 :g/litre and 4-nitrophenol levels between <0.1
and 18.8 :g/litre were reported for the densely populated
and highly industrialized Malaysian Klang river basin in
1990 and 1991 (Tan & Chong, 1993).
6.2 Human exposure
Workers may be exposed to 2- and 4-nitrophenol
via inhalation and skin contact during production and
processing (mainly in the manufacturing of pesticides).
However, data on nitrophenol concentrations at the
workplace were not identified.
Based on the measured concentrations given in
section 6.1, an exposure of the general population to
nitrophenols via the environment — predominantly
through ambient air and drinking-water — cannot be
excluded.
4-Nitrophenol accumulates in fog, whereas 2-
nitrophenol is rapidly photochemically transformed (see
sections 5 and 6.1). The mean measured level of 4-
nitrophenol in fog water is about 20 :g/litre.

In Dutch drinking-water samples, maximum con-
centrations of 1 :g 2-nitrophenol/litre and <0.1 :g
4-nitrophenol/litre were reported in 1988 (BUA, 1992).
Further data are not available.
7. COMPARATIVE KINETICS AND
METABOLISM IN LABORATORY ANIMALS
AND HUMANS
Studies providing quantitative information on the
absorption, metabolism, or elimination of 2- or 4-nitro-
phenol in humans were not identified.
7.1 2-Nitrophenol
There is only very limited information available for
2-nitrophenol. In rabbits given a single dose of
200–330 mg/kg body weight via gavage, most of the
applied dose (o80%) was excreted via the urine within 24
h. About 71% was conjugated with glucuronic acid and
about 11% with sulfate, whereas about 3% was reduced
to aminophenols (Robinson et al., 1951).
Skin permeation for 2-nitrophenol was shown in
several in vitro experiments (Huq et al., 1986; Jetzer et al.,
1986; Ohkura et al., 1990).
Although the information is limited, bioaccumula-
tion of 2-nitrophenol in organisms is not to be expected
owing to its rapid metabolism and excretion.
7.2 4-Nitrophenol
After oral, dermal, intravenous, or intraperitoneal
application of 4-nitrophenol to several test species (rats,
mice, dogs, or rabbits), most of the applied dose (up to
95%) was excreted as glucuronide and sulfate conjugates
of 4-nitrophenol via the urine within 24–48 h. Only small
amounts were excreted via faeces (about 1%) or as
unchanged 4-nitrophenol (about 2–7%). The
percentages of glucuronide and sulfate conjugates were
shown to be species, sex, and dose dependent.
Although sulfate conjugation dominates at lower 4-
nitrophenol concentrations, the percentage of
glucuronide conjugates increases at higher dosages
(Robinson et al., 1951; Gessner & Hamada, 1970;
Machida et al., 1982; Rush et al., 1983; Snodgrass, 1983;
Tremaine et al., 1984; Meerman et al., 1987). As shown in
rabbits after oral dosing, 4-nitrophenol undergoes
reduction to 4-aminophenol as well as glucuronidation
and sulfation. Up to 14% of the administered dose was
detected as amino compounds in the urine (Robinson et
al., 1951). After intraperitoneal administration in mice, 4-
11
Mononitrophenols
nitrophenyl glucoside was identified as a minor
metabolite of 4-nitrophenol (about 1–2% of the
administered dose) (Gessner & Hamada, 1970).
For 4-nitrophenol, the pretreatment of laboratory
animals with ethanol (induction of cytochrome P-450)
resulted in a marked increase in hepatic microsomal
hydroxylation. The 4-nitrocatechol then formed com-
peted with 4-nitrophenol for the glucuronidation and
sulfation pathways (Reinke & Moyer, 1985; Koop, 1986;
McCoy & Koop, 1988; Koop & Laethem, 1992).
Specific investigations on dermal resorption under
non-occlusive conditions showed dermal uptake of
about 35% and 11% of the applied dose of 14C-4-nitro-
phenol within 7 days in rabbits and dogs, respectively.
Skin permeation for 4-nitrophenol was also shown in
several in vitro experiments (Huq et al., 1986; Jetzer et al.,
1986; Ohkura et al., 1990).
Owing to its rapid metabolism and excretion,
bioaccumulation of 4-nitrophenol in organisms is not to
be expected.
8. EFFECTS ON LABORATORY
MAMMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure
For 2-nitrophenol, the oral LD 50 is in the range of
2830–5376 mg/kg body weight in rats (BASF AG, 1970;
Vasilenko et al., 1976; Vernot et al., 1977; Koerdel et al.,
1981) and 1300–2080 mg/kg body weight in mice
(Vasilenko et al., 1976; Vernot et al., 1977). Clinical signs
following oral exposure were unspecific and included
dyspnoea, staggering, trembling, somnolence, apathy,
and cramps. The macroscopic examination performed in
some studies revealed congestion in liver and kidneys
and ulcers of the stomach in high-dose rats. The
inhalation exposure of rats to an atmosphere saturated
with the test substance at 20 °C for 8 h (no further
information available) resulted in no mortality and no
signs of toxicity (BASF AG, 1970). In a limit test, the
dermal LD 50 for the rat was >5000 mg/kg body weight
(Koerdel et al., 1981). In cats (two animals per dose
group), the oral application of 2-nitrophenol (50, 100, or
250 mg/kg body weight; no controls) resulted in a dose-
dependent increase in methaemoglobin (6, 44, and 57%,
respectively).1 One animal dosed with 250 mg/kg body
1
Methaemoglobin formation is discussed in greater
detail in section 8.8.
Concise International Chemical Assessment Document 20
weight died. No formation of methaemoglobin was
detected after dermal application of a 50% solution of 2-
nitrophenol in water to rabbits (dose not specified,
exposure time 1 min to 20 h on the back or 20 h on the
ear) (BASF AG, 1970).
The oral LD 50 of 4-nitrophenol is in the range of
220–620 mg/kg body weight in rats (BASF AG, 1969;
Vasilenko et al., 1976; Hoechst AG, 1977a; Vernot et al.,
1977; Andrae et al., 1981) and 380–470 mg/kg body
weight in mice (Vasilenko et al., 1976; Vernot et al., 1977).
Clinical signs following oral exposure of rats were
unspecific and included tachypnoea and cramps, and the
macroscopic examination performed in some studies
revealed a greyish discoloration with dark red patches of
the lungs. No mortality was observed in rats after single
exposure (head only) to 4700 mg/m3 (application as dust
[sodium salt]; particle size not given) for 4 h. In four of
six rats, a corneal opacity was observed at the end of
exposure, which persisted through the 14-day
observation period. In two extra rats exposed to
1510 mg/m3, the methaemoglobin concentrations were
not altered compared with controls. A determination of
methaemoglobin concentrations after exposure to
4700 mg/m3 was not performed (Smith et al., 1988). In
another inhalation study with rats (exposure to an
atmosphere saturated with the test substance at 20 °C for
8 h; no further information available), no mortality and
no signs of toxicity were seen (BASF AG, 1969). The
dermal LD 50 for rats and guinea-pigs is $1000 mg/kg
body weight (Hoechst AG, 1977b; Eastman Kodak Co.,
1980; Andrae et al., 1981). In contrast to 2-nitrophenol,
no formation of methaemoglobin was noted in cats (two
animals per dose group) after oral dosing with 100, 200,
or 500 mg 4-nitrophenol/kg body weight. The mortality
rate was 0/2, 1/2, and 2/2, respectively (BASF AG, 1969).
8.2 Irritation and sensitization
From studies comparable to OECD Guidelines 404
and 405, it can be concluded that 2-nitrophenol is
slightly irritating to the skin but not to the eye (scores
not given). In a Buehler test with guinea-pigs compa-
rable to OECD Guideline 406, the substance showed no
skin-sensitizing effects (Koerdel et al., 1981).
In a study performed according to US Food and
Drug Administration (FDA) guidelines, non-dissolved 4-
nitrophenol was slightly irritating to the skin (score 2 of
8) (Hoechst AG, 1977c); in another study comparable to
OECD Guideline 404, however, the non-dissolved
substance showed no skin-irritating effects (score 0 of 4)
(Andrae et al., 1981). 4-Nitrophenol applied as a 10%
solution to the eyes was slightly irritating in a test
conducted according to FDA guidelines (scores not
12
given; Hoechst AG, 1977c). Results with the non-
dissolved substance were either strongly irritating in a
test conducted according to FDA guidelines (scores not
given; Hoechst AG, 1977c) or slightly irritating in a test
comparable to OECD Guideline 405 (score 1–2 of 4;
Andrae et al., 1981).
In a guinea-pig maximization test comparable to
OECD Guideline 406, skin sensitization was shown in 5
of 20 animals (Andrae et al., 1981).
Data on respiratory tract sensitization for 2- and 4-
nitrophenol were not identified in the literature.
8.3 Short-term exposure
8.3.1 Oral exposure
The effect of 2-nitrophenol in rats was studied in a
28-day study to evaluate OECD Guideline 407 (five
animals per sex per dose group; daily oral doses of 0, 22,
67, or 200 mg/kg body weight via gavage). Food intake
decreased in high-dose males and in mid- and high-dose
females, and final body weight decreased non-signifi-
cantly in all dosed animals. The absolute liver and kid-
ney weights were decreased in mid-dose animals, and
the relative testes weight increased in low- and mid-dose
males and decreased in high-dose males. In all dosed
animals, the relative and absolute weights of the adrenal
glands increased. The haematological examination,
clinical chemistry, and histopathological examination of
the major organs and tissues did not give any indication
of a substance-related toxic effect in comparison with
controls (Koerdel et al., 1981). Owing to insufficient
documentation and the fact that there were minor effects
(weight of adrenal glands) shown by all exposed animals,
a reliable NO(A)EL cannot be deduced.
In a 28-day study that was also conducted to eval-
uate OECD Guideline 407, Sprague-Dawley rats (10 per
sex per dose group) received daily oral doses of 0, 70,
210, or 630 mg 4-nitrophenol/kg body weight via gavage.
After dosing, locomotor inhibition, which lasted for
about 2 h, was seen in mid- and high-dose animals. In
mid-dose animals, 1/10 males died; in high-dose males
and females, the mortality rate was 4/10 and 6/10, respec-
tively (specific signs of intoxication were not given). In
the lowest dose group, the macroscopic examination
revealed seven cases of pale liver, and the histo-
pathological examination showed 14 cases of finely
dispersed fatty degeneration. A focal fatty degeneration
of the liver was also observed in 13/20 rats of the mid-
dose group, but not in high-dose animals. However, it
must be noted that finely dispersed fatty degeneration
was also seen in 6/20 control animals. In 4/10 high-dose

males but not females, a hydropic liver cell swelling was
noted, and all high-dose rats that died before the end of
the study showed vascular congestion of the liver. A
slight increase in the leukocyte count was seen at 210
and 630 mg/kg body weight in males and females; the
increase was significant in high-dose females. In high-
dose males, the alanine aminotransferase (ALAT)
activity was significantly increased. Other substance-
related effects in high-dose animals included increased
nephrosis (two males and five females), testicular
atrophy and inhibition of spermatogenesis (one and two
males, respectively), and follicular atresia in the ovaries
(four females) (Andrae et al., 1981). Because of unclear
effects in the liver, a NO(A)EL cannot be deduced.
8.3.2 Inhalation exposure
8.3.2.1 2-Nitrophenol
In Sprague-Dawley rats (15 per sex per group), no
mortality was observed after exposure to 0, 5, 30, or
60 mg 2-nitrophenol vapour/m3 (“whole body” exposure;
to generate the vapour, melted 2-nitrophenol was used)
for 6 h/day, 5 days/week, over a period of 4 weeks.
Except for squamous metaplasia of the epithelium lining
the maxilloturbinates and nasoturbinates in all high-dose
animals, the clinical and histopathological examinations
gave no consistent exposure-related effects. The met-
haemoglobin values determined after the 11th exposure
were significantly increased only in low-dose animals
(males: 1.0, 2.3, 1.8, and 1.6%; females: 2.0, 4.1, 2.1, and
1.1%), but were within control values at the end of the
study (Hazleton Lab., 1984).
8.3.2.2 4-Nitrophenol
No mortality was observed in male albino Crl:CDR
rats (10 per group) after exposure to 0, 340, or 2470 mg 4-
nitrophenol dust/m3 (application as sodium salt; “head
only” exposure; mass median aerodynamic diameter
[MMAD] 4.6–7.5 :m) for 6 h/day, 5 days/week, over a
period of 2 weeks. Both exposure concentrations
resulted in signs of irritation (not further specified). After
exposure to 340 and 2470 mg/m3, darker urine,
proteinuria, elevated aspartate aminotransferase (ASAT)
values, and a dose-dependent increase in methaemo-
globin values were observed. These effects were still
evident after a 14-day recovery period; however, the
methaemoglobin value was then still elevated in only 2/5
high-dose animals. The methaemoglobin values were 0.2,
0.87, and 1.53% after 10 exposures and 0.2, 0.13, and
0.7% after 14 days’ recovery. The erythrocyte,
haemoglobin, and haematocrit values decreased during
exposure but were elevated after the 14-day recovery
period. In treated rats, the urine volume decreased in a
dose-dependent manner during exposure and during the
14-day recovery period. In high-dose animals, the
13
Mononitrophenols
absolute spleen weight was significantly lower than that
of controls after 10 exposures, and the absolute/relative
spleen and lung weights were significantly lower in
comparison with controls at the end of the recovery
period. According to the authors, the biological signifi-
cance of the changes in organ weights is unknown
owing to the absence of corroborating pathological
effects (Smith et al., 1988).
In a second trial (exposure to 0, 30, or 130 mg/m3;
MMAD 4.0–4.8 :m), both exposure concentrations
again resulted in signs of irritation (not further speci-
fied). Methaemoglobinaemia, an effect that was rever-
sible within a 14-day recovery period, was seen only at
130 mg/m3. The methaemoglobin values were 0.5, 0.3, and
1.5% after 10 exposures and 0.4, 0.5, and 0.2% after 14
days’ recovery. The gross and histopathological
examination revealed no adverse effects in any dose
group. From these results, the authors of the study
decided upon a NO(A)EL of 30 mg/m3 (Smith et al., 1988).
Groups of Sprague-Dawley rats (15 per sex) were
exposed to 0, 1, 5, or 30 mg 4-nitrophenol dust/m3
(“whole body” exposure; MMAD 5.2–6.7 :m) for
6 h/day, 5 days/week, over a period of 4 weeks. The
exposure resulted in no deaths, and no exposure-related
effects were noted in terms of haematology or clinical
chemistry values, gross examination, histopathology,
and body or organ weights. In high-dose animals,
unilateral and bilateral diffuse anterior capsular cataracts
were observed. The methaemoglobin values determined
after 2 weeks of exposure showed great variability and
appeared to be unusually high (>3 %) in some unex-
posed controls. However, the group total methaemo-
globin value was increased at a concentration of
5 mg/m3, which was significant in males and not
significant in females (males: 0.8, 0.5, 2.2, and 1.1%;
females: 1.3, 1.1, 2.0, and 1.0%) (Hazleton Lab., 1983).
Therefore, a NO(A)EL of 5 mg/m3 can be derived for local
effects (cataracts), whereas the NO(A)EL for systemic
effects (formation of methaemoglobin) may be lower.
8.3.3 Dermal exposure
Data concerning short-term dermal exposure were
not identified in the literature.
8.4 Long-term exposure
In the literature, subchronic and chronic studies
are available only for 4-nitrophenol.
8.4.1 Subchronic exposure
In a 13-week gavage study with Sprague-Dawley
rats (20 per sex per dose group) given 0, 25, 70, or 140 mg
4-nitrophenol/kg body weight in water 5 days/week,
Concise International Chemical Assessment Document 20
premature deaths were seen in animals dosed with
70 and 140 mg/kg body weight (1 male/1 female at
70 mg/kg body weight and 15 males/6 females at
140 mg/kg body weight); these were usually preceded by
clinical signs, including pale appearance, languid behav-
iour, prostration, wheezing, and dyspnoea, shortly after
dosing. The histopathological examination of these
animals revealed minimal to moderately severe conges-
tion in the lung, liver, kidney, adrenal cortex, and pitui-
tary; in surviving animals, no treatment-related changes
compared with controls were reported. A statement
concerning altered methaemoglobin values cannot be
given owing to a non-reliable analytical method (about
13% in controls at week 7) (Hazleton Lab., 1989).
Therefore, only a provisional NO(A)EL (changes in liver,
kidneys, and lungs) of 25 mg/kg body weight can be
derived from this study. The NO(A)EL based on the
formation of methaemoglobin may be lower.
The dermal application of 4-nitrophenol to Swiss-
Webster mice (10 per sex and dose group; given 0, 22,
44, 88, 175, or 350 mg/kg body weight in acetone, 3 times
per week over 13 weeks) resulted in dose-dependent
mortality as well as skin irritation/inflammation and
necrosis at $175 mg/kg body weight.1
8.4.2 Chronic exposure and carcinogenicity
In a long-term study with Swiss-Webster mice (50
per sex per dose group), 4-nitrophenol in acetone was
applied to the interscapular skin at doses of 0, 40, 80, or
160 mg/kg body weight, 3 days/week for 78 weeks. At
termination of the study, the survival rates were 29/60,
17/60, 26/60, and 24/60 for males and 35/60, 26/60, 33/60,
and 27/60 for females. The increased mortality after 60
weeks was due to a generalized amyloidosis (the severity
of the amyloidosis was similar among dosed and control
animals) and secondary kidney failure. The final mean
body weights of the dosed animals were similar to those
of the controls. NTP (1993) stated that there were no
substance-related neoplastic or non-neoplastic effects
associated with the dermal administration of 4-nitro-
phenol and that there was no evidence of a carcinogenic
activity of the substance in male or female mice.
In another study, which had several procedural
deficiencies (only the skin was examined; only 12 weeks
of exposure), no skin tumours were observed in
31 female Sutter mice after dermal application of a 20%
solution (25 :l of solution applied twice weekly) of 2- or
4-nitrophenol in dioxane (Boutwell & Bosch, 1959).
1
Gulf South Research Institute, not dated; no further
information available; results cited from NTP (1993).
14
8.5 Genotoxicity and related end-points
The available in vitro and in vivo genotoxicity
studies on 2- and 4-nitrophenol are summarized in
Table 3.
2-Nitrophenol showed no mutagenicity in several
limited bacterial assays. From the available data, it is not
possible to draw any conclusions regarding its mutagen-
icity.
For 4-nitrophenol, positive results were obtained in
in vitro tests for chromosomal aberrations in mammalian
cells. However, apart from one well-documented study
published by NTP (1993), the other available assays
were inadequately reported. 4-Nitrophenol was shown to
be mutagenic in some but not all of the bacterial assays,
whereas other studies (i.e., host-mediated bacterial
assay, mouse lymphoma assay, unscheduled DNA
synthesis assay [apparently in vitro ], sister chromatid
exchange assay, sex-linked recessive lethal [SLRL] assay
in Drosophila) gave negative results. In the absence of
any in vivo mutagenicity studies in mammals, it is not
possible to conclude whether or not the mutagenic
potential of 4-nitrophenol is expressed in vivo.
8.6 Reproductive and developmental
toxicity
8.6.1 Reproductive toxicity
In a valid two-generation study with groups of
24 female and 12 male Sprague-Dawley rats carried out
by Angerhofer (1985), 4-nitrophenol dissolved in ethanol
was applied dermally at doses of 0, 50, 100, or 250 mg/kg
body weight per day, 5 days/week. The F0 generation
was exposed over a period of 140 days before mating.
Dosing of the F0 females continued throughout
breeding, gestation, and lactation. Groups of 26 females
and 13 males of the F1 generation were then exposed for
168 days in the same manner as had been the F0 rats; the
females were again exposed throughout breeding, gesta-
tion, and lactation. Apart from dose-related signs of skin
irritation (erythema, scaling, scabbing, and cracking) in
dosed animals, the gross and histopathological examina-
tions provided no indication of significant adverse
effects. The calculated indices concerning fertility, gesta-
tion, viability, and lactation were not different from those
of controls. The testis to body weight ratios in the F0
generation were not affected, and histological lesions
were not observed in the testes. In a 28-day study in rats
(see section 8.3.1), testicular atrophy and inhibition of
spermatogenesis were observed in some animals after
oral dosing at a level of 630 mg/kg body weight, but not
at 210 mg/kg body weight.
 Table 3: Genotoxicity of 2- and 4-nitrophenol in vitro and in vivo.

Results a
Without With
metabolic metabolic
Species (test system) End-point Concentration range activation activation Remarks Reference
2-Nitrophenol (in vitro studies)
8 phage DNA Induction of DNA breakage 35 mg ! 0 Yamada et al. (1987)
Bacillus subtilis H17, Recombination assay 0.01–0.5 mg/plate ! 0 Shimizu & Yano (1986)
M45
Salmonella Reverse mutations 0.003–2.5 mg/plate ! ! Koerdel et al. (1981); Haworth et al.
typhimurium (1983); Shimizu & Yano (1986)
TA1535, TA1537
Salmonella Reverse mutations 0.01–2.5 mg/plate ! ! Koerdel et al. (1981); Shimizu &
typhimurium Yano (1986)
TA1538
Salmonella Reverse mutations 0.0007–5 mg/plate ! ! Suzuki et al. (1983) also tested both Chiu et al. (1978); Koerdel et al.
typhimurium strains in the presence of norharman, (1981); Haworth et al. (1983); Suzuki
TA98, TA100 which also gave negative results et al. (1983); Shimizu & Yano
(1986); Kawai et al. (1987); Dellarco
& Prival (1989); Massey et al. (1994)
2-Nitrophenol (in vivo studies)
Drosophila SLRL assay via feed (400 and 500 ! Foureman et al. (1994)
melanogaster ppm) or injection
(2500 and 5000 ppm)
4-Nitrophenol (in vitro studies)
8 phage DNA Induction of DNA breakage 35 mg ! 0 Yamada et al. (1987)
Bacillus subtilis H17, Recombination assay 0.01–5 mg/plate + 0 positive at 0.5 mg/plate Shimizu & Yano (1986)
M45
Escherichia coli Gene mutation 0.001–2.5 mg/plate ! ! Hoechst AG (1980)
WP2uvrA
Escherichia coli K-12 Gene mutation 0.125–2 mg/plate ! 0 Rashid & Mumma (1986)
(Pol A1+/Pol1!), WP2
(WP2, WP2uvrA,
WP67, CM611,
CM571)
Escherichia coli Q13 DNA cell binding assay 7 or 70 mg + + positive at 70 mg Kubinski et al. (1981)
Saccharomyces Mitotic gene conversion 2.9 mg/ml (+) 0 Fahrig (1974)
cerevisiae
ade 2, trp 5
Salmonella DNA damage (umu test) up to 0.75 mg/ml ! ! Nakamura et al. (1987)
typhimurium
TA1535/pSK 1002
Table 3 (Contd).
Results a
Without With
metabolic metabolic
Species (test system) End-point Concentration range activation activation Remarks Reference
Salmonella Reverse mutation 0.001–2.5 mg/plate + ! positive at $0.1 mg/plate Hoechst AG (1980)
typhimurium
TA1538
Salmonella Reverse mutation 0.01–5 mg/plate ! ! Andrae et al. (1981); Shimizu &
typhimurium Yano (1986)
TA1538
Salmonella Reverse mutation 0.125–2 mg/plate ! 0 Rashid & Mumma (1986)
typhimurium
TA1538, TA1978
Salmonella Reverse mutation 0.0007– 5 mg/plate ! ! Suzuki et al. (1983) also tested both McCann et al. (1975); Hoechst AG
typhimurium strains in the presence of norharman, (1980); Andrae et al. (1981); Haworth
TA98, TA100 which also gave negative results et al. (1983); Suzuki et al. (1983);
Shimizu & Yano (1986); Kawai et al.
(1987); Dellarco & Prival (1989);
Massey et al. (1994)
Salmonella Reverse mutation 0.001–5 mg/plate ! ! McCann et al. (1975); Hoechst AG
typhimurium (1980); Andrae et al. (1981); Haworth
TA1535, TA1537 et al. (1983); Shimizu & Yano (1986)
Rat hepatocytes DNA damage (alkaline 42–417 mg (+) 0 Weakly positive at $97 mg Storer et al. (1996)
elution)
Rat hepatocytes DNA repair 4.2–417 mg ! 0 Andrae et al. (1981)
Chinese hamster ovary Chromosomal aberration without S9 mix: ! + NTP (1993)
(CHO) cells 0.1–0.5 mg/ml
with S9 mix:
1.25–2 mg/ml
Chinese hamster ovary Sister chromatid exchange without S9 mix: ! ! NTP (1993)
(CHO) cells 0.00017–0.025
mg/ml
with S9 mix:
0.05–1.5 mg/ml
Mouse lymphoma Forward mutation without S9 mix: ! ! Oberly et al. (1984)
assay L5178Y TK+/– 0.7–1.5 mg/ml
cells with S9 mix:
0.0001–0.03 mg/ml
Mouse lymphoma Forward mutation 0.06–0.78 mg/ml 0 ! Amacher & Turner (1982)
assay L5178Y TK+/–
cells
Rat hepatocytes Unscheduled DNA 0.00007–0.14 mg/ml ! 0 Probst et al. (1981)
synthesis
Human lymphocytes Chromosomal aberration not given + No data about metabolic activation; Huang et al. (1996)
validity cannot be judged
(documentation and study design
insufficient for assessment)
lowest positive concentration: 1.4 mg/ml
 Table 3 (Contd).
Results a
Without With
metabolic metabolic
Species (test system) End-point Concentration range activation activation Remarks Reference
Human lymphocytes Chromosomal aberration 0.001–0.3 mg/ml + No data about metabolic activation; Huang et al. (1995)
validity cannot be judged
(documentation and study design
insufficient for assessment)
Human fibroblasts (WI- DNA repair 0.14–139 mg + No data about metabolic activation; Poirier et al. (1975)
38) validity cannot be judged
(documentation insufficient for
assessment)
positive at $13.9 mg
4-Nitrophenol (in vivo studies)
NMRI mice Host-mediated assay (tester single subcutaneous ! application of test substance Buselmaier et al. (1972)
strains Salmonella injection of 75 mg/kg immediately after the bacteria had been
typhimurium G 46 and body weight injected into the abdominal cavities; test
Serratia marcescens a 21 duration 3 h
Leu –)
Drosophila SLRL assay via feed (1000, 2500, ! Zimmering et al. (1985); Foureman
melanogaster 6000, or 7500 ppm) et al. (1994)
or injection (1000 or
1500 ppm)
a !, negative; +, positive; (+), weakly positive; 0, not tested.
Concise International Chemical Assessment Document 20
8.6.2 Developmental toxicity
8.6.2.1 2-Nitrophenol
In a range-finding study with Charles River COBS©
©
CD rats (five dams per group; application of 0, 50, 125,
250, 500, or 1000 mg/kg body weight via gavage from day
6 to day 15 of gestation; uterine examination on day 20),
dose levels of 500 and 1000 mg/kg body weight caused
signs of maternal toxicity (transient but dose-related
decrease in weight gain early during treatment). One
high-dose animal died, but no cause of death could be
determined. Other clinical findings included darkly
coloured urine at $250 mg/kg body weight and yellow
staining of haircoat (at the nose, mouth, anogenital area)
at $125 mg/kg body weight; the necropsy findings gave
no biologically meaningful differences in surviving
dams. At the highest dose level of 1000 mg/kg body
weight, a slight but statistically significant (also com-
pared with historical controls) increase in group mean
post-implantation losses (13.8% versus 8.2% in controls)
and mean early resorptions (2.3 versus 1.2 in controls)
was seen. No effects were observed on the number of
viable fetuses, implantations, or corpora lutea
(International Research and Developmental Corporation,
1983).
8.6.2.2 4-Nitrophenol
In both studies cited below, a complete examina-
tion of the pups for possible teratogenic effects was not
performed. In addition, owing to limitations of these
studies (i.e., use of only one dose group or exposure to a
mixture), reliable NO(A)EL values cannot be derived.
In a study performed by Booth et al. (1983), groups
of 50 female CD-1 mice received daily oral doses of
400 mg 4-nitrophenol/kg body weight via gavage from
day 7 to day 14 of gestation. The survival rate in
pregnant mice (n = 36) was 81% versus 100% in controls,
and dosed animals showed less maternal weight gain. No
changes were observed in the reproductive index (ratio
between survivors delivered and pregnant survivors).
The average number of live pups per litter was slightly
decreased, but 4-nitrophenol produced no gross
abnormalities.
Kavlock (1990) studied the developmental toxicity
of 4-nitrophenol in Sprague-Dawley rats. The substance
(dissolved in a mixture of water, Tween 20, propylene
glycol, and ethanol [4:4:1:1]) was applied via gavage to
groups of 12–13 animals at doses of 0, 100, 333, 667, or
1000 mg/kg body weight on day 11 of gestation. End-
points concerning maternal toxicity included signs of
toxicity, mortality, body weight gain, and the number of
implantation scars in the uteri at weaning. In the off-
spring, viability, body weight on postnatal days 1–6,
18
overt malformations, and perinatal loss were recorded. In
dams, the mortality was increased at a dose level of
$667 mg/kg body weight; at a dose level of $333 mg/kg
body weight, the litter size on postnatal days 1 and 6
was non-significantly decreased.
8.7 Immunological and neurological
effects
There are no studies available dealing specifically
with immunological or neurological effects. There is an
indication from an in vitro study that 4-nitrophenol may
act as a suppressor of cell-mediated immune response
(Pruett & Chambers, 1988). However, the biological
significance is uncertain.
8.8 Methaemoglobin formation
Methaemoglobin formation by 2-nitrophenol and
4-nitrophenol has been tested in several studies using
different species, routes, and durations of applications.
An overview is given in Table 4.
2-Nitrophenol clearly leads to the formation of
methaemoglobin in a dose-dependent manner in cats
(BASF AG, 1970), the most sensitive species. The lowest
dose tested, 50 mg/kg body weight, produced increased
methaemoglobin levels. In inhalation experiments in rats,
elevated methaemoglobin levels were observed at an
exposure level of 5 mg/m3; methaemoglobin levels were
less elevated at exposure levels of 30 and 60 mg/m3
(Hazelton Lab., 1984).
4-Nitrophenol, in contrast, did not lead to methae-
moglobin formation in cats at concentrations up to
500 mg/kg body weight (BASF AG, 1969). In rats, at high
concentrations in inhalation experiments, the met-
haemoglobin-forming capacity seemed to be very low
(1.5% at 2470 mg/m3). In conclusion, 4-nitrophenol may
induce methaemoglobin formation, but the effect seems
to be rather weak, without clear dose–response.
9. EFFECTS ON HUMANS
Naniwa (1979) performed patch tests with 4-
nitrophenol, 4-aminophenol, 2-amino-4-chlorophenol, 3'-
chlorodiphenylamine-2-carboxylic acid, and 4-dichloro-
nitrobenzene (0.1, 0.5, or 1% in petrolatum) on
31 employees probably exposed to these chemicals in a
chemical factory and on 5 control persons. In four
employees, a positive reaction to 4-nitrophenol was
observed, although none of these persons reacted
positively to all three tested concentrations. All four
 Mononitrophenols

Table 4: Methaemoglobin formation by 2-nitrophenol and 4-nitrophenol.

Species
(strain/number/ Frequency/ Results
dose/sex) Route duration Dose (% metHb) Reference
2-Nitrophenol

cat oral 1x 50 mg/kg body weight 6 BASF AG (1970)

2 100 44
sex not given 250 57

rabbit dermal 1x 50% solution no increase BASF AG (1970)

number and sex in water
not given

rat inhalation 6 h/day m f Hazleton Lab.

Sprague-Dawley 5 days/week 0 mg/m 3 1.0 2.0 (1984)
15 m/15 f 4 weeks 5 2.3 4.1
30 1.8 2.1
60 1.6 1.1
11th day of treatment

4-Nitrophenol
cat oral 1x 100 mg/kg body weight no increase BASF AG (1969)
2 200
sex not given 500

rat oral 5 days/week 0 mg/kg body weight analytical method not Hazleton Lab.
Sprague-Dawley 13 weeks 25 reliable (13% in controls) (1989)
20 m/20 f 70
140

rat inhalation 6 h/day 0 mg/m 3 0.2 0.2 Smith et al. (1988)

Crl:CDR 5 days/week 340 0.87 0.13
10 m 2 weeks 2470 1.53 0.7
end of treatment and
after 14 days of recovery

rat inhalation 6 h/day 0 mg/m 3 0.5 0.4 Smith et al. (1988)

Crl:CDR 5 days/week 30 0.3 0.5
10 m 2 weeks 130 1.5 0.2
end of treatment and
after 14 days of recovery

rat inhalation 6 h/day m f Hazleton Lab.

Sprague-Dawley 5 days/week 0 mg/m 3 0.8 1.3 (1983)
15 m/15 f 4 weeks 1 0.5 1.1
5 2.2 2.0
30 1.1 1.0
after 2 weeks of exposure,
values unusually high in
some control animals

Abbreviations used: m = male; f = female; metHb = methaemoglobin.

employees also reacted positively to 2-amino-4-chloro- 10. EFFECTS ON OTHER ORGANISMS IN

phenol, which was shown to be a strong sensitizer. THE LABORATORY AND FIELD
Therefore, 2-amino-4-chlorophenol may act as the
primary allergen, and the effects observed with 4-nitro-
phenol may be due to cross-sensitization. 10.1 Aquatic environment

In 27 patients primarily sensitized to 1-chloro-2,4-
dinitrobenzene, no cross-sensitization due to 4-nitro-
phenol (1–2% in petrolatum) was observed. In addition,
15 patients with a chloramphenicol allergy failed to react
to 4-nitrophenol (Eriksen, 1978).
Experimental test results for the most sensitive
species are summarized in Table 5. Additional data on
the toxicity of 2- and 4-nitrophenol to aquatic organisms

19
Concise International Chemical Assessment Document 20

Table 5: Aquatic toxicity of nitrophenols.

Most sensitive species Effective concentration

(test method/end-point) Substance (mg/litre) Reference

Bacteria

Pseudomonas putida 2-NP 16-h MICa: 0.9 Bringmann & Kuehn (1977)
(cell multiplication inhibition test) 4-NP 16-h MIC: 4.0

Protozoa
Entosiphon sulcatum 2-NP 72-h MIC: 0.40 Bringmann (1978); Bringmann et
(cell multiplication inhibition test) 4-NP 72-h MIC: 0.83 al. (1980)

Algae

Scenedesmus subspicatus 2-NP 96-h EC50: 0.39 Broecker et al. (1984); Kramer et
Chlorella vulgaris 2-NP 6-h EC50: 1.53 al. (1986)
(cell multiplication inhibition test) 4-NP 6-h EC50: 6.97

Invertebrates
Moina macrocopa (acute) 2-NP 3-h LC50: 1.9 Yoshioka et al. (1985)
(immobilization) 4-NP 3-h LC50: 1.3
Daphnia magna (long-term) 2-NP 21-day LOEC: 1.0 Koerdel et al. (1984)
(immobilization/reproduction) 4-NP 21-day NOEC: 1.3
Barentsia matsushimana (marine) 4-NP 49-day EC50: 0.21 Kuehn et al. (1988)
(growth of germinated spores) 4-NP 49-day ECmb: 0.03 Scholz (1986)

Fish

Cyprinus carpio (static) 2-NP 96-h LC50: 36.6 Lang et al. (1996)
Oncorhynchus mykiss (static) 4-NP 96-h LC50: 3.8 Howe et al. (1994)
Oncorhynchus mykiss (flow-through) 4-NP 96-h LC50: 7.93

Abbreviations used: 2-NP = 2-nitrophenol; 4-NP = 4-nitrophenol.

a MIC = minimum inhibitory concentration.

b EC = minimal effective concentration.

m

are cited in BUA (1992). Among all tested organisms, the
protozoan Entosiphon sulcatum and the green alga
Scenedesmus subspicatus proved to be most sensitive in
chronic cell multiplication inhibition tests with fresh-
water species. Daphnia magna exhibited a 21-day
lowest-observed-effect concentration (LOEC) of 1.0 mg
2-nitrophenol/litre in the Daphnia reproduction test
(Koerdel et al., 1984). The entoproct Barentsia
matsushimana was the most sensitive marine inverte-
brate species tested, exhibiting a 49-day EC50 value of
0.21 mg 4-nitrophenol/litre and a minimal effective
concentration (ECm ) of 0.03 mg/litre (end-point: growth
of germinated spores) (Scholz, 1986). Freshwater fish
showed less sensitivity. The lowest 96-h LC50 value of
3.8 mg 4-nitrophenol/litre was determined for rainbow
trout (Oncorhynchus mykiss) (Howe et al., 1994). The
measured no-observed-effect concentration (NOEC) for
behavioural changes in a 28-day flow-through test with
zebra fish was 2 mg 2-nitrophenol/litre (Broecker et al.,
1984). After prolonged exposure of zebra fish to 4-
nitrophenol, minor morphological alterations of the liver,
even at a concentration of 0.1 mg/litre, were observed.
At 1 and 5 mg/litre, about 25% of the animals showed
symptoms of degenerative transformation of the liver
tissue (Braunbeck et al., 1989).
10.2 Terrestrial environment
The toxicity of 2- and 4-nitrophenol on higher
plants according to OECD Guideline 208 was tested in
independent studies. After incubation of seeds with
different test substance concentrations, 14-day EC50
values for reduced fresh weight of grown shoots were in
the range of 52–420 mg 2-nitrophenol/kg soil (Broecker et
al., 1984; Koerdel et al., 1984) and 35–260 mg 4-
nitrophenol/kg soil (Ballhorn et al., 1984; Marquart et al.,
1984). The 14-day EC10 value for 2-nitrophenol was 10
mg/kg soil for both species. Overall, turnip (Brassica
rapa) proved to be more sensitive than oat (Avena
sativa).
In tests conducted according to OECD Guideline
207, the adverse effects of 2- and 4-nitrophenol on
earthworms were examined in several independent
studies. In the contact test, in which the animals are
exposed on filter paper soaked with the test substance,
Neuhauser et al. (1985) established a 48-h LC50 value of
5.9 :g/cm² for the toxicity of 2-nitrophenol on Eisenia
fetida. For 4-nitrophenol, the 48-h LC50 values were in
the range of 0.7–2.7 :g/cm², with Eisenia fetida and
Eudrilus eugeniae being the most sensitive species
tested (Roberts & Dorough, 1984; Neuhauser et al., 1985,
1986). When exposed in an artificial soil mixture, 28-day
LC50 values for 2-nitrophenol were in the range of
250–500 mg/kg soil (Eisenia fetida) (Broecker et al., 1984;

20

Koerdel et al., 1984), and 14-day LC50 values for 4-
nitrophenol were in the range of 38–67 mg/kg soil, again
with Eisenia fetida and Eudrilus eugeniae as the most
sensitive species tested (Ballhorn et al., 1984; Marquart
et al., 1984; Neuhauser et al., 1985, 1986).
The environmental relevance, particularly of the
earthworm contact test, seems questionable. Critical
results from this test, as sole effect data on terrestrial
organisms, should not justify a classification of tested
substances as highly toxic to earthworms or other soil
organisms. The available data on microorganisms and
plants indicate only a moderate toxicity potential in the
terrestrial environment.
11. EFFECTS EVALUATION
11.1 Evaluation of health effects
11.1.1 Hazard identification and dose–response
assessment
In general, there is only limited information con-
cerning the toxicological profiles of 2- and 4-nitrophenol.
In experimental animals given 4-nitrophenol orally,
intravenously, or intraperitoneally, most of the applied
dose was excreted via the urine within 24–48 h as glucur-
onide and sulfate conjugates, while only very small
amounts were excreted via faeces or as unchanged 4-
nitrophenol. In rabbits, after oral dosing, 4-nitrophenol
undergoes reduction to 4-aminophenol as well as
glucuronidation and sulfation. In vivo and in vitro
studies gave an indication for dermal uptake. For 2-
nitrophenol, the information is very limited. However, a
comparable metabolic transformation is assumed based
on the available data. Owing to their rapid metabolism
and excretion, bioaccumulation of 2- and 4-nitrophenol in
organisms is not to be expected.
With oral LD 50 values of 220–620 mg/kg body
weight in rats and 380–470 mg/kg body weight in mice, 4-
nitrophenol is harmful after oral uptake and was found to
be more toxic than 2-nitrophenol. A dose-dependent
increase in the formation of methaemoglobin was seen in
cats after oral exposure to 2-nitrophenol — but not after
exposure to 4-nitrophenol — and in rats after exposure
by inhalation to 4-nitrophenol.
Most of the studies concerning skin- or eye-
irritating effects in experimental animals are limited as a
result of insufficient documentation. However, from the
available data, it can be concluded that 2-nitrophenol is
slightly irritating to the skin but non-irritating to the eye,
and the substance proved to have no sensitizing effects.
21
Mononitrophenols
For 4-nitrophenol, irritating effects on skin and eye are
assumed based on the studies performed according to
OECD/FDA guidelines; in addition, signs of irritation
were reported after exposure by inhalation as well as
subchronic dermal exposure. In a guinea-pig maximiza-
tion test, 4-nitrophenol was considered to be sensitizing.
Positive patch tests were recorded in humans exposed to
4-nitrophenol. Although this may have been due to
cross-sensitization, sensitization to 4-nitrophenol in
humans cannot be excluded.
Only a few limited studies concerning repeated oral
exposure to 2- and 4-nitrophenol in experimental animals
were identified. With 2-nitrophenol, decreases in body
weight gain accompanied by decreased food con-
sumption and differences in organ weights without clear
dose dependency were found. However, the haema-
tological examination, clinical chemistry, and
histopathological examination of the major organs and
tissues gave no indication for a substance-related toxic
effect compared with controls. In rats dosed with 4-
nitrophenol, a focal fatty degeneration of the liver as well
as congestion in several organs were the major
histopathological findings. Other reported effects
included haematological changes, nephrosis, testicular
atrophy, and follicular atresia in the ovaries. The
exposure by inhalation to 2-nitrophenol vapour caused
squamous metaplasia of the epithelium of the upper
respiratory tract; with 4-nitrophenol dust (applied as
sodium salt), haematological changes, increased met-
haemoglobin values, and differences in organ weights
were noted. For the effects given in these studies, it was
not possible to identify a clear dose–response or reliable
NO(A)EL values.
Insufficient data are available on 2-nitrophenol to
allow any conclusions to be made about its possible
mutagenicity. For 4-nitrophenol, more mutagenicity
studies are available, and the substance was shown to
be mutagenic in some but not all of the bacterial assays.
In addition, positive results were obtained in in vitro
tests for chromosomal aberrations in mammalian cells;
however, apart from one well-documented study, the
available assays were inadequately reported. In the
absence of any in vivo mutagenicity studies in mammals,
it is not possible to conclude whether or not the muta-
genic potential of 4-nitrophenol is expressed in vivo.
4-Nitrophenol was not carcinogenic in male or
female mice after dermal application over 78 weeks. In a
limited study with female mice, no skin tumours were
seen after dermal application of 2- or 4-nitrophenol over
12 weeks. No carcinogenicity studies using the oral or
inhalation routes were available for either of the isomers.
No reproductive effects were observed in rats
exposed to 4-nitrophenol in a two-generation study. For
developmental toxicity, the available studies were inade-
Concise International Chemical Assessment Document 20
quately performed (i.e., only one dose was applied, or
animals were dosed only on one day with a mixture). In
an oral study with rats, 2-nitrophenol induced develop-
mental effects in the offspring only at doses that also
produced maternal toxicity. However, the fetuses were
not examined for internal malformations.
Data on humans relevant for the assessment of
potential adverse effects are limited to some patch tests
performed with 4-nitrophenol.
11.1.2 Criteria for setting guidance values for
2- and 4-nitrophenol
As given in section 8, the database for 2-nitrophe-
nol is inadequate for calculating a tolerable daily intake
(TDI) or a tolerable concentration (TC).
For 4-nitrophenol, the formation of methaemo-
globin was shown to be the most critical end-point after
exposure by inhalation and is assumed to be relevant for
oral exposure too. However, owing to the inaccuracy of
the analytical method used in the 13-week study with
oral application, a reliable NO(A)EL cannot be derived.
Therefore, at present, no TDI for 4-nitrophenol can be
developed owing to inadequacy of the database.
Longer-term toxicity studies concerning inhalation
exposure were not identified in the literature, and the
NO(A)EL values derived for 4-nitrophenol from short-
term studies gave considerable differences (2-week
exposure: NO(A)EL of about 30 mg/m3; 4-week exposure:
NO(A)EL of about 5 mg/m3). The NO(A)EL of 5 mg/m3
was derived for local effects (cataracts), whereas the
NO(A)EL for systemic effects (formation of
methaemoglobin) may be lower. Therefore, a reliable TC
for exposure by inhalation cannot be calculated, as the
formation of methaemoglobin is the critical end-point.
11.1.3 Sample risk characterization
As given in section 6.2, workers may be exposed to
2- and 4-nitrophenol via inhalation and skin contact
during production and processing (mainly in the manu-
facturing of pesticides). However, data on nitrophenol
concentrations at the workplace were not identified.
For the general population, an exposure to nitro-
phenols via the environment cannot be excluded (see
also section 6.2). Assuming an ambient atmospheric
concentration of about 1 :g/m3, an inhalation uptake of
100%, a daily respiratory volume of 22 m3 for adults, a
mean body weight of 64 kg for males and females, and
that 4 of 24 h are spent outdoors (IPCS, 1994), the uptake
by inhalation of nitrophenols is calculated to be 0.06
:g/kg body weight per day. In addition, 4-nitrophenol
22
accumulates in fog. From the mean measured level of 20
:g/litre, the uptake of the substance by inhalation
(using the same assumptions as above) can be
calculated to be about 8 ng during a 1-h exposure period
(i.e., 0.12 ng/kg body weight), assuming a maximum water
content of fog of 0.1 g/m3 (Pruppacher & Klett, 1978).
The uptake via drinking-water for 2- and 4-nitrophenol
can be calculated to be about 0.02 :g/kg body weight
per day, assuming a maximum concentration of 1 :g/litre
drinking-water, a daily drinking-water consumption of 1.4
litres, and a mean body weight of 64 kg for males and
females.
From these data, it can be concluded that exposure
of the general population to the nitrophenol isomers is
mainly through ambient air and drinking-water.
11.2 Evaluation of environmental effects
Releases of 2- and 4-nitrophenol into the environ-
ment are primarily emissions into air, water, and soil from
diffuse sources, such as vehicle traffic and hydrolytic
and photolytic degradation of the respective pesticides.
2-Nitrophenol emitted to the troposphere will stay
predominantly in the gaseous phase and should be
rapidly removed by nitration. The major portion of
airborne 4-nitrophenol is expected to be particle bound
and can be washed out to surface waters and soil by wet
and dry deposition. Because of their removal from air
and their insignificant volatility, nitrophenols are not
considered to contribute directly to the depletion of the
stratospheric ozone layer or to global warming. Mea-
sured bioconcentration factors indicate a low potential
for bioaccumulation.
Nitrophenols exhibit moderate to high toxicity to
aquatic organisms, with lowest effect concentrations
reported from chronic studies on algae, Daphnia, and
aquatic invertebrates. The lowest effect concentrations
found in chronic studies with freshwater organisms
(Scenedesmus subspicatus, 96-h EC50: 0.39 mg 2-nitro-
phenol/litre; Entosiphon sulcatum, 72-h MIC: 0.83 mg 4-
nitrophenol/litre) were 40–50 times higher than maximum
levels determined in a densely populated and highly
industrialized Asian river basin (0.0072 mg
2-nitrophenol/litre and 0.019 mg 4-nitrophenol/litre).
From these data, the safety margin between the LOEC
and maximum surface water concentrations is insufficient
to exclude any risk for sensitive aquatic organisms,
particularly under surface water conditions not favour-
ing both elimination pathways. Taking into account the
missing chronic effect data for fish, an uncertainty/
assessment factor of 100 has to be applied to derive a
predicted no-effect concentration (PNEC) according to
standard procedures for environmental risk assessment.
 Mononitrophenols

From acute tests (see section 10.1), however, fish 12. PREVIOUS EVALUATIONS BY
obviously seem to be the least sensitive aquatic species INTERNATIONAL BODIES
tested. Thus, an assessment factor of 10 might be
appropriate. Furthermore, the use pattern and the release
scenario outlined in section 4 lead to the conclusion that Previous evaluations of mononitrophenols by
nitrophenols emitted to surface waters will pose only a international bodies were not identified.
minor risk to aquatic organisms.
Information on international hazard classification
There were no data available on the occurrence of and labelling for mononitrophenols is included in the
nitrophenols in the terrestrial compartment. Therefore, an International Chemical Safety Card reproduced in this
assessment of possible effects on organisms for this document.
compartment could be conducted only with regard to the
degradation of pesticides. For the insecticides
mentioned in section 4 (parathion, parathion-methyl,
carbofuran, phosalon, fluorodifen) and the herbicides 13. HUMAN HEALTH PROTECTION AND
bifenox and nitrofen, predicted soil concentrations were
EMERGENCY ACTION
calculated from the maximum application rates (taken
from Domsch, 1992) according to the EPPO (1993) guide-
lines for environmental risk assessment of plant protec-
Human health hazards, together with preventative
tion products. Based on the relative molecular mass of
and protective measures and first aid recommendations,
the pesticides, the maximum concentration of nitrophe-
are presented on the enclosed International Chemical
nols in the top 5 cm of soil was calculated (worst case;
Safety Card (ICSC 1342) reproduced in this document.
one application). For pesticides that are applied at times
when the soil is plant covered to a high degree, it is
assumed that only half of the amount applied reaches
the soil. Thus, the predicted environmental
14. CURRENT REGULATIONS,
concentration (PEC) for the insecticides was reduced by
50%. Dividing the PECsoil by the lowest LC50 value for a GUIDELINES, AND STANDARDS
terrestrial species gives the toxicity exposure ratio (TER).
The lowest LC50 value for earthworms (38 mg/kg body
weight; see section 10.2) has to be corrected by a factor Information on national regulations, guidelines,
of 2 because of the higher organic matter content in and standards is available from the International Register
artificial soil compared with natural agricultural soil. The of Potentially Toxic Chemicals (IRPTC) legal file.
following TERs were derived:
The reader should be aware that regulatory deci-
Insecticides Herbicides sions about chemicals taken in a certain country can be
Parathion: 244 Bifenox: 131 fully understood only in the framework of the legislation
Parathion-methyl: 557 Nitrofen: 18 of that country. The regulations and guidelines of all
Carbofuran: 47 countries are subject to change and should always be
Phosalon: 36 verified with appropriate regulatory authorities before
Fluorodifen: 69 application.

According to the EPPO (1993) guidelines, the trig-

ger value for concern is <10. Therefore, these pesticides
are expected to pose only a minor risk to earthworms,
even under a worst-case scenario. Furthermore, the
herbicide nitrofen and the insecticides phosalon and
fluorodifen are no longer manufactured or marketed for
crop protection use.

23
MONONITROPHENOLS 1342
November 1998
CAS No: 25154-55-6 Nitrophenols (mixed isomers)
RTECS No: Nitrophenols
UN No: 1663 C6H5O3N
Molecular mass: 139.1

TYPES OF
HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING
EXPOSURE

FIRE Combustible. Gives off irritating or NO open flames. Powder, water spray, foam, carbon
toxic fumes (or gases) in a fire. dioxide.

EXPLOSION Finely dispersed particles form Prevent deposition of dust; closed In case of fire: keep drums, etc.,
explosive mixtures in air. system, dust explosion-proof cool by spraying with water.
electrical equipment and lighting.

EXPOSURE PREVENT DISPERSION OF DUST!

STRICT HYGIENE!

Inhalation Blue lips or finger nails. Blue skin. Local exhaust or breathing Fresh air, rest. Refer for medical
Confusion. Convulsions. Cough. protection. attention.
Dizziness. Headache. Nausea.
Sore throat. Unconsciousness.

Skin MAY BE ABSORBED! Protective gloves. Protective Remove contaminated clothes.

clothing. Rinse and then wash skin with
water and soap. Refer for medical
attention.

Eyes Redness. Pain. Safety goggles, or eye protection in First rinse with plenty of water for
combination with breathing several minutes (remove contact
protection. lenses if easily possible), then take
to a doctor.

Ingestion Abdominal pain. Sore throat. Do not eat, drink, or smoke during Rinse mouth. Rest. Refer for
Vomiting. (See Inhalation). work. medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Sweep spilled substance into sealable containers. UN Hazard Class: 6.1 Do not transport with food and
Carefully collect remainder, then remove to safe UN Pack Group: III feedstuffs.
place. Do NOT let this chemical enter the
environment. (Extra personal protection: P2 filter
respirator for harmful particles).

EMERGENCY RESPONSE STORAGE

Separated from combustible and reducing substances, food and feedstuffs.

Dry. Well closed.

Prepared in the context of cooperation between the International

IPCS Programme on Chemical Safety and the European Commission
International © IPCS 2000
Programme on
Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK.
1342 MONONITROPHENOLS

IMPORTANT DATA
Physical State; Appearance Routes of exposure
YELLOW CRYSTALS The substance can be absorbed into the body by inhalation of
its aerosol, through the skin and by ingestion.
Physical dangers
Dust explosion possible if in powder or granular form, mixed Inhalation risk
with air. Evaporation at 20°C is negligible; a harmful concentration of
airborne particles can, however, be reached quickly.
Chemical dangers
May explode on heating. On combustion, forms nitrogen oxides. Effects of short-term exposure
The substance decomposes on heating producing toxic fumes The substance irritates the eyes and the skin and the
including nitrogen oxides. Reacts with strong oxidants. respiratory tract. The substance may cause effects on the
blood, resulting in formation of methaemoglobin. The effects
Occupational exposure limits may be delayed. Medical observation is indicated.
TLV not established.
Effects of long-term or repeated exposure
Repeated or prolonged contact may cause skin sensitization.

PHYSICAL PROPERTIES
Boiling point: 194-279 Vapour pressure, Pa at 20°C: 0.0032 - 7
Melting point: 44-116°C Relative vapour density (air = 1): 4.81
Density: 1.5 g/cm3 Flash point: 169°C
Solubility in water, g/100 ml: 0.13-1.2

ENVIRONMENTAL DATA
The substance is toxic to aquatic organisms. Avoid release to the environment in circumstances different to normal use.

NOTES
Depending on the degree of exposure, periodic medical examination is indicated.
Specific treatment is necessary in case of poisoning with this substance; the appropriate means with instructions must be available.

ADDITIONAL INFORMATION

Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible
LEGAL NOTICE for the use which might be made of this information

©IPCS 2000
Concise International Chemical Assessment Document 20
REFERENCES
Aelion CM, Swindoll CM, Pfaender FK (1987) Adaptation to and
biodegradation of xenobiotic compounds by microbial
communities from a pristine aquifer. Applied environmental
microbiology, 53:2212–2217.
Amacher DE, Turner GN (1982) Mutagenic evaluation of
carcinogens and non-carcinogens in the L5178Y/TK assay
utilizing postmitochondrial fractions (S9) from normal rat liver.
Mutation research, 97:49–65.
Andrae U, Bieniek D, Freitag D, Goeggelmann W, Huber W,
Klein W, Kotzias D, Lahaniatis E, Mansour M, Parlar H, Politzki
G, Rohleder H, Rott B, Scheunert I, Spieser H, Viswanathan R
(1981) Feasibility of test guidelines and evidence of the base-
set testing according to the chemicals legislation. Muenchen,
Gesellschaft für Strahlen- und Umweltfoschung mbH (in
German).
Angerhofer RA (1985) Final phase: Effect of dermal applications
of paranitrophenol on the reproductive functions of rats.
Aberdeen Proving Ground, MD, US Army Environmental
Hygiene Agency (Study No. 75-51-0047-85).
ATSDR (1992) Toxicological profile for nitrophenols: 2- and 4-
nitrophenol. Atlanta, GA, US Department of Health and Human
Services, Public Health Service, Agency for Toxic Substances
and Disease Registry (Report No. TP-91/23).
Ballhorn D, Freitag D, Geyer H, Quast I, Rott B, Scheunert I,
Spieser H, Viswanathan R (1984) Assessment of the feasibility
and evidence of the test methods of levels I and II of the
chemicals act. Berlin, Umweltbundesamt (in German).
BASF AG (1969) Results of the toxicological testing of Rongal-
Stabilisator A. Ludwigshafen (unpublished report) (in German).
BASF AG (1970) Results of the toxicological testing of o-nitro-
phenol. Ludwigshafen (unpublished report) (in German).
Battersby NS, Wilson V (1989) Survey of the anaerobic
biodegradation potential of organic chemicals in digesting
sludge. Applied environmental microbiology, 55:433–439.
Baumgartner A, Liebscher H-J (1990) Allgemeine Hydrologie.
Quantitative Hydrologie. Berlin, Gebrueder Borntraeger Verlag,
pp. 93–96.
Booth G (1991) Nitro compounds, aromatic. In: Ullmann’s
encyclopedia of industrial chemistry. Vol. A17. Weinheim, VCH
VerlagsGmbH, pp. 411–455.
Booth GM, Bradshaw WS, Carter MW (1983) Screening of
priority chemicals for potential reproductive hazard. Orem, UT,
MESA Corp. (Report No. PB83-213017).
Boutwell RK, Bosch DK (1959) The tumor-promoting action of
phenol and related compounds for mouse skin. Cancer research,
19:413–424.
Boyd SA (1982) Adsorption of substituted phenols by soil. Soil
science, 134:337–343.
26
Boyd SA, Shelton DR, Berry D, Tiedje JM (1983) Anaerobic
biodegradation of phenolic compounds in digested sludge.
Applied environmental microbiology, 46:50–54.
Braunbeck T, Storch V, Nagel R (1989) Sex-specific reaction of
liver ultrastructure in zebra fish (Brachydanio rerio) after
prolonged sublethal exposure to 4-nitrophenol. Aquatic
toxicology, 14:185–202.
Bringmann G (1978) Determination of the toxicity of water
pollutants on protozoa. I. Bacteriovorous flagellates. Zeitschrift
fuer Wasser und Abwasser Forschung, 11:210–215 (in German).
Bringmann G, Kuehn R (1977) Results of the damaging effects
of water pollutants on Daphnia magna. Zeitschrift fuer Wasser
und Abwasser Forschung, 10:161–165 (in German).
Bringmann G, Kuehn R, Winter A (1980) Determination of the
biological effect of water pollutants in protozoa. III. Saprozoic
flagellates. Zeitschrift fuer Wasser und Abwasser Forschung,
13:170–173 (in German).
Broecker B, Fischer R, Gerber HG, Goerlitz G, Markert M,
Wellens H (1984) Assessment of the feasibility and evidence of
the test method of level 1 and 2 of the chemical act. Berlin,
Umweltbundesamt (in German).
BUA (1992) BUA-Stoffbericht 2- und 4-Nitrophenol.
Beratergremium fuer Umweltrelevante Altstoffe. Weinheim, VCH
VerlagsGmbH (Report No. 75; February 1992).
Budavari S, O’Neil MJ, Smith A, Heckelmann PE, Kinneary JE,
eds. (1996) The Merck Index. An encyclopedia of chemicals,
drugs and biologicals, 12th ed. Whitehouse Station, NJ, Merck &
Co. Inc.
Buselmaier W, Roehrborn G, Propping P (1972) Mutagenitaets-
Untersuchungen mit Pestiziden im Host-mediated assay und mit
dem Dominanten Letaltest an der Maus. Biologisches
Zentralblatt, 91:311–325.
Capel PD, Leuenberger C, Giger W (1991) Hydrophobic organic
chemicals in urban fog. Atmospheric environment,
25A:1335–1346.
Chiu CW, Lee LH, Wang CY, Bryan GT (1978) Mutagenicity of
some commercially available nitro compounds for Salmonella
typhimurium. Mutation research, 58:11–22.
CITI (1992) Biodegradation and bioaccumulation. Data of
existing chemicals based on the CSCL Japan. Tokyo, Japan
Chemical Industry Ecology-Toxicology & Information Center,
Chemicals Inspection & Testing Institute.
Dellarco VL, Prival MJ (1989) Mutagenicity of nitro compounds
in Salmonella typhimurium in the presence of flavin
mononucleotide in a preincubation assay. Environmental
molecular mutagenesis, 13:116–127.
Domsch KH (1992) Pesticides in soil. Weinheim, VCH-Verlag (in
German).
Eastman Kodak Co. (1980) Toxicology Laboratory Report No.
125877V; US Environmental Protection Agency Report No. 86-
890000202. Rochester, NY [cited in Cantilli R (1991) Drinking
water health advisory for p-nitrophenol. Washington, DC, US
Environmental Protection Agency (Report No. PB92-135490)].

Ensenbach U, Nagel R (1991) Toxicokinetics of xenobiotics in zebrafish
— comparison between tap and river water. Comparative biochemistry
and physiology, 100C:49–53.
EPPO (1993) Decision-making scheme for the environmental risk
assessment of plant protection products. Paris, European and
Mediterranean Plant Protection Organization.
Eriksen K (1978) Cross allergy between paranitro compounds with
special reference to DNCB and chloramphenicol. Contact dermatitis,
4:29–32.
Fahrig R (1974) Comparative mutagenicity studies with pesticides. IARC
scientific publications, 10:161–181.
Figge K, Klahn J, Koch J (1985) Chemicals in ecosystems. Inventory,
evaluation and application of distribution models. Society for Water, Soil
and Air Hygiene, 61:1–234 (in German).
Foureman P, Mason JM, Valencia R, Zimmering S (1994) Chemical
mutagenesis testing in Drosophila. IX. Results of 50 coded compounds
tested for the National Toxicology Program. Environmental molecular
mutagenesis, 23:51–63.
Freitag D, Geyer H, Kraus A, Viswanathan R, Kotzias D, Attar A, Klein
W, Korte F (1982) Ecotoxicological profile analysis. VII. Screening
chemicals for their environmental behavior by comparative evaluation.
Ecotoxicology and environmental safety, 6:60–81.
Geissler A, Schoeler HF (1993) Atmospheric deposition of pesticides
and nitrophenols in the Rhine/Sieg-area (Germany). Vom Wasser,
80:357–370.
Geissler A, Schoeler HF (1994) Gas chromatographic determination of
phenol, methylphenols, chlorophenols, nitrophenols and nitroquinones in
water at 0.1 :g l –1. Water research, 28:2047–2053.
Gerike P, Fischer WK (1979) A correlation study of biodegradability
determination with various chemicals in various tests. Ecotoxicology
and environmental safety, 3:159–173.
Gessner T, Hamada N (1970) Identification of p-nitrophenol glucoside
as a urinary metabolite. Journal of pharmaceutical sciences,
59:1528–1529.
Geyer H, Viswanathan R, Freitag D, Korte F (1981) Relationship
between water solubility of organic chemicals and their bioaccumulation
by the alga Chlorella. Chemosphere, 14:1307–1313.
Gile JD, Gillett JW (1981) Transport and fate of organophosphate
insecticides in a laboratory model ecosystem. Journal of agricultural
and food chemistry, 29:616–621.
Hansch C, Leo A (1979) Substituent constants for correlation analysis in
chemistry and biology. New York, NY, John Wiley & Sons.
Harrison I, Leader RU, Higgo JJW, Tjell JC (1994) Determination of
organic pollutants in small samples of groundwaters by liquid–liquid
extraction and capillary gas chromatography. Journal of chroma-
tography, 688:181–188.
Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E (1983)
Salmonella mutagenicity test results for 250 chemicals. Environmental
mutagenesis, 5 (Suppl. 1):3–142.
Hazleton Lab. (1983) Subacute dust inhalation toxicity study in rats. p-
Nitrophenol. Final report. Sponsored by Monsanto Co., St. Louis, MO
(HLA Study No. 82-242).
Hazleton Lab. (1984) Subacute inhalation toxicity study in rats. o-
Nitrophenol. Final report. Sponsored by Monsanto Co., St. Louis, MO
(HLA Study No. 82-254).
27
Mononitrophenols
Hazleton Lab. (1989) Subchronic toxicity study in rats with para-
nitrophenol. Sponsored by Monsanto Co., St. Louis, MO (HLA Study
No. 241-221).
Herterich R, Herrmann R (1990) Comparing the distribution of nitrated
phenols in the atmosphere of two German hill sites. Environmental
technology letters, 11:961–972.
Hoechst AG (1977a) Acute oral toxicity of p-nitrophenol in female SPF-
Wistar rats. Frankfurt/Main, Hoechst AG (unpublished report) (in
German).
Hoechst AG (1977b) Acute dermal toxicity of p-nitrophenol in female
SPF-Wistar rats. Frankfurt/Main, Hoechst AG (unpublished report) (in
German).
Hoechst AG (1977c) Skin and eye irritating effects of p-nitrophenol in
rabbits. Frankfurt/Main, Hoechst AG (unpublished report) (in German).
Hoechst AG (1980) A mutagenicity screening of 408 / 80 A in bacteria
(Ames test). Frankfurt/Main, Hoechst AG (unpublished report).
Hoover DG, Borgonovi GE, Jones SH, Alexander M (1986) Anomalies in
mineralization of low concentrations of organic compounds in lake water
and sewage. Applied environmental microbiology, 51:226–232.
Howe GE, Marking LL, Bills TD, Rach JJ, Mayer FLJ (1994) Effects of
water temperature and pH on toxicity of terbufos, trichlorfon, 4-
nitrophenol and 2,4-dinitrophenol to the amphipod Gammarus
pseudolimnaeus and rainbow trout (Oncorhynchus mykiss). Environmental
toxicology and chemistry, 13:51–66.
HSDB (1998) Hazardous substances data bank. Bethesda, MD, National
Library of Medicine.
Huang Q, Wang L, Han S (1995) The genotoxicity of substituted
nitrobenzenes and the quantitative structure–activity relationship
studies. Chemosphere, 30:915–923.
Huang Q-G, Kong L-R, Liu Y-B, Wang L-S (1996) Relationships between
molecular structure and chromosomal aberrations in in vitro human
lymphocytes induced by substituted nitrobenzenes. Bulletin of
environmental contamination and toxicology, 57:349–353.
Huq AS, Ho NFH, Husari N, Flynn GL, Jetzer WE, Condie LJ Jr (1986)
Permeation of water contaminative phenols through hairless mouse
skin. Archives of environmental contamination and toxicology,
15:557–566.
Hustert K, Mansour M, Parlar H, Korte F (1981) The EPA test — A
method for the determination of the photochemical degradation of
organic compounds in aquatic systems. Chemosphere, 10(9):995–998
(in German).
International Research and Developmental Corporation (1983) Range-
finding teratology study in rats. Sponsored by Monsanto Co., St. Louis,
MO (IR-83-100).
IPCS (1994) Assessing human health risks of chemicals: derivation of
guidance values for health-based exposure limits. Geneva, World Health
Organization, International Programme on Chemical Safety
(Environmental Health Criteria 170).
IPCS (1998) International Chemical Safety Card — Mononitrophenols.
Geneva, World Health Organization, International Programme on
Chemical Safety (ICSC 1342).
Japan Environment Agency (1979) Chemicals in the environment.
Monitoring of the general environment in Japan 1978. Tokyo.
Japan Environment Agency (1980) Chemicals in the environment.
Monitoring of the general environment in Japan 1979. Tokyo.
Concise International Chemical Assessment Document 20
Japan Environment Agency (1995) Chemicals in the environment.
Monitoring of the general environment in Japan 1994. Tokyo.
Jetzer WE, Huq AS, Ho NFH, Flynn GL, Duraiswamy N, Condie L Jr
(1986) Permeation of mouse skin and silicone rubber membranes by
phenols: relationship to in vitro partitioning. Journal of pharmaceutical
sciences, 75:1098–1103.
Kavlock RJ (1990) Structure–activity relationships in the developmental
toxicity of substituted phenols: In vivo effects. Teratology, 41:43–59.
Kawai A, Goto S, Matsumoto Y, Matsushita H (1987) Mutagenicity of
aliphatic and aromatic nitro compounds. Japanese journal of industrial
health, 29:34–54.
Kayser G, Koch M, Ruck W (1994) Simultaneous quantitative
measurement of biodegradation and toxicity of environmental
chemicals. Vom Wasser, 82:219–232.
Koerdel W, Schoene K, Bruckert J, Pfeiffer U, Schreiber G, Rittmann
D, Hochrainer D, Otto F, Spielberg T, Fingerhut R, Kuhnen-Clausen D,
Koenig J (1981) Assessment of the feasibility of test guidelines as well
as the evidence of the base set of the law on chemicals. Hanover,
Fraunhofer Institute for Toxicology and Aerosol Research (in German).
Koerdel W, Kuhnen-Clausen D, Fabig W, Otto F (1984) Evaluation of
test guidelines for environmental chemicals. Schmallenberg, Fraunhofer
Institute for Environmental Chemistry and Ecotoxicology (in German).
Koop DR (1986) Hydroxylation of p-nitrophenol by rabbit ethanol-
inducible cytochrome P-450 isozyme 3a. Molecular pharmacology,
29:399–404.
Koop DR, Laethem CL (1992) Inhibition of rabbit microsomal
cytochrome P-450 2E1-dependent p-nitrophenol hydroxylation by
substituted benzene derivatives. Drug metabolism and disposition,
20:775–777.
Kramer CR, Truemper l, Berger L (1986) Quantitative structure–activity
relations for the autotrophic growth inhibition of synchrone Chlorella
vulgaris suspensions by monosubstituted nitrobenzenes. Biochemie und
Physiologie der Pflanzen, 181:411–420 (in German).
Kubinski H, Gutzke GE, Kubinski ZO (1981) DNA-cell-binding (DCB)
assay for suspected carcinogens and mutagens. Mutation research,
89:95–136.
Kuehn R, Pattard M, Pernak K-D, Winter A (1988) Damaging effects of
environmental chemicals in the Daphnia reproductive toxicity test as a
basis for the evaluation of environmental hazards in aquatic systems.
Berlin, Institute for Water, Soil and Air Hygiene (in German).
Landrum PF, Crosby DG (1981) Comparison of the disposition of
several nitrogen-containing compounds in the sea-urchin and other
marine invertebrates. Xenobiotica, 11:351–361.
Lang P-Z, Ma X-F, Lu G-H, Wang YI, Bian Y (1996) QSAR for the acute
toxicity of nitroaromatics to the carp (Cyprinus carpio). Chemosphere,
32:1547–1552.
Leone JA, Seinfeld JH (1985) Comparative analysis of chemical
reaction mechanism for photochemical smog. Atmospheric environment,
19:437–464.
Leone JA, Flagan RC, Grosjean D, Seinfeld JH (1985) An outdoor smog
chamber and modeling study of toluene–NOx photooxidation.
International journal of chemical kinetics, 17:177–216.
León-González ME, Perez-Arribas LV, Santos-Delgado MJ, Polo-Diez LM
(1992) Simultaneous flow-injection determination of o- and p-nitrophenol
using a photodiode-array detector. Analytica Chimica Acta, 258:269–273.
28
Leuenberger C, Czuczwa J, Tremp J, Giger W (1988) Nitrated phenols in
rain: atmospheric occurrence of phytotoxic pollutants. Chemosphere,
17(3):511–516.
Levsen K, Behnert S, Priess B, Svoboda M, Winkeler H-D, Zietlow J
(1990) Organic compounds in precipitation. Chemosphere,
21:1037–1061.
Levsen K, Behnert S, Mussmann P, Raabe M, Priess B (1993) Organic
compounds in cloud and rain water. International journal of environmental
analytical chemistry, 52:87–97.
Løkke H (1984) Sorption of selected organic pollutants in Danish soils.
Ecotoxicology and environmental safety, 8:395–409.
Luettke J, Levsen K (1994) Partitioning of phenol and nitrophenols in
gas and liquid phase of clouds. In: Borrell PM, Borrell P, Cvitas T, Seiler
W, eds. Transport and transformation of pollutants in the troposphere.
Proceedings of EUROTRAC Symposium ’94 Garmisch-Patenkirchen,
11–15 April 1994. Garmisch-Patenkirchen, SPB Academic Publishing bv
/ EUROTRAC International Scientific Secretariat (ISS); Fraunhofer
Institute for Atmospheric Environmental Research, pp.1075–1078.
Luettke J, Scheer V, Levsen K, Wuensch G, Cape JN, Hargreaves KJ,
Storeton-West RL, Acker K, Wieprecht W, Jones B (1997) Occurrence
and formation of nitrated phenols in and out of cloud. Atmospheric
environment, 31:2637–2648.
Machida M, Morita Y, Hayashi M, Awazu S (1982) Pharmacokinetic
evidence for the occurrence of extrahepatic conjugative metabolism of
p-nitrophenol in rats. Biochemical pharmacology, 31:787–791.
Mansour M (1996) Abiotic degradation of pesticides and other organic
chemicals in aquatic systems. Pesticide outlook, 7:9–10.
Marquart HW, Sewekow B, Hamburger B, Harzdorf C, Hellbusch HD
(1984) Assessment of the feasibility and evidence of the test methods of
levels I and II of the chemicals act. Part II. Leverkusen, Bayer-AG, pp.
1–128 (in German).
Massey IJ, Aitken MD, Ball LM, Heck PE (1994) Mutagenicity screening
of reaction products from the enzyme-catalyzed oxidation of phenolic
pollutants. Environmental toxicology and chemistry, 13:1743–1752.
McCann J, Choi E, Yamasaki E, Ames BN (1975) Detection of
carcinogens as mutagens in the Salmonella/microsome test: assay of
300 chemicals. Proceedings of the National Academy of Sciences of the
United States of America, 72:5135–5139.
McCoy GD, Koop DR (1988) Biochemical and immunochemical
evidence for the induction of an ethanol-inducible cytochrome P-450
isoenzyme in male Syrian golden hamsters. Biochemical pharmacology,
37:1563–1568.
Means JL, Anderson SJ (1981) Comparison of five different methods
for measuring biodegradability in aqueous environment. Water, air, and
soil pollution, 16:301–315.
Meerman JH, Nijland C, Mulder GJ (1987) Sex differences in sulfation
and glucuronidation of phenol, 4-nitrophenol and N-hydroxy-2-
acetylaminofluorene in the rat in vivo. Biochemical pharmacology,
36:2605–2608.
Mussmann P, Levsen K, Radeck W (1994) Gas-chromatographic
determination of phenols in aqueous samples after solid phase
extraction. Fresenius journal of analytical chemistry, 348:654–659.
Nakamura S, Oda Y, Shimada T, Oki I, Sugimoto K (1987) SOS-inducing
activity of chemical carcinogens and mutagens in Salmonella
typhimurium TA1535/pSK1002: examination with 151 chemicals. Mutation
research, 192:239–246.

Naniwa S (1979) Industrial contact dermatitis due to nitro and amino
derivatives. 1st report: mass-examination of a factory. Journal of
dermatology, 6:59–63.
Nasseredine-Sebaei SM, Crider AM, Carroll RT, Hinko CN (1993)
Determination of m-nitrophenol and nipecotic acid in mouse tissues by
high-performance liquid chromatography after administration of the
anticonvulsant m-nitrophenyl-3-piperidinecarboxylate hydrochloride.
Journal of pharmaceutical sciences, 82:39–43.
Neuhauser EF, Loehr RC, Malecki MR, Milligan DL, Durkin PR (1985)
The toxicity of selected organic chemicals to the earthworm Eisenia
fetida. Journal of environmental quality, 14:383–388.
Neuhauser EF, Durkin PR, Malecki MR, Anatra M (1986) Comparative
toxicity of ten organic chemicals to four earthworm species.
Comparative biochemistry and physiology, C 83:197–200.
Nick K, Schoeler HF (1992) Gas-chromatographic determination of
nitrophenols after derivatization with diazomethane. Fresenius journal of
analytical chemistry, 343:304–307.
Nojima K, Kawaguchi A, Ohya T, Kanno S, Hirobe M (1983) Studies on
photochemical reaction of air pollutants. X. Identification of nitrophenols
in suspended particulates. Chemical and pharmaceutical bulletin,
31:1047–1051.
NTP (1993) Toxicology and carcinogenesis studies of p-nitrophenol (CAS
No. 100-02-7) in Swiss Webster mice (dermal studies). Research Triangle
Park, NC, US Department of Health and Human Services, National
Toxicology Program (NTP Report No. TR-417).
Nyholm N, Lindgaard-Jœrgensen P, Hansen N (1984) Biodegradation of
4-nitrophenol in standardized aquatic degradation tests. Ecotoxicology
and environmental safety, 8:451–470.
Oberly TJ, Bewsey BJ, Probst GS (1984) An evaluation of the L5178Y
TK+/– mouse lymphoma forward mutation assay using 42 chemicals.
Mutation research, 125:291–306.
Ohkura K, Iwamoto K, Terada H (1990) Transcellular permeation of
nitrophenols through newborn rat skin epidermal cells in monolayer
culture. Chemical and pharmaceutical bulletin, 38:2788–2791.
Ou L-T (1985) Methyl parathion degradation and metabolism in soil:
Influence of high soil-water contents. Soil biology and biochemistry,
17:241–243.
Pagga U, Haltrich WG, Guenthner W (1982) Investigations of the effect
of 4-nitrophenol on activated sludge. Vom Wasser, 59:51–65 (in
German).
Paterson B, Cowie CE, Jackson PE (1996) Determination of phenols in
environmental waters using liquid chromatography with electrochemical
detection. Journal of chromatography, A 731:95–102.
Pitter P (1976) Determination of biological degradability of organic
substances. Water research, 10:231–235.
Pocurull E, Marce RM, Borrull F (1996) Determination of phenolic
compounds in natural waters by liquid chromatography with ultraviolet
and electrochemical detection after on-line trace enrichment. Journal of
chromatography, 738:1–9.
Poirier MC, De Cicco BT, Lieberman MW (1975) Nonspecific inhibition
of DNA repair synthesis by tumor promoters in human diploid
fibroblasts damaged with N-acetoxy-2-acetylaminofluorene. Cancer
research, 35:1392–1397.
Probst GS, McMahon RE, Hill LE, Thompson CZ, Epp JK, Neal SB
(1981) Chemically-induced unscheduled DNA synthesis in primary rat
hepatocyte cultures: a comparison with bacterial mutagenicity using 218
compounds. Environmental mutagenesis, 3:11–32.
29
Mononitrophenols
Pruett SB, Chambers JE (1988) Effects of paraoxon, p-nitrophenol,
phenyl saligenin cyclic phosphate, and phenol on the rat interleukin 2
system. Toxicology letters, 40:11–20.
Pruppacher HR, Klett JD (1978) Microphysics of clouds and
precipitation. Dordrecht/Boston/London, D. Reidel Publishing Co.
Puig D, Barcelo D (1996) Determination of phenolic compounds in water
and waste water. Trends in analytical chemistry, 15:362–375.
Rashid KA, Mumma RO (1986) Screening pesticides for their ability to
damage bacterial DNA. Journal of environmental science and health,
21:319–334.
Reinke LA, Moyer MJ (1985) p-Nitrophenol hydroxylation. A microsomal
oxidation which is highly inducible by ethanol. Drug metabolism and
disposition, 13:548–552.
Richartz H, Reischl A, Trautner F, Hutzinger O (1990) Nitrated phenols
in fog. Atmospheric environment, 24:3067–3072.
Rippen G, Flothmann D, Witt W (1984) Improvement of the OECD test
guideline A 80/9 and comparative evaluation of other relevant methods
for the measurement of volatility. Frankfurt a. M., Batelle-Institut e.V.
(Report No. 106 02 024/06) (in German).
Roberts BL, Dorough HW (1984) Relative toxicities of chemicals to the
earthworm Eisenia fetida. Environmental toxicology and chemistry,
3:67–78.
Robinson D, Smith JN, Williams RT (1951) Studies in detoxication. 39.
Nitro compounds. (a) The metabolism of o-, m-, and p-nitrophenols in
the rabbit. (b) The glucuronides of the mononitrophenols and
observations on the anomalous optical rotations of triacetyl $ -o-
nitrophenylglucuronide and its methyl ester. Biochemical journal,
50:221–227.
Rott B, Viswanathan R, Freitag D, Korte F (1982) Comparative
investigation on the feasibility of different tests for the evaluation of
the degradation of environmental chemicals. Chemosphere, 11:531–538
(in German).
Ruana J, Urbe I, Borrull F (1993) Determination of phenols at the ng/l
level in drinking and river waters by liquid chromatography with UV and
electrochemical detection. Journal of chromatography, A 655:217–226.
Rubin HE, Subba-Rao RV, Alexander M (1982) Rates of mineralization
of trace concentrations of aromatic compounds in lake water and
sewage samples. Applied environmental microbiology, 43:1133–1138.
Rush GF, Newton JF, Hook JB (1983) Sex differences in the excretion
of glucuronide conjugates: The role of intrarenal glucuronidation. Journal
of pharmacology and experimental therapeutics, 227:658–662.
Sax NI, Lewis RJ (1987) Hawley’s condensed chemical dictionary, 11th
ed. New York, NY, Van Nostrand Reinhold Co.
Scheer V, Luettke J, George C, Levsen K, Frenzel A, Behnke W,
Zetzsch C (1996) Atmospheric nitration of phenol in clouds by N2O5 and
ClNO2. In: Borrell PM, Borrell P, Kelly K, Cvitas T, Seiler W, eds.
Transport and transformation of pollutants in the troposphere.
Proceedings of EUROTRAC Symposium ‘96. Garmisch-Patenkirchen,
25–29 March 1996. Southhampton, Computational Mechanics
Publications.
Scheubel JB (1984) Assessment of the feasibility and evidence of the
test method of level 1 and 2 of the chemical act. Marl, Chemische Werke
Huels AG (Report No. 106 04 011/5 CWH) (in German).
Scheunert I (1984) Examination and optimization of the “GSF-Cold-Finger-
Method” and comparative calculations of the volatility. Gesellschaft fuer
Strahlen- und Umweltforschung (Report No. 10602024/08) (in German).
Concise International Chemical Assessment Document 20
Schoene K, Steinhanses J (1984) Comparative measurements of the
volatility in open systems. Schmallenberg, Fraunhofer Institute for
Toxicology and Aerosol Research (Report No. 10602024/7 Part II) (in
German).
Scholz N (1986) Development of test guidelines on marine species for
ecotoxicological studies according to the chemicals act -
Bryozota/Camptozoa. Berlin, Umweltbundesamt (Report No.
10603042/02) (in German).
Schwarzenbach RP, Stierli R, Folsom BR, Zeyer J (1988) Compound
properties relevant for assessing the environmental partitioning of
nitrophenols. Environmental science and technology, 22:83–92.
Sewekow B (1983) Feasibility of test guidelines and evidence of the
base-set testing according to the chemicals legislation. Muenchen,
Gesellschaft fuer Strahlen- und Umweltforschung (in German).
Shimizu M, Yano E (1986) Mutagenicity of mono-nitrobenzene
derivatives in the Ames test and rec assay. Mutation research,
170:11–22.
Smith LW, Hall GT, Kennedy GL (1988) Acute and repeated dose
inhalation toxicity of para-nitrophenol sodium salt in rats. Drug chemistry
and toxicology, 11:319–327.
Snodgrass HL Jr (1983) Phase I, dermal penetration and distribution of
14
C-labeled paranitrophenol (PNP). Aberdeen Proving Ground, MD, US
Army Environmental Hygiene Agency (Study No. 75-51-0047-84).
Spain JC, van Veld PA, Monti CA, Pritchard PH, Cripe CR (1984)
Comparison of p-nitrophenol biodegradation in field and laboratory test
systems. Applied environmental microbiology, 48:944–950.
Storer RD, McKelvey TW, Kraynak AR, Elia MC, Barnum JE, Harmon
LS, Nichols WW, DeLuca JG (1996) Revalidation of the in vitro alkaline
elution/rat hepatocyte assay for DNA damage: improved criteria for
assessment of cytotoxicity and genotoxicity and results for 81
compounds. Mutation research, 368:59–101.
Subba-Rao RV, Rubin HE, Alexander M (1982) Kinetics and extent of
mineralization of organic chemicals at trace levels in freshwater and
sewage. Applied environmental microbiology, 43:1139–1150.
Suzuki J, Koyama T, Suzuki S (1983) Mutagenicities of mono-
nitrobenzene derivatives in the presence of norharman. Mutation
research, 120:105–110.
Tabak HH, Quave SA, Mashni CI, Barth EF (1981) Biodegradability
studies with organic priority pollutant compounds. Journal of the Water
Pollution Control Federation, 52:1503–1518.
Tan GH, Chong CL (1993) Trace monitoring of water-borne phenolics in
the Klang River basin. Environmental monitoring and assessment,
24:267–277.
Thompson MJ, Ballinger LN, Cross SE, Roberts MS (1996) High-
performance liquid chromatographic determination of phenol, 4-
nitrophenol, beta-naphthol and a number of their glucuronide and sulfate
conjugates in organ perfusate. Journal of chromatography, B
677:117–122.
Tremaine LM, Diamond GL, Quebbemann AJ (1984) In vivo
quantification of renal glucuronide and sulfate conjugation of 1-naphthol
and p-nitrophenol in the rat. Biochemical pharmacology, 33:419–427.
Tremp J, Mattrel P, Fingler S, Giger W (1993) Phenols and nitrophenols
as tropospheric pollutants: Emissions from automobile exhausts and
phase transfer in the atmosphere. Water, air, and soil pollution,
68:113–123.
TRI (1998) Toxics release inventory. Washington, DC, US
Environmental Protection Agency, Office of Toxic Substances
(17 December 1998).
30
Tseng S, Lin M (1994) Treatment of organic wastewater by anaerobic
biological fluidized bed reactor. Water science and technology,
29:157–166.
Urano K, Kato Z (1986) Evaluation of biodegradation ranks of priority
organic compounds. Journal of hazardous materials, 13:147–159.
Van Veld PA, Spain JC (1983) Degradation of selected xenobiotic
compounds in three types of aquatic test systems. Chemosphere,
12:1291–1305.
Vasilenko NM, Volodchenko VA, Baturina TS, Kolodub FA (1976)
Toxicological peculiarities of mononitrophenols with regard for their
isomeric form. Farmakologiya i Toksikologiya, 39:718–721.
Vernot EH, MacEwen JD, Haun CC, Kinkead ER (1977) Acute toxicity
and skin corrosion data for some organic and inorganic compounds and
aqueous solutions. Toxicology and applied pharmacology, 42:417–423.
Verschueren K, ed. (1983) Handbook of environmental data on organic
chemicals, 2nd ed. New York, NY, Van Nostrand Reinhold Co.
Vozñáková Z, Podehradská J, Kohlicková M (1996) Determination of
nitrophenols in soil. Chemosphere, 33:285–291.
Wagner R, Braeutigam H-J (1981) Development and testing of a
method for studying the degradation of organic compounds under
anaerobic conditions (report no. 03 7221). In: Biehl HM, Fuehr F, Seibert
K, eds. Methods for the ecotoxicological evaluation of chemicals, Part 1,
Aquatic systems. Juelich, Forschungszentrum, pp. 20–41 (in German).
Weast RC (1979) CRC handbook of chemistry and physics, 69th ed.
Boca Raton, FL, CRC Press, Inc.
Wiggins BA, Jones SH, Alexander M (1987) Explanations for the
acclimation period preceding the mineralization of organic chemicals in
aquatic environments. Applied environmental microbiology, 43:791–796.
Yamada K, Murakami H, Yasumura K, Shirahata S, Shinohara K, Omura
H (1987) Production of DNA-breaking substance after treatment of
monophenols with sodium nitrite and then with dimethyl sulfoxide.
Agricultural and biological chemistry, 51:247–248.
Yoshida K, Shigeoka T, Yamauchi F (1983) Non-steady-state
equilibrium model for the preliminary prediction of the fate of chemicals
in the environment. Ecotoxicology and environmental safety, 7:179–190.
Yoshioka Y, Ose Y, Sato T (1985) Testing for the toxicity of chemicals
with Tetrahymena pyriformis. The science of the total environment,
43:149–157.
Zetzsch C, Rinke M, Scharpring H, Schueler P, Urbanik E, Wahner A,
Wiedelmann A, Witte F (1984) Upper limits of the persistence of
chemicals in the atmosphere from their reactivity against OH radicals.
University of Bochum, Bochum, pp. 1–20 (BMFT Report No. PTU
037253).
Zimmering S, Mason JM, Valencia R, Woodruff RC (1985) Chemical
mutagenesis testing in Drosophila. II. Results of 20 coded compounds
tested for the National Toxicology Program. Environmental mutagenesis,
7:87–100.
 Mononitrophenols

APPENDIX 1 — 3-NITROPHENOL wastewater. From the available results, a slow mineralization of

Identity and physical/chemical properties
3-Nitrophenol (CAS No. 554-84-7; 3-hydroxy-1-
nitrobenzene, m-nitrophenol) has the empirical formula C 6H5NO3.
Its structural formula is shown below:
3-nitrophenol under anaerobic conditions by adapted
microorganisms can be expected.
A soil sorption coefficient (K oc) of 52.83, determined by
Boyd (1982), and the n-octanol/water partition coefficient (log
K ow) of 2.0, reported by Hansch & Leo (1979), indicate a low to
moderate potential for soil sorption as well as for
bioaccumulation.

OH Environmental levels

3-Nitrophenol was not detected in 27 samples of air

(detection limit 8 ng/m 3) in Japan in 1994 (Japan Environment
Agency, 1995). It was not detected in 177 samples of Japanese
surface waters (detection limits 0.04–10 :g/litre) or in 177
sediment samples (detection limits 0.002–0.8 :g/kg) in 1978,
NO 2 1979, and 1994 (Japan Environment Agency, 1979, 1980,
1995). 3-Nitrophenol was not detected in 129 fish samples
(detection limits 0.005–0.2 :g/kg) in Japan in 1979 and 1994
(Japan Environment Agency, 1980, 1995).
Physicochemical properties of 3-nitrophenol are given in
Table A-1. Comparative kinetics and metabolism in
laboratory animals and humans
Table A-1: Physicochemical properties of 3-nitrophenol.
Studies providing quantitative information on the
absorption, metabolism, or elimination of 3-nitrophenol in
Parameter Value humans were not identified. In addition, there is only very
Molecular mass (g/mol) 139.11 limited information available for experimental animals. In
rabbits given a single dose of 150–200 mg/kg body weight via
Melting point (°C) 96–97 (1)(2) gavage, most of the applied dose (o80%) was excreted via the
Boiling point (°C) 194 (1) urine within 24 h. About 68–86% was conjugated with
glucuronic acid and sulfonic acid, whereas about 7–13% was
Vapour pressure (kPa; 20 °C) 0.10 (3) reduced to aminophenols (Robinson et al., 1951). Skin
permeation was shown in several in vitro experiments (Huq et
Water solubility (g/litre; 25 °C) 13.5 (1)
al., 1986; Jetzer et al., 1986; Ohkura et al., 1990). Although the
n-Octanol/water partition coefficient 2.00 (4) information is limited, bioaccumulation of 3-nitrophenol in
(log K ow) organisms is not to be expected owing to the isomer’s rapid
metabolism and excretion.
Dissociation constant (p K a) (18 °C) 8.34 (2)

Conversion factors 1 mg/m 3 = 0.173 ppmv Effects on laboratory mammals and in vitro test
1 ppmv = 5.78 mg/m 3
systems

References: (1) Verschueren (1983); (2) Budavari et al. (1996);
(3) HSDB (1998); (4) Hansch & Leo (1979)
Environmental transport, distribution, and
transformation
Data on the abiotic degradation of 3-nitrophenol were not
available.
Three studies on biotic degradation, summarized in
Table A-2, indicate the isomer to be inherently biodegradable
in water under aerobic conditions.
In tests on biotic degradation under anaerobic conditions
using sewage sludge and sludge from the primary anaerobic
stage of a municipal sewage treatment plant, respectively, initial
3-nitrophenol concentrations in the range of 96.5–579 mg/litre
were not degraded at all within 7–60 days (Wagner &
Braeutigam, 1981; Battersby & Wilson, 1989). Boyd et al.
(1983), however, found complete anaerobic removal of 50
mg/litre within 1 week of incubation. In this test, mineralization
was demonstrated only if the incubation period was extended to
10 weeks. Anaerobic degradation, even of high initial
nitrophenol concentrations, was found by Tseng & Lin (1994),
who observed 90% removal of 3-nitrophenol (350–650 mg/litre)
in a biological fluidized bed reactor with three different kinds of
The oral LD50 of 3-nitrophenol is quoted to be $930
mg/kg body weight for rats (Vasilenko et al., 1976; Vernot et al.,
1977) and $1070 mg/kg body weight for mice (Vasilenko et al.,
1976; Vernot et al., 1977).
The available in vitro and in vivo genotoxicity studies on
3-nitrophenol are summarized in Table A-3. 3-Nitrophenol was
shown to be mutagenic in a rec-assay and gave inconsistent
results in Salmonella/microsome assays. One study showed it to
be non-mutagenic in the Salmonella typhimurium TA98 and
TA100 strains, whereas another study showed mutagenicity in
both of these strains in both the presence and absence of
metabolic activation. In view of the conflicting results from
Salmonella/microsome assays and the absence of any data on
clastogenicity, no conclusions can be made regarding the
mutagenicity of 3-nitrophenol.
For 3-nitrophenol, there are no studies available
concerning irritating or sensitizing effects, repeated exposure,
reproductive and developmental toxicity, or effects on humans.
Effects on aquatic species
In tests performed on the toxicity of 3-nitrophenol to
various aquatic organisms (see Table A-4), 3-nitrophenol
exhibited a moderate to high toxicity.

31
Concise International Chemical Assessment Document 20

Table A-2: Biotic degradation of 3-nitrophenol under aerobic conditions.

Concentration Additional Test duration Removal

Test (mg/litre) carbon source (days) (%) Reference

Tests on ready biodegradability

MITI I 100 no 14 0 Gerike & Fischer (1979);

Urano & Kato (1986)

Tests on inherent biodegradability

Batch test, aerated 200 CODa no 5 95 Pitter (1976)

Respirometric test 300 yes 10 44 Kayser et al. (1994)

a COD = chemical oxygen demand.

Table A-3: Genotoxicity of 3-nitrophenol in vitro and in vivo.

Results a

Without With
Concentration metabolic metabolic
Species (test system) End-point range activation activation Remarks References
In vitro studies

Bacillus subtilis H17, Recombinatio 0.01–5 + 0 positive at $0.5 Shimizu &

M45 n assay mg/plate mg/plate Yano (1986)

Salmonella Reverse 0.01–5 ! ! Shimizu &

typhimurium TA1535, mutations mg/plate Yano (1986)
TA1537, TA1538

Salmonella Reverse 0.1–5 mg/plate + + Study in Japanese Kawai et al.

typhimurium TA98, mutations (data taken from (1987)
TA100 tables)

Salmonella Reverse 0.01–5 ! ! Suzuki et al. (1983) Suzuki et al.

typhimurium TA98, mutations mg/plate also tested both (1983); Shimizu
TA100 strains in the pres- & Yano (1986)
ence of norharman,
which also gave
negative results

In vivo studies

Drosophila SLRL assay via feed (5000 Foureman et al.

melanogaster ppm) or injec- (1994)
tion (1200
ppm)

a !, negative; +, positive; 0, not tested.

Table A-4: Aquatic toxicity of 3-nitrophenol.

Species Effective concentration

(test method/end-point) (mg/litre) Reference

Bacteria
Pseudomonas putida (cell multiplication inhibition 16-h MICa: 7.0 Bringmann & Kuehn (1977)
test)

Protozoa

Entosiphon sulcatum (cell multiplication inhibition 72-h MIC: 0.97 Bringmann (1978); Bringmann et al.
test) (1980)

Algae

Scenedesmus subspicatus 6-h EC50: 6.21 Kramer et al. (1986)

Chlorella vulgaris (cell multiplication inhibition test)

Invertebrates

Moina macrocopa (acute) (immobilization) 3-h LC50: 1.7 Yoshioka et al. (1985)

Fish

Cyprinus carpio (static) 96-h LC50: 17.5 Lang et al. (1996)

a MIC = minimum inhibitory concentration.

32
 Mononitrophenols

APPENDIX 2 — SOURCE DOCUMENTS APPENDIX 3 — CICAD PEER REVIEW

BUA (1992): BUA-Stoffbericht 2- und 4-
Nitrophenol. Beratergremium fuer
Umweltrelevante Altstoffe. Weinheim, VCH
VerlagsGmbH (Report No. 75; February 1992)
For the BUA review process, the company that is in charge
of writing the report (usually the largest producer in Germany)
prepares a draft report using literature from an extensive
literature search as well as internal company studies. This draft is
subject to a peer review during several readings of a working
group consisting of representatives from government agencies,
the scientific community, and industry.
The draft CICAD on mononitrophenols was sent for review
to institutions and organizations identified by IPCS after contact
with IPCS national Contact Points and Participating Institutions,
as well as to identified experts. Comments were received from:
Federal Institute for Health Protection of Consumers &
Veterinary Medicine, Berlin, Germany
Gesellschaft Deutscher Chemiker, Frankfurt, Germany
Institute of Occupational Medicine, Chinese Academy of
Preventive Medicine, Ministry of Health, Beijing, People’s
Republic of China

The English translation of BUA Report No. 75 (BUA
Report 2- and 4-Nitrophenol. GDCh-Advisory Committee on
Existing Chemicals of Environmental Relevance. Stuttgart,
Hirzel Verlag [February 1992]) was released in 1993.
Institute of Terrestrial Ecology, Huntingdon, United
Kingdom
Joint Food Safety and Standards Group, Department of
Health, London, United Kingdom

National Institute of Health Sciences, Tokyo, Japan

ATSDR (1992): Toxicological profile for
nitrophenols: 2- and 4-nitrophenol. Atlanta, GA,
US Department of Health and Human Services,
Public Health Service, Agency for Toxic
Substances and Disease Registry (Report No.
TP-91/23)
National Institute of Public Health, Prague, Czech
Republic
United States Department of Health and Human Services
(National Institute of Environmental Health Sciences,
Research Triangle Park), USA

Copies of the ATSDR Toxicological profile for United States Environmental Protection Agency (National
nitrophenols: 2- and 4-nitrophenol (ATSDR, 1992) may be Center for Environmental Assessment, Washington, DC;
obtained from the: Region VIII), USA

Agency for Toxic Substances and Disease Registry World Health Organization/International Programme on
Division of Toxicology Chemical Safety, Montreal, Canada
1600 Clifton Road, E-29
Atlanta, Georgia 30333
USA

Initial drafts of the Toxicology profile for nitrophenols: 2-

and 4-nitrophenol were reviewed by scientists from the Agency
for Toxic Substances and Disease Registry, the US Centers for
Disease Control, the US National Toxicology Program, and other
federal agencies. The document was also reviewed by an expert
panel of nongovernmental reviewers, consisting of the following
members:

Dr Martin Alexander, Cornell University

Dr Gary Booth, Brigham Young University
Dr Samuel Cohen, University of Nebraska Medical Center
Dr Loren Koller, Oregon State University
Dr Frederick Oehme, Kansas State University

33
Concise International Chemical Assessment Document 20

APPENDIX 4 — CICAD FINAL REVIEW Dr M. Sweeney, Document Development Branch, National

Institute for Occupational Safety and Health, Cincinnati, OH,
BOARD USA

Washington, DC, USA, 8–11 December 1998 Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und
Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim,
Germany

Members

Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Secretariat

Sweden (Vice-Chairperson)
Mr R. Cary, Toxicology Unit, Health Directorate, Health and
Safety Executive, Bootle, Merseyside, United Kingdom
(Rapporteur)
Dr M. Baril, Institut de Recherches en Santé et Sécurité du
Travail du Québec (IRSST), Montreal, Quebec, Canada
Dr H. Galal-Gorchev, Chevy Chase, MD, USA

Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Ms M. Godden, Health and Safety Executive, Bootle,
Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom Merseyside, United Kingdom

Dr O. Faroon, Agency for Toxic Substances and Disease
Registry, Centers for Disease Control and Prevention, Atlanta,
GA, USA
Dr G. Foureman, National Center for Environmental Assessment,
US Environmental Protection Agency, Research Triangle Park,
NC, USA
Dr H. Gibb, National Center for Environmental Assessment, US
Environmental Protection Agency, Washington, DC, USA
(Chairperson)
Dr R.G. Liteplo, Environmental Health Directorate, Health
Canada, Ottawa, Ontario, Canada
Ms L. Regis, Programme for the Promotion of Chemical Safety,
World Health Organization, Geneva, Switzerland
Mr A. Strawson, Health and Safety Executive, London, United
Kingdom
Dr P. Toft, Programme for the Promotion of Chemical Safety,
World Health Organization, Geneva, Switzerland

Dr R.F. Hertel, Federal Institute for Health Protection of

Consumers & Veterinary Medicine, Berlin, Germany

Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,

Fraunhofer Institute for Toxicology and Aerosol Research,
Hanover, Germany

Dr A. Nishikawa, Division of Pathology, National Institute of

Health Sciences, Tokyo, Japan

Dr E.V. Ohanian, Office of Water/Office of Science and

Technology, Health and Ecological Criteria Division, US
Environmental Protection Agency, Washington, DC, USA

Dr J. Sekizawa, Division of Chem-Bio Informatics, National

Institute of Health Sciences, Tokyo, Japan

Professor P. Yao, Institute of Occupational Medicine, Chinese

Academy of Preventive Medicine, Ministry of Health, Beijing,
People’s Republic of China

Observers

Dr K. Austin, National Center for Environmental Assessment, US

Environmental Protection Agency, Washington, DC, USA

Dr I. Daly (ICCA representative), Regulatory and Technical

Associates, Lebanon, NJ, USA

Ms K.L. Lang (CEFIC, European Chemical Industry Council,

representative), Shell International, London, United Kingdom

Ms K. Roberts (ICCA representative), Chemical Self-funded

Technical Advocacy and Research (CHEMSTAR), Chemical
Manufacturers Association, Arlington, VA, USA

Dr W. Snellings (ICCA representative), Union Carbide

Corporation, Danbury, CN, USA

34

RÉSUMÉ D’ORIENTATION
Ce CICAD relatif aux isomères en position 2-, 3- et
4- du nitrophénol a été préparé par l’Institut Fraunhofer
de recherche en toxicologie et sur les aérosols de
Hanovre (Allemagne). Il est basé sur des mises au point
rédigées par le Comité consultatif allemand sur les
produits chimiques qui posent un problème écologique
(BUA, 1992) et par l’US Agency for Toxic Substances
and Disease Registry (ATSDR, 1992) afin d’évaluer les
effets potentiels du 2- et du 4-nitrophénol sur
l’environnement et la santé humaine. Les données prises
en compte dans ces mises au point vont jusqu’en 1992.
Une recherche bibliographique exhaustive a été effectuée
en 1998 sur plusieurs bases de données afin de relever
les références intéressantes sur le 2- et le 4-nitrophénol
publiées après celles qui figurent dans les documents de
base et d’obtenir toutes celles qui contiennent des
données utiles sur le 3-nitrophénol. On a trouvé très peu
de données sur cet isomère, ce qui rend impossible une
véritable évaluation. Les données concernant cet
isomère sont donc récapitulées à l’appendice 1. On
trouvera à l’appendice 2 des indications sur le mode
d’examen par des pairs ainsi que sur les sources
documentaires utilisées. Les renseignements concernant
l’examen du CICAD par des pairs font l’objet de l’appen-
dice 3. Ce CICAD a été approuvé en tant qu’évaluation
internationale lors de la réunion du Comité d’évaluation
finale qui s’est tenue à Washington du 8 au 11 décembre
1998. La liste des participants à cette réunion figure à
l’appendice 4. La fiche d’information internationale sur la
sécurité chimique (ICSC No 1342) relative au mélange
d’isomères du nitrophénol, établie par le Programme
international sur la sécurité chimique (IPCS, 1998) est
également reproduite dans ce document.
Les isomères du nitrophénol sont des solides
solubles dans l’eau qui sont légèrement acides dans ce
solvant par suite de leur dissociation. Les isomères 2- et
4- sont utilisés comme intermédiaires dans la synthèse
d’un certain nombre d’insecticides organophosphorés et
de composés à usage médical. Lorsqu’ils passent dans
l’environnement, c’est principalement par suite
d’émissions dans l’eau, l’air et le sol provenant de
sources diffuses comme la circulation automobile ou la
décomposition par photolyse ou hydrolyse de certains
insecticides. Le dépôt par voie sèche ou humide de
nitrophénols présents dans l’atmosphère constitue un
apport supplémentaire dans l’hydrosphère et la géo-
sphère. La formation photo-oxydative du 2- et du 4-
nitrophénol dans l’atmosphère est encore débattue.
Les données disponibles montrent que le 2-nitro-
phénol ne devrait se volatiliser que lentement dans
35
Mononitrophenols
l’atmosphère et qu’il ne passe sans doute qu’en quantité
négligeable de l’eau à l’air selon ce processus. On
constate un enrichissement en 2-nitrophénol de la phase
aqueuse des nuages; en revanche, dans la phase
gazeuse, la proportion de 4-nitrophénol est plus
importante qu’on pourrait le penser en fonction des
données physico-chimiques, par suite d’une importante
fixation du composé sur les particules. Compte tenu de
leur solubilité dans l’eau et de leur concentration dans la
phase gazeuse, on peut s’attendre à ce que les
nitrophénols présents dans l’atmosphère se déposent
par voie humide sur la surface du sol et de l’eau. La
principale voie de transformation du 2-nitrophénol
présent dans l’atmosphère est vraisemblablement sa
nitration rapide en 2,4-dinitrophénol, le 4-nitrophénol
étant quant à lui en majeure partie fixé aux particules
aéroportées et donc disponible en petites quantités
seulement pour des réactions photochimiques. La
majeure partie du 4-nitrophénol devrait d’ailleurs
disparaître de l’atmosphère en se déposant soit par voie
sèche, soit par voie humide. Il ne semble pas que les
nitrophénols contribuent directement à la dégradation de
la couche d’ozone stratosphérique ni au réchauffement
général de la planète. Soumis à une photodécomposition
en milieu aqueux, le 4-nitrophénol a une demi-vie qui
peut aller de 2,8 à 13,7 jours selon les mesures. Les
nombreuses études consacrées à la biodégradation du 2-
et du 4-nitrophénol montrent que ces deux isomères sont
intrinsèquement biodégradables dans l’eau en aérobiose.
La minéralisation des nitrophénols en anaérobiose exige
à l’évidence une importante adaptation des populations
microbiennes.
La valeur du coefficient de sorption par les
particules du sol (K oc), qui se situe entre 44 et 530,
indique que le potentiel de sorption est faible à modéré.
Les nitrophénols qui passent dans le sol vont vraisem-
blablement subir une biodégradation aérobie. Il ne
devrait y avoir infiltration dans les eaux souterraines que
lorsque les conditions ne sont pas favorables à une bio-
dégradation. Pour le 2- et le 4-nitrophénol, la mesure du
facteur de bioconcentration donne des valeurs allant de
11 à 76, ce qui indique un faible potentiel de bioconcen-
tration.
On connaît plutôt mal le profil toxicologique du 2-
et du 4-nitrophénol. Lorsqu’il est administré à des
animaux de laboratoire par voie orale, intraveineuse ou
intrapéritonéale, le 4-nitrophénol est en majeure partie
excrété dans les urines en l’espace de 24 à 48 h sous
forme de glucuronide ou de sulfo-conjugué, une faible
partie seulement passant dans les matières fécale ou
restant inchangée. On a montré que la proportion de
glucuronide et de sulfo-conjugués variait selon les
espèces. Après administration par voie orale à des
Concise International Chemical Assessment Document 20
lapins, le 4-nitrophénol est réduit en p-aminophénol et
subit aussi une transformation en glucuronide et sulfo-
conjugués. Les données tirées des études in vivo et in
vitro donnent une indication sur la résorption du 4-
nitrophénol par la voie transcutanée. En revanche, les
données concernant le 2-nitrophénol sont très limitées.
Quoi qu'il en soit, on peut considérer, en se basant sur
les données disponibles, que les deux isomères ont un
métabolisme comparable. Le 2- et le 4-nitrophénol ne
devraient pas s’accumuler dans l’organisme en raison de
leur métabolisation et de leur excrétion rapides.
Les études de toxicité aiguë montrent que le 4-
nitrophénol a un effet nocif après ingestion et qu’il est
plus toxique que le 2-nitrophénol. Chez des chats, on a
constaté une augmentation du taux de méthémoglobine
liée à la dose après ingestion de 2-nitrophénol; la même
constatation a été faite chez des rats après inhalation de
4-nitrophénol. Une exposition répétée à du 4-nitrophénol
a montré que la formation de méthémoglobine est l’effet
le plus déterminant d’une exposition par la voie
respiratoire et cela vaut sans doute aussi pour la voie
orale. Parmi les autres effets observés, on peut citer un
moindre gain de poids, une modification du poids des
organes, une dégénérescence graisseuse du foie et des
anomalies hématologiques. Il n’a pas été possible de
dégager une véritable relation dose-réponse ni de
déterminer de manière fiable la dose sans effet (nocif)
observable (NO(A)EL) correspondant à ces effets.
Le 2-nitrophénol est légèrement irritant pour la
peau mais il n’irrite pas la muqueuse oculaire. Le test de
Buehler montre que le composé n’a pas non plus d’effet
sensibilisateur. En s’appuyant sur des études valables
effectuées sur l’animal, on peut conclure que le 4-
nitrophénol a par contre une légère action irritante sur la
peau et les yeux. Un test de maximalisation sur le cobaye
a montré que le 4-nitrophénol avait également une légère
action sensibilisatrice. Chez l’homme, on ne peut exclure
une légère sensibilisation après un contact avec le
composé, d’autant plus que la pose d’un timbre cutané
chez des ouvriers pouvant avoir été en contact avec du
4-nitrophénol a permis de constater une telle
sensibilisation.
Aucun des deux isomères n’a fait l’objet
d’épreuves de génotoxicité suffisamment complètes.
S’agissant du 2-nitrophénol, les données sont insuf-
fisantes pour que l’on puisse tirer la moindre conclusion
concernant une mutagénicité éventuelle. Dans le cas du
4-nitrophénol, les études de mutagénicité sont plus
nombreuses, mais le compte rendu en est parfois
insuffisant. On est fondé à penser que ce composé est
susceptible de provoquer des aberrations chromoso-
miques in vitro . Faute d’études de mutagénicité in vivo
36
sur des mammifères, il n’est pas possible de savoir si le
pouvoir mutagène de cet isomère peut s’exprimer in vivo.
Chez la souris l’application cutanée de 4-nitro-
phénol pendant une durée de 78 semaines n’a pas donné
d’indices d’effets cancérogènes. Dans une autre étude
sur la souris, qui présentait toutefois un certain nombre
d’insuffisances, on n’a pas non plus observé de tumeurs
cutanées après application cutanée de ces deux isomères
pendant 12 semaines. Aucune étude de cancérogénicité
utilisant la voie orale ou respiratoire n’était disponible.
Les données relatives au 4-nitrophénol ne révèlent
aucun effet indésirable sur la reproduction ou le
développement qui soit statistiquement significatif après
exposition de rats et de souris par voie orale ou cutanée.
Après administration par voie orale de 2-nitrophénol à
des rats, on a constaté dans la progéniture des animaux
des effets indésirables sur le développement, mais
seulement aux doses toxiques pour les mères. On n’a
toutefois pas recherché la présence de malformations
internes.
La base de données relative au 2-nitrophénol est
extrêmement limitée et celle qui concerne le 4-nitrophénol
est insuffisante pour qu’on puisse en tirer une valeur
fiable de la NO(A)EL. Il est donc impossible de fixer pour
l’instant une valeur pour la dose journalière tolérable
(DJT) ou pour la concentration tolérable (CT) de ces
deux isomères.
D’après les résultats des études toxicologiques
valables effectuées sur divers organismes aquatiques ,
on peut considérer que ces deux nitrophénols sont
modérément à fortement toxiques pour la vie aquatique.
La concentration sans effet la plus faible qui ait été
obtenue lors d’études de longue durée sur des
organismes d’eau douce (Scenedesmus subspicatus,
EC50 à 96 h : 0,39 mg de 2-nitrophénol/litre; Entosiphon
sulcatum, concentration minimale inhibitrice à 72 h ou
CMI : 0,83 mg de 4-nitrophénol/l) était 40 à 50 fois plus
forte que la valeur maximale obtenue dans un bassin
fluvial d’Asie situé dans une zone très industrialisée et
densément peuplée (respectivement 0,0072 mg/l et 0,019
mg/l). Par conséquent, malgré la biodégradation et la
décomposition photochimique, les nitrophénols
déversés dans l’eau peuvent présenter un certain risque
pour les organismes aquatiques sensibles, notamment
dans des eaux superficielles où les conditions ne sont
pas favorables à ces deux modes d’élimination.
Cependant, compte tenu de leurs usages et de leurs
possibilités de libération dans l’environnement, ces deux
nitrophénols ne présentent qu’un risque mineur pour les
organismes aquatiques.
 Mononitrophenols

Les données disponibles indiquent que la toxicité

potentielle de ces nitrophénols est modérée dans l’envi-
ronnement terrestre. Le calcul du rapport d’exposition
toxique (TER) des nitrophénols provenant de la décom-
position de certains pesticides montre que, dans ce
milieu, le risque reste faible pour la faune et la flore,
même dans la pire des hypothèses.

37
Concise International Chemical Assessment Document 20
RESUMEN DE ORIENTACIÓN
Preparó el presente CICAD sobre los isómeros 2-,
3- y 4-nitrofenol el Instituto Fraunhofer de Toxicología y
de Investigación sobre los Aerosoles de Hannover,
Alemania. Se basa en los exámenes compilados por el
Comité Consultivo Alemán sobre las Sustancias
Químicas Importantes para el Medio Ambiente (BUA,
1992) y la Agencia para el Registro de Sustancias
Tóxicas y Enfermedades de los Estados Unidos
(ATSDR, 1992) para evaluar los efectos potenciales del
2- y el 4-nitrofenol en el medio ambiente y en el ser
humano. En estos exámenes se incluyeron los datos
identificados hasta 1992. En 1998 se realizó una
búsqueda bibliográfica amplia de varias bases de datos
para identificar todas las referencias importantes
relativas al 2- y el 4-nitrofenol publicadas con
posterioridad a las que figuran en los documentos
originales y para conocer todas las referencias con datos
pertinentes sobre el isómero 3-nitrofenol. La información
obtenida sobre el 3-nitrofenol fue muy escasa, lo que
impide una evaluación válida. En consecuencia, los
datos sobre este isómero se resumen en el apéndice 1. La
información relativa al carácter del examen colegiado y a
la disponibilidad de los documentos originales figura en
el apéndice 2. La información sobre el examen colegiado
de este CICAD se presenta en el apéndice 3. Este CICAD
se aprobó como evaluación internacional en una reunión
de la Junta de Evaluación Final celebrada en
Washington, DC, Estados Unidos, los días 8-11 de
diciembre de 1998. La lista de participantes en esta
reunión figura en el apéndice 4. La Ficha internacional de
seguridad química (ICSC 1342) para las mezclas de
isómeros de nitrofenoles, preparada por el Programa
Internacional de Seguridad de las Sustancias Químicas
(IPCS, 1998), también se reproduce en el presente
documento.
Los isómeros del nitrofenol son sólidos hidro-
solubles con una acidez moderada en agua debido a la
disociación. El 2-nitrofenol y el 4-nitrofenol se utilizan
como intermediarios en la síntesis de diversos
plaguicidas órganofosforados y algunos productos
médicos. La liberación en el medio ambiente se produce
fundamentalmente por emisiones en el aire, el agua y el
suelo a partir de fuentes difusas, como el tráfico de
vehículos y la degradación hidrolítica y fotolítica de los
respectivos plaguicidas. También se produce liberación
en la hidrosfera y la geosfera a partir de la atmósfera
debido a la deposición seca y húmeda de nitrofenoles
suspendidos en el aire. La formación fotooxidativa de 2-
y 4-nitrofenol en la atmósfera es todavía objeto de
estudio.
38
Con los datos disponibles sólo cabe esperar una
volatilización lenta desde el agua hacia el aire para el 2-
nitrofenol y no significativa para el 4-nitrofenol. El 2-
nitrofenol se enriquece en la fase líquida de las nubes,
mientras que es posible encontrar más 4-nitrofenol del
previsto a partir de los datos fisicoquímicos en la fase
gaseosa de las nubes, debido a una amplia unión a
partículas. Habida cuenta de la solubilidad en agua y la
presencia prevista en la fase de vapor, cabe esperar una
deposición húmeda de nitrofenoles del aire en las aguas
superficiales y en el suelo. La vía principal de trans-
formación del 2-nitrofenol emitido a la troposfera debe
ser la nitración rápida a 2,4-dinitrofenol, mientras que se
supone que la mayor parte del 4-nitrofenol suspendido
en el aire se encuentra unido a partículas y, por con-
siguiente, disponible solamente en menor cantidad para
reacciones fotoquímicas. La mayor parte del 4-nitrofenol
del aire debe precipitar por deposición húmeda y seca.
No se considera que los nitrofenoles contribuyan
directamente al agotamiento de la capa de ozono
estratosférico o al calentamiento mundial. La semivida
medida para la descomposición fotoquímica del 4-
nitrofenol en agua osciló entre 2,8 y 13,7 días. Numero-
sos estudios sobre la biodegradación del 2- y el 4-
nitrofenol indican que los isómeros son inherentemente
biodegradables en agua en condiciones aerobias. La
mineralización de los nitrofenoles en condiciones
anaerobias requiere evidentemente una amplia adap-
tación de las comunidades microbianas.
Los coeficientes de sorción en el suelo (K oc)
medidos del orden de 44-530 indican un potencial de
bajo a moderado para la sorción en el suelo. Los
nitrofenoles liberados al suelo se deben biodescomponer
en condiciones aerobias. Cabe prever filtración hacia el
agua freática sólo en condiciones desfavorables para la
biodegradación. Para el 2- y el 4-nitrofenol, los factores
de bioconcentración medidos de 11 a 76 ponen de
manifiesto un potencial bajo de bioacumulación.
Se dispone sólo de información limitada relativa a
los perfiles toxicológicos del 2- y el 4-nitrofenol. Los
animales experimentales a los que se administró 4-
nitrofenol por vía oral, intravenosa o intraperitoneal
excretaron la mayor parte de la dosis aplicada por vía
urinaria en un plazo de 24-48 horas en forma de conju-
gados de glucurónidos y sulfatos, mientras que por las
heces se excretaron solamente cantidades muy
pequeñas, o bien como 4-nitrofenol inalterado. Se
observó que los porcentajes de conjugados de
glucurónidos y sulfatos eran dependientes de la especie
y de la dosis. Tras la administración oral a conejos, el 4-
nitrofenol sufre una reducción a p-aminofenol, así como
una glucuronización y sulfatación. Los datos
disponibles de estudios in vivo e in vitro dan una idea

de la absorción cutánea del 4-nitrofenol. Los datos para
el 2-nitrofenol son muy limitados. Sin embargo, teniendo
cuenta los datos disponibles, se supone que se produce
una transformación metabólica comparable. No cabe
prever bioacumulación de 2- y 4-nitrofenol en los
organismos debido a la rapidez de su metabolismo y
excreción.
En estudios de toxicidad aguda, el 4-nitrofenol es
perjudicial tras la absorción oral, y se observó que era
más tóxico que el 2-nitrofenol. Se detectó un aumento en
la formación de metahemoglobina dependiente de la
dosis en gatos tras la exposición oral al 2-nitrofenol y en
ratas tras la exposición por inhalación al 4-nitrofenol.
Después de una exposición repetida al 4-nitrofenol, se
observó la formación de metahemoglobina como el
efecto final más importante de la exposición por
inhalación, y se considera que esto es aplicable también
a la exposición oral. Otros efectos observados fueron la
reducción del aumento del peso corporal, diferencias en
el peso de los órganos, degeneración adiposa focal del
hígado y cambios hematológicos. Para esos efectos no
fue posible determinar una relación clara dosis-respuesta
o concentraciones sin efectos (adversos) observados
(NO(A)EL) fidedignas.
El 2-nitrofenol es ligeramente irritante para la piel,
pero no para los ojos. En una prueba de Buehler no se
observó efecto sensibilizador. Tomando como base los
estudios válidos con animales experimentales, se supone
que el 4-nitrofenol tiene efectos irritantes en la piel y los
ojos. En una prueba de maximización en cobayas, se
observó que el 4-nitrofenol era ligeramente sensibili-
zante. En el ser humano no se puede excluir una posible
sensibilización tras el contacto con 4-nitrofenol,
especialmente teniendo en cuenta que se ha observado
sensibilización cutánea en pruebas de parche en
trabajadores de fábricas que podían haber estado
expuestos al 4-nitrofenol.
No se ha sometido a pruebas completas de
genotoxicidad ninguno de los dos isómeros del
nitrofenol. Los datos disponibles sobre el 2-nitrofenol
son insuficientes para poder sacar conclusiones acerca
de su posible mutagenicidad. Hay más estudios de
mutagenicidad para el 4-nitrofenol, aunque algunos se
notificaron de manera inadecuada. Hay pruebas que
parecen indicar que el 4-nitrofenol puede producir
aberraciones cromosómicas in vitro . En ausencia de
estudios de mutagenicidad in vivo en mamíferos, no es
posible llegar a la conclusión de si se expresa o no in
vivo el potencial mutagénico del 4-nitrofenol.
Tras la aplicación cutánea de 4-nitrofenol a
ratones durante 78 semanas no se observaron efectos
39
Mononitrophenols
carcinogénicos. En otro estudio con ratones, que tiene
varias limitaciones, no se detectaron tumores cutáneos
tras la aplicación en la piel de 2- ó 4-nitrofenol durante 12
semanas. Para ninguno de los isómeros había estudios
de carcinogenicidad utilizando la vía oral o la inhalación.
Los datos disponibles para el 4-nitrofenol no
pusieron de manifiesto efectos específicos o estadística-
mente significativos de toxicidad reproductiva o del
desarrollo tras la administración cutánea u oral a ratas y
ratones. En un estudio de administración por vía oral a
ratas, el 2-nitrofenol indujo efectos en el desarrollo de la
camada sólo con dosis que también producían toxicidad
materna. Sin embargo, en estos estudios no se examin-
aron los fetos para investigar malformaciones internas.
La base de datos para el 2-nitrofenol es
enormemente limitada y la relativa al 4-nitrofenol es
insuficiente para deducir valores fidedignos de la
(NO(A)EL). Por consiguiente, es imposible determinar en
este momento la ingesta diaria tolerable o las
concentraciones tolerables para el 2- ó el 4-nitrofenol.
De los resultados disponibles de pruebas válidas
sobre la toxicidad del 2-y el 4-nitrofenol para diversos
organismos acuáticos, los nitrofenoles se pueden
clasificar como sustancias con una toxicidad entre
moderada y alta en el compartimento acuático. Las
concentraciones más bajas con efectos obtenidas en
estudios crónicos con organismos de agua dulce
(Scenedesmus subspicatus, CE50: 0,39 mg de 2-nitro-
fenol/litro a las 96 h; Entosiphon sulcatum, concentra-
ción inhibitoria mínima a las 72 horas: 83 mg de 4-
nitrofenol/litro) fueron 40-50 veces superiores a los
niveles máximos determinados en una cuenca fluvial
asiática densamente poblada y muy industrializada
(0,0072 mg de 2-nitrofenol/litro y 0,019 mg de 4-nitro-
fenol/litro). Por consiguiente, a pesar de la descomposi-
ción biótica y fotoquímica, los nitrofenoles emitidos al
agua pueden representar algún peligro para los organis-
mos acuáticos sensibles, particularmente en las condici-
ones de las aguas superficiales que no favorecen ambas
vías de eliminación. Habida cuenta de sus pautas de uso
y sus características de liberación, probablemente los
nitrofenoles plantean sólo un pequeño riesgo para los
organismos acuáticos.
Los datos disponibles indican solamente una
toxicidad potencial moderada de los nitrofenoles en el
medio ambiente terrestre. A partir de los cálculos de la
razón exposición-toxicidad de los nitrofenoles a partir de
la degradación de plaguicidas, sólo cabe esperar un
pequeño riesgo para los organismos en este comparti-
mento, incluso en el peor de los casos.