Mononitrophenols: Concise International Chemical Assessment Document 20

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
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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)

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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
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
Mononitrophenols
FOREWORD While every effort is made to ensure that CICADs

represent the current status of knowledge, new
Concise International Chemical Assessment information is being developed constantly. Unless
Documents (CICADs) are the latest in a family of otherwise stated, CICADs are based on a search of the
publications from the International Programme on scientific literature to the date shown in the executive
Chemical Safety (IPCS) — a cooperative programme of summary. In the event that a reader becomes aware of
the World Health Organization (WHO), the International new information that would change the conclusions
Labour Organisation (ILO), and the United Nations drawn in a CICAD, the reader is requested to contact
Environment Programme (UNEP). CICADs join the IPCS to inform it of the new information.
Environmental Health Criteria documents (EHCs) as
authoritative documents on the risk assessment of Procedures
chemicals.
The flow chart shows the procedures followed to
CICADs are concise documents that provide produce a CICAD. These procedures are designed to
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conclusions drawn. that developed the original review. A standard outline
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The primary objective of CICADs is The first draft undergoes primary review by IPCS to
characterization of hazard and dose–response from ensure that it meets the specified criteria for CICADs.
exposure to a chemical. CICADs are not a summary of all
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include only that information considered critical for review by scientists known for their particular expertise
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of exposure. Responsible authorities are strongly
encouraged to characterize risk on the basis of locally The CICAD Final Review Board has several
measured or predicted exposure scenarios. To assist the important functions:
reader, examples of exposure estimation and risk
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possible. These examples cannot be considered as an appropriate and thorough peer review;
representing all possible exposure situations, but are – to verify that the peer reviewers’ comments have
provided as guidance only. The reader is referred to EHC been addressed appropriately;
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guidance values. 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
1
International Programme on Chemical Safety (1994)
– to approve CICADs as international assessments.
Assessing human health risks of chemicals: derivation
of guidance values for health-based exposure limits.
Board members serve in their personal capacity, not as
Geneva, World Health Organization (Environmental
representatives of any organization, government, or
Health Criteria 170).
1
CICAD PREPARATION FLOW CHART
SELECTION OF PRIORITY CHEMICAL
SELECTION OF HIGH QUALITY

NATIONAL/REGIONAL
ASSESSMENT DOCUMENT(S)
FIRST DRAFT
PREPARED
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( 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
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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,

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

78 weeks gave no indication of carcinogenic effects. In 2-Nitrophenol (CAS No. 88-75-5; 2-hydroxy-1-
another study with mice, which has several limitations, nitrobenzene, o-nitrophenol) and 4-nitrophenol (CAS
no skin tumours were noted after dermal application of 2- No. 100-02-7; 4-hydroxy-1-nitrobenzene, p-nitrophenol)
or 4-nitrophenol over 12 weeks. Carcinogenicity studies share the empirical formula C6H5NO3. Their structural
using the oral or inhalation routes were not available for formulas are shown below.
either of the isomers.
OH OH
For 4-nitrophenol, the available data gave no
evidence of specific or statistically significant reproduc- NO2
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 NO2
examined for internal malformations.
2-nitrophenol 4-nitrophenol
The database for 2-nitrophenol is extremely limited,
and the database for 4-nitrophenol is insufficient for Technical-grade 2- and 4-nitrophenol from the
deriving reliable NO(A)EL values. Therefore, at present, German producer have a typical purity of >99%. Named
no tolerable daily intakes (TDIs) or tolerable con- impurities are the corresponding isomer for each product
centrations (TCs) can be derived for either 2- or 4-nitro- (0.3%) and traces of 3-nitrochlorobenzene (<0.05%).
phenol. Polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/
5
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); # acid hydrolysis of the glucuronide with
(3) Verschueren (1983); (4) Koerdel et al. (1981); subsequent derivatization for blood and urine
(5) Sewekow (1983); (6) Andrae et al. (1981); (7) BUA (1992);
samples or denaturation (Nasseredine-Sebaei et al.,
(8) Schwarzenbach et al. (1988); (9) Weast (1979)
1993; Thompson et al., 1996).
Additional physicochemical properties for The detection limits are <10 ng/m3 for air, 0.03–
mononitrophenols are presented in the International 10 :g/litre for water, and 200–1600 :g/kg for soil. A
Chemical Safety Card (ICSC 1342) reproduced in this detection limit for the determination of the nitrophenol
document. 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
Mononitrophenols
Within the European Union, 2- and 4-nitrophenol and to about 2% at normal motor load (Tremp et al.,
are produced mainly by three companies. Six other large 1993). A rough estimation combining the above-
manufacturers are known in the USA and Japan (as of mentioned exhaust gas concentrations with estimations
1989). In 1983, the production volume for Western of the total exhaust gas volumes from vehicle traffic for
Europe was estimated at about 6400 t 2-nitrophenol and Germany resulted in an airborne nitrophenol load of at
about 20 500 t 4-nitrophenol. In 1988–89, the German least several tonnes per year from this source (BUA,
production volumes originating from one manufacturer 1992). Data concerning nitrophenol releases from other
were approximately 500 t 2-nitrophenol and about 2000 t combustion processes (heating, burning of refuse) were
4-nitrophenol, with about 20 t of each being exported. not identified.
Both 2- and 4-nitrophenol are intermediates in the
synthesis of azo dyes and a number of pesticides, mainly From laboratory experiments, there is some
insecticides (2-nitrophenol: carbofuran, phosalon; 4- evidence that 2- and 4-nitrophenol are generated in the
nitrophenol: parathion, parathion-methyl, fluorodifen) atmosphere during the photochemical degradation of
and, to a lesser extent, herbicides (4-nitrophenol: aromatic compounds such as benzene and toluene in the
nitrofen, bifenox). The corresponding aminophenols that presence of nitric oxide or hydroxyl radicals and nitrous
are gained by reduction are used as a photographic dioxide. These results were at least partly obtained in
developer (2-aminophenol) and as an intermediate in the model experiments with unrealistically high nitric oxide
synthesis of the tuberculostatic 4-aminosalicylic acid concentrations, and there are competing reactions with-
and the analgesic 4-acetaminophenol (paracetamol) (4- out nitrophenol formation for which the rate constant is
aminophenol) (see also Booth, 1991). In the 1980s, the not known (BUA, 1992). However, smog chamber
production volumes for 2- and 4-nitrophenol showed a experiments confirmed the formation of nitrophenol
decreasing tendency in Germany as a result of changes isomers during irradiation (Leone & Seinfeld, 1985;
in and termination of the production of some organo- Leone et al., 1985). Recent cloud water model experi-
phosphorus pesticides. ments showed that 2- and 4-nitrophenol are also formed
from the reaction of phenol with nitrogen pentoxide or
The releases of 2- and 4-nitrophenol during pro- monochloronitrogen dioxide, especially under alkaline
duction and processing at the only German manufacturer conditions (Scheer et al., 1996). Estimations of the
appear to be of minor importance. In 1988–89, about contribution of photochemically formed nitrophenols to
2.5 kg 2-nitrophenol and 10 kg 4-nitrophenol were total emissions into the atmosphere are not possible with
emitted to air, and #93 kg 2-nitrophenol and <64 kg 4- the available data.
nitrophenol were emitted to surface water.
Significant releases of 4-nitrophenol into the
For 1996, the following releases of 2- and 4-nitro- hydrosphere may occur from the hydrolytic degradation
phenol to the environment were reported by manufac- of the insecticides parathion and parathion-methyl and
turers in the USA (TRI, 1998): — although to a lesser extent — from the photolytic
degradation of the herbicides nitrofen and bifenox.
# 2-nitrophenol: from three manufacturers (one Quantification of releases is not possible with the avail-
production site each) with production volumes able data. Furthermore, a considerable portion of air-
between 450 and 45 000 kg/year, total releases of 15 borne nitrophenols, especially 4-nitrophenol, can be
kg to air and 23 kg into water were reported. released to the hydrosphere and the geosphere by wet
and dry deposition (see section 5) (Herterich & Herr-
# 4-nitrophenol: from three manufacturers (six mann, 1990; Luettke et al., 1997). Numerous studies
production sites) with production volumes of concerning the concentrations of 2- and 4-nitrophenol in
45–450 kg/year up to 45 000–450 000 kg/year, a wet deposition samples are available (see section 6.1).
total release of 420 kg to air was reported. Data on From precipitation data (average 746 mm rain per year for
releases into water were not given. land masses, according to Baumgartner & Liebscher,
1990) and the measured concentrations of 2- and 4-
2-Nitrophenol and 4-nitrophenol have been nitrophenol in rainwater, the release of nitrophenols via
detected in the exhaust gases of light-duty gasoline and rain can be estimated to be at least in the order of several
diesel vehicles. Depending on the motor load, the thousand tonnes per year on a global basis.
exhaust concentrations of the isomers were <50 :g/m3
exhaust gas (idle) and about 1000 :g 4-nitrophenol/m3 The application of the herbicides nitrofen and
and 2000 :g 2-nitrophenol/m3 (driving at constant bifenox, which are photolytically degraded to 4-nitro-
velocity) (Nojima et al., 1983; Tremp et al., 1993). A phenol in aqueous solutions, may especially lead to
regulated three-way catalytic converter reduced the emissions into the geosphere and the biosphere. Further,
nitrophenol emissions to about 8% at high motor load nitrophenol-contaminated rain, snow, and other wet and
7
dry deposition may contribute to nitrophenol levels in From experimental results on direct photodegrada-
soils. Data concerning the release of nitrophenols into tion (Koerdel et al., 1981) and the atmospheric photo-
the biosphere are not available. 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-
5. ENVIRONMENTAL TRANSPORT, nitrophenol should be rapid nitration to 2,4-dinitrophe-
DISTRIBUTION, AND TRANSFORMATION 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
Environmental releases of nitrophenols are mostly available for photochemical reactions. Thus, most of the
to ambient air, surface waters, and — to a smaller extent 4-nitrophenol can be washed out from air by wet and dry
— soil. Using a non-steady-state equilibrium model, the deposition. Measured half-lives for the photochemical
following distribution of 4-nitrophenol in different envi- decomposition of 4-nitrophenol in water exposed to
ronmental compartments was predicted: air, 0.0006%; sunlight ranged from 2.8 to 13.7 days (Hustert et al.,
water, 94.6%; sediment, 4.44%; soil, 0.95%; biota, 1981; Mansour, 1996), being longer with increasing pH
0.000 09% (Yoshida et al., 1983). The distribution pat- (Hustert et al., 1981). Traces of 4-aminophenol were
terns of 2- and 4-nitrophenol sprayed on a natural soil in found as a photoproduct in river water (Mansour, 1996).
a standardized terrestrial ecosystem were determined via In experiments conducted according to OECD guide-
radiotracer technique (14C). Of the applied radioactivity lines, Andrae et al. (1981) and Koerdel et al. (1981) found
(2-nitrophenol/4-nitrophenol), 49.45%/20.01% was no hydrolysis of 2- or 4-nitrophenol under environmental
recovered in air, 27.38%/40.21% in soil (including conditions.
animals), 12.73%/7.57% in plants, and 0.05%/0.02% in
leachate (Figge et al., 1985). Distribution of 4-nitrophenol Numerous studies on the biodegradation of 2- and
in a terrestrial microcosm chamber with artificial soil 4-nitrophenol have been conducted. Standardized tests
largely corresponded to this result (Gile & Gillett, 1981). on ready or inherent biodegradability provide data of
Owing to the expected decomposition within the incuba- large variability, indicating 2- and 4-nitrophenol to be
tion periods of 30 and 28 days, respectively, it can be inherently biodegradable under aerobic conditions
assumed that most of the recovered radioactivity referred (depending on origin and density of inoculum and the
to breakdown products of the applied nitrophenols. applied test method) (see Table 2). Results from different
tests point to a possible bacteriotoxic effect of 4-
In volatility experiments conducted according to nitrophenol at concentrations above 300 mg/litre (Gerike
Organisation for Economic Co-operation and Develop- & Fischer, 1979; Nyholm et al., 1984; Kayser et al., 1994).
ment (OECD) guidelines, half-lives of 2-nitrophenol in
water ranged from 14.5 to 27.3 days, indicating a slow Non-standardized experiments with different
rate of volatilization (Koerdel et al., 1981; Rippen et al., inocula (e.g., natural water, soil, sediment) showed that
1984; Scheunert, 1984; Schoene & Steinhanses, 1984). microbial decomposition of nitrophenols can occur in
Measurements concerning the partitioning between the different environmental compartments after adaptation of
gas and liquid phases of clouds during different rain the microflora (Rubin et al., 1982; Subba-Rao et al., 1982;
events showed that 2-nitrophenol is enriched in the Van Veld & Spain, 1983; Spain et al., 1984; Ou, 1985;
liquid phase to a larger extent than would be predicted Hoover et al., 1986; Aelion et al., 1987; Wiggins et al.,
from its water solubility and vapour pressure. On the 1987). Time for acclimation and degree of removal
other hand, 4-nitrophenol is extensively adsorbed to depended mostly on substance concentration, microbial
particles. Therefore, elevated levels of this isomer are population, climate, and additional substrates.
detected in the gaseous phase of clouds (Luettke et al.,
1997). From the available data, a significant volatilization Biotic degradation of nitrophenols under anaerobic
of 4-nitrophenol from water to air is not expected. Since conditions requires extended acclimatization of microbial
nitrophenols dissociate in aqueous solution, volatiliza- communities. In tests with sewage sludge and sludge
tion may further decrease with increasing pH in surface from the primary anaerobic stage of a municipal sewage
waters. This leads to the conclusion that dry and wet treatment plant, respectively, initial 2- and 4-nitrophenol
deposition of nitrophenols from air to surface waters and concentrations in the range of 96.5–579 mg/litre were not
soil are to be expected. The occurrence of this partition degraded at all within 7–60 days (Wagner & Braeutigam,
mechanism is supported by the detection of 2- and 4- 1981; Battersby & Wilson, 1989). Boyd et al. (1983)
nitrophenol in rainwater and wet deposition samples (see found complete anaerobic removal of 50 mg/litre for all
section 6.1). nitrophenol isomers within 1 week, but complete
8
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 and from 56 to 530 (4-nitrophenol) (Boyd, 1982; Broecker
period was extended to 10 weeks. Anaerobic degradation et al., 1984; Koerdel et al., 1984; Løkke, 1984; Marquart et
even of high initial nitrophenol concentrations was al., 1984). Nitrophenols emitted to soil are expected to be
found by Tseng & Lin (1994), who observed >90% biodecomposed under aerobic conditions. Infiltration
removal of 2- and 4-nitrophenol (350–650 mg/litre) in a into groundwater is expected only under conditions
biological fluidized bed reactor with three different kinds unfavourable for biodegradation (e.g., anaerobic
of wastewater. From the available results, a slow conditions). From the available experimental results,
degradation of nitrophenols under anaerobic conditions nitrophenols have to be classified as substances with a
by adapted microorganisms can be expected. 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
to 24.4 were determined for 2-nitrophenol in a semistatic these concentration ranges (Herterich & Herrmann, 1990;
test system with zebra fish (Brachydanio rerio) (Koerdel Levsen et al., 1990; Richartz et al., 1990; Capel et al., 1991;
et al., 1984); in a flow-through experiment, Geissler & Schoeler, 1993; Levsen et al., 1993; Luettke et
bioconcentration factors ranged from 30 to 76 for al., 1997). The 2-nitrophenol levels are mostly below or
common carp (Cyprinus carpio), including possible slightly above the detection limit (i.e., <0.1 :g/litre),
conjugates (Broecker et al., 1984). In static tests, whereas mean 4-nitrophenol concentrations of about 5
accumulation factors for 4-nitrophenol of 11 for the :g/litre rainwater and cloud water and 20 :g/litre fog
green alga Chlorella fusca after 1 day (Geyer et al., 1981) water were detected. The nitrophenol concentrations in
and 57 for the freshwater golden orfe (Leuciscus idus fog are significantly higher than those in rainwater or
melanotus) after 3 days of exposure were determined cloud water owing to the higher droplet surface and
(Freitag et al., 1982). Zebra fish exposed in tap and river longer residence times of the droplets in air compared
water nearly completely eliminated the accumulated 14C- with rain. The lower concentrations of 2-nitrophenol in
4-nitrophenol within 48 h (Ensenbach & Nagel, 1991). the deposition samples compared with 4-nitrophenol are
Star fish (Pisaster ochraceus) and sea urchin presumably due to the lower photochemical stability of
(Strongylocentrotus purpuratus) eliminated 89% and this compound (see section 5).
36%, respectively, of injected 14C-4-nitrophenol (3.48 and
3.70 mg/kg body weight, respectively) within 8 h In the 1970s and early 1980s, the 2- and 4-nitro-
(Landrum & Crosby, 1981). 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-
6. ENVIRONMENTAL LEVELS AND nese surface waters (detection limits 0.04–10 :g/litre) or
HUMAN EXPOSURE 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
6.1 Environmental levels was not detected in 129 fish samples (detection limits
0.005–0.2 :g/kg) in Japan in 1979 and 1994, 2-nitro-
From the concentrations in rainwater, the total phenol was detected in 1 out of 129 saltwater fish
atmospheric nitrophenol pollution in Switzerland is samples (detection limits 0.005–0.3 :g/kg) in 1994 (Japan
estimated at about 1 :g/m3 (Leuenberger et al., 1988). Environment Agency, 1980, 1995). 2-Nitrophenol
Recent measurements in the air of remote areas in Europe concentrations between <0.15 :g/litre (detection limit)
(German Alps, Fichtelgebirge, Germany; Mount Brocken, and 7.2 :g/litre and 4-nitrophenol levels between <0.1
Germany; Great Dun Fell summit, United Kingdom) gave and 18.8 :g/litre were reported for the densely populated
2-nitrophenol concentrations between 0.8 and 25 ng/m3 and highly industrialized Malaysian Klang river basin in
and 4-nitrophenol levels between 1.2 and 360 ng/m3 1990 and 1991 (Tan & Chong, 1993).
(Herterich & Herrmann, 1990; Luettke et al., 1997). The
higher atmospheric 4-nitrophenol levels are apparently 6.2 Human exposure
due to the higher photochemical stability of this isomer
(see section 5). 2-Nitrophenol was found in 22 out of 27 Workers may be exposed to 2- and 4-nitrophenol
samples of air (range 1–140 ng/m3; detection limit 1 via inhalation and skin contact during production and
ng/m3) in Japan in 1994, and 4-nitrophenol was detected processing (mainly in the manufacturing of pesticides).
in 27 out of 27 air samples (range 1–71 ng/m3; detection However, data on nitrophenol concentrations at the
limit 1 ng/m3) (Japan Environment Agency, 1995). In workplace were not identified.
street dust samples from a Japanese city, up to 3.9 mg 2-
nitrophenol/kg and up to 42 mg 4-nitrophenol/kg were Based on the measured concentrations given in
detected (Nojima et al., 1983). section 6.1, an exposure of the general population to
nitrophenols via the environment — predominantly
Numerous studies deal with the distribution, depo- through ambient air and drinking-water — cannot be
sition, and degradation behaviour of airborne 2- and 4- excluded.
nitrophenol in clouds and rainwater. 2-Nitrophenol levels
in rainwater and snow between 0.03 and 5.7 :g/litre and 4-Nitrophenol accumulates in fog, whereas 2-
4-nitrophenol concentrations from <0.5 to 19 :g/litre are nitrophenol is rapidly photochemically transformed (see
given in reports mainly from Germany and the USA sections 5 and 6.1). The mean measured level of 4-
(BUA, 1992). The recent measurements in rainwater, nitrophenol in fog water is about 20 :g/litre.
cloud water, and “fog” (water vapour; not further char-
acterized) from rural and urban areas in Europe confirm
10
Mononitrophenols
In Dutch drinking-water samples, maximum con- nitrophenyl glucoside was identified as a minor
centrations of 1 :g 2-nitrophenol/litre and <0.1 :g metabolite of 4-nitrophenol (about 1–2% of the
4-nitrophenol/litre were reported in 1988 (BUA, 1992). administered dose) (Gessner & Hamada, 1970).
Further data are not available.
For 4-nitrophenol, the pretreatment of laboratory
animals with ethanol (induction of cytochrome P-450)
resulted in a marked increase in hepatic microsomal
7. COMPARATIVE KINETICS AND hydroxylation. The 4-nitrocatechol then formed com-
METABOLISM IN LABORATORY ANIMALS peted with 4-nitrophenol for the glucuronidation and
AND HUMANS sulfation pathways (Reinke & Moyer, 1985; Koop, 1986;
McCoy & Koop, 1988; Koop & Laethem, 1992).
Studies providing quantitative information on the Specific investigations on dermal resorption under
absorption, metabolism, or elimination of 2- or 4-nitro- non-occlusive conditions showed dermal uptake of
about 35% and 11% of the applied dose of 14C-4-nitro-
phenol in humans were not identified.
phenol within 7 days in rabbits and dogs, respectively.
Skin permeation for 4-nitrophenol was also shown in
7.1 2-Nitrophenol
several in vitro experiments (Huq et al., 1986; Jetzer et al.,
1986; Ohkura et al., 1990).
There is only very limited information available for
2-nitrophenol. In rabbits given a single dose of
Owing to its rapid metabolism and excretion,
200–330 mg/kg body weight via gavage, most of the
bioaccumulation of 4-nitrophenol in organisms is not to
applied dose (o80%) was excreted via the urine within 24
be expected.
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 8. EFFECTS ON LABORATORY

several in vitro experiments (Huq et al., 1986; Jetzer et al., MAMMALS AND IN VITRO TEST SYSTEMS
1986; Ohkura et al., 1990).
Although the information is limited, bioaccumula- 8.1 Single exposure

tion of 2-nitrophenol in organisms is not to be expected
owing to its rapid metabolism and excretion. For 2-nitrophenol, the oral LD 50 is in the range of
2830–5376 mg/kg body weight in rats (BASF AG, 1970;
7.2 4-Nitrophenol Vasilenko et al., 1976; Vernot et al., 1977; Koerdel et al.,
1981) and 1300–2080 mg/kg body weight in mice
After oral, dermal, intravenous, or intraperitoneal (Vasilenko et al., 1976; Vernot et al., 1977). Clinical signs
application of 4-nitrophenol to several test species (rats, following oral exposure were unspecific and included
mice, dogs, or rabbits), most of the applied dose (up to dyspnoea, staggering, trembling, somnolence, apathy,
95%) was excreted as glucuronide and sulfate conjugates and cramps. The macroscopic examination performed in
of 4-nitrophenol via the urine within 24–48 h. Only small some studies revealed congestion in liver and kidneys
amounts were excreted via faeces (about 1%) or as and ulcers of the stomach in high-dose rats. The
unchanged 4-nitrophenol (about 2–7%). The inhalation exposure of rats to an atmosphere saturated
percentages of glucuronide and sulfate conjugates were with the test substance at 20 °C for 8 h (no further
shown to be species, sex, and dose dependent. information available) resulted in no mortality and no
Although sulfate conjugation dominates at lower 4- signs of toxicity (BASF AG, 1970). In a limit test, the
nitrophenol concentrations, the percentage of dermal LD 50 for the rat was >5000 mg/kg body weight
glucuronide conjugates increases at higher dosages (Koerdel et al., 1981). In cats (two animals per dose
(Robinson et al., 1951; Gessner & Hamada, 1970; group), the oral application of 2-nitrophenol (50, 100, or
Machida et al., 1982; Rush et al., 1983; Snodgrass, 1983; 250 mg/kg body weight; no controls) resulted in a dose-
Tremaine et al., 1984; Meerman et al., 1987). As shown in dependent increase in methaemoglobin (6, 44, and 57%,
rabbits after oral dosing, 4-nitrophenol undergoes respectively).1 One animal dosed with 250 mg/kg body
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 1
Methaemoglobin formation is discussed in greater
al., 1951). After intraperitoneal administration in mice, 4- detail in section 8.8.
11
weight died. No formation of methaemoglobin was given; Hoechst AG, 1977c). Results with the non-
detected after dermal application of a 50% solution of 2- dissolved substance were either strongly irritating in a
nitrophenol in water to rabbits (dose not specified, test conducted according to FDA guidelines (scores not
exposure time 1 min to 20 h on the back or 20 h on the given; Hoechst AG, 1977c) or slightly irritating in a test
ear) (BASF AG, 1970). comparable to OECD Guideline 405 (score 1–2 of 4;
Andrae et al., 1981).
The oral LD 50 of 4-nitrophenol is in the range of
220–620 mg/kg body weight in rats (BASF AG, 1969; In a guinea-pig maximization test comparable to
Vasilenko et al., 1976; Hoechst AG, 1977a; Vernot et al., OECD Guideline 406, skin sensitization was shown in 5
1977; Andrae et al., 1981) and 380–470 mg/kg body of 20 animals (Andrae et al., 1981).
weight in mice (Vasilenko et al., 1976; Vernot et al., 1977).
Clinical signs following oral exposure of rats were Data on respiratory tract sensitization for 2- and 4-
unspecific and included tachypnoea and cramps, and the nitrophenol were not identified in the literature.
macroscopic examination performed in some studies
revealed a greyish discoloration with dark red patches of 8.3 Short-term exposure
the lungs. No mortality was observed in rats after single
exposure (head only) to 4700 mg/m3 (application as dust 8.3.1 Oral exposure
[sodium salt]; particle size not given) for 4 h. In four of
six rats, a corneal opacity was observed at the end of The effect of 2-nitrophenol in rats was studied in a
exposure, which persisted through the 14-day 28-day study to evaluate OECD Guideline 407 (five
observation period. In two extra rats exposed to animals per sex per dose group; daily oral doses of 0, 22,
1510 mg/m3, the methaemoglobin concentrations were 67, or 200 mg/kg body weight via gavage). Food intake
not altered compared with controls. A determination of decreased in high-dose males and in mid- and high-dose
methaemoglobin concentrations after exposure to females, and final body weight decreased non-signifi-
4700 mg/m3 was not performed (Smith et al., 1988). In cantly in all dosed animals. The absolute liver and kid-
another inhalation study with rats (exposure to an ney weights were decreased in mid-dose animals, and
atmosphere saturated with the test substance at 20 °C for the relative testes weight increased in low- and mid-dose
8 h; no further information available), no mortality and males and decreased in high-dose males. In all dosed
no signs of toxicity were seen (BASF AG, 1969). The animals, the relative and absolute weights of the adrenal
dermal LD 50 for rats and guinea-pigs is $1000 mg/kg glands increased. The haematological examination,
body weight (Hoechst AG, 1977b; Eastman Kodak Co., clinical chemistry, and histopathological examination of
1980; Andrae et al., 1981). In contrast to 2-nitrophenol, the major organs and tissues did not give any indication
no formation of methaemoglobin was noted in cats (two of a substance-related toxic effect in comparison with
animals per dose group) after oral dosing with 100, 200, controls (Koerdel et al., 1981). Owing to insufficient
or 500 mg 4-nitrophenol/kg body weight. The mortality documentation and the fact that there were minor effects
rate was 0/2, 1/2, and 2/2, respectively (BASF AG, 1969). (weight of adrenal glands) shown by all exposed animals,
a reliable NO(A)EL cannot be deduced.
8.2 Irritation and sensitization
In a 28-day study that was also conducted to eval-
From studies comparable to OECD Guidelines 404 uate OECD Guideline 407, Sprague-Dawley rats (10 per
and 405, it can be concluded that 2-nitrophenol is sex per dose group) received daily oral doses of 0, 70,
slightly irritating to the skin but not to the eye (scores 210, or 630 mg 4-nitrophenol/kg body weight via gavage.
not given). In a Buehler test with guinea-pigs compa- After dosing, locomotor inhibition, which lasted for
rable to OECD Guideline 406, the substance showed no about 2 h, was seen in mid- and high-dose animals. In
skin-sensitizing effects (Koerdel et al., 1981). mid-dose animals, 1/10 males died; in high-dose males
and females, the mortality rate was 4/10 and 6/10, respec-
In a study performed according to US Food and tively (specific signs of intoxication were not given). In
Drug Administration (FDA) guidelines, non-dissolved 4- the lowest dose group, the macroscopic examination
nitrophenol was slightly irritating to the skin (score 2 of revealed seven cases of pale liver, and the histo-
8) (Hoechst AG, 1977c); in another study comparable to pathological examination showed 14 cases of finely
OECD Guideline 404, however, the non-dissolved dispersed fatty degeneration. A focal fatty degeneration
substance showed no skin-irritating effects (score 0 of 4) of the liver was also observed in 13/20 rats of the mid-
(Andrae et al., 1981). 4-Nitrophenol applied as a 10% dose group, but not in high-dose animals. However, it
solution to the eyes was slightly irritating in a test must be noted that finely dispersed fatty degeneration
conducted according to FDA guidelines (scores not was also seen in 6/20 control animals. In 4/10 high-dose
12
Mononitrophenols
males but not females, a hydropic liver cell swelling was absolute spleen weight was significantly lower than that
noted, and all high-dose rats that died before the end of of controls after 10 exposures, and the absolute/relative
the study showed vascular congestion of the liver. A spleen and lung weights were significantly lower in
slight increase in the leukocyte count was seen at 210 comparison with controls at the end of the recovery
and 630 mg/kg body weight in males and females; the period. According to the authors, the biological signifi-
increase was significant in high-dose females. In high- cance of the changes in organ weights is unknown
dose males, the alanine aminotransferase (ALAT) owing to the absence of corroborating pathological
activity was significantly increased. Other substance- effects (Smith et al., 1988).
related effects in high-dose animals included increased
nephrosis (two males and five females), testicular In a second trial (exposure to 0, 30, or 130 mg/m3;
atrophy and inhibition of spermatogenesis (one and two MMAD 4.0–4.8 :m), both exposure concentrations
males, respectively), and follicular atresia in the ovaries again resulted in signs of irritation (not further speci-
(four females) (Andrae et al., 1981). Because of unclear fied). Methaemoglobinaemia, an effect that was rever-
effects in the liver, a NO(A)EL cannot be deduced. sible within a 14-day recovery period, was seen only at
130 mg/m3. The methaemoglobin values were 0.5, 0.3, and
8.3.2 Inhalation exposure 1.5% after 10 exposures and 0.4, 0.5, and 0.2% after 14
days’ recovery. The gross and histopathological
8.3.2.1 2-Nitrophenol examination revealed no adverse effects in any dose
group. From these results, the authors of the study
In Sprague-Dawley rats (15 per sex per group), no decided upon a NO(A)EL of 30 mg/m3 (Smith et al., 1988).
mortality was observed after exposure to 0, 5, 30, or
60 mg 2-nitrophenol vapour/m3 (“whole body” exposure; Groups of Sprague-Dawley rats (15 per sex) were
to generate the vapour, melted 2-nitrophenol was used) exposed to 0, 1, 5, or 30 mg 4-nitrophenol dust/m3
for 6 h/day, 5 days/week, over a period of 4 weeks. (“whole body” exposure; MMAD 5.2–6.7 :m) for
Except for squamous metaplasia of the epithelium lining 6 h/day, 5 days/week, over a period of 4 weeks. The
the maxilloturbinates and nasoturbinates in all high-dose exposure resulted in no deaths, and no exposure-related
animals, the clinical and histopathological examinations effects were noted in terms of haematology or clinical
gave no consistent exposure-related effects. The met- chemistry values, gross examination, histopathology,
haemoglobin values determined after the 11th exposure and body or organ weights. In high-dose animals,
were significantly increased only in low-dose animals unilateral and bilateral diffuse anterior capsular cataracts
(males: 1.0, 2.3, 1.8, and 1.6%; females: 2.0, 4.1, 2.1, and were observed. The methaemoglobin values determined
1.1%), but were within control values at the end of the after 2 weeks of exposure showed great variability and
study (Hazleton Lab., 1984). appeared to be unusually high (>3 %) in some unex-
posed controls. However, the group total methaemo-
8.3.2.2 4-Nitrophenol globin value was increased at a concentration of
5 mg/m3, which was significant in males and not
No mortality was observed in male albino Crl:CDR significant in females (males: 0.8, 0.5, 2.2, and 1.1%;
rats (10 per group) after exposure to 0, 340, or 2470 mg 4- females: 1.3, 1.1, 2.0, and 1.0%) (Hazleton Lab., 1983).
nitrophenol dust/m3 (application as sodium salt; “head Therefore, a NO(A)EL of 5 mg/m3 can be derived for local
only” exposure; mass median aerodynamic diameter effects (cataracts), whereas the NO(A)EL for systemic
[MMAD] 4.6–7.5 :m) for 6 h/day, 5 days/week, over a effects (formation of methaemoglobin) may be lower.
period of 2 weeks. Both exposure concentrations
resulted in signs of irritation (not further specified). After 8.3.3 Dermal exposure
exposure to 340 and 2470 mg/m3, darker urine,
proteinuria, elevated aspartate aminotransferase (ASAT) Data concerning short-term dermal exposure were
values, and a dose-dependent increase in methaemo- not identified in the literature.
globin values were observed. These effects were still
evident after a 14-day recovery period; however, the 8.4 Long-term exposure
methaemoglobin value was then still elevated in only 2/5
high-dose animals. The methaemoglobin values were 0.2, In the literature, subchronic and chronic studies
0.87, and 1.53% after 10 exposures and 0.2, 0.13, and are available only for 4-nitrophenol.
0.7% after 14 days’ recovery. The erythrocyte,
haemoglobin, and haematocrit values decreased during 8.4.1 Subchronic exposure
exposure but were elevated after the 14-day recovery
period. In treated rats, the urine volume decreased in a In a 13-week gavage study with Sprague-Dawley
dose-dependent manner during exposure and during the rats (20 per sex per dose group) given 0, 25, 70, or 140 mg
14-day recovery period. In high-dose animals, the 4-nitrophenol/kg body weight in water 5 days/week,
13
premature deaths were seen in animals dosed with 8.5 Genotoxicity and related end-points
70 and 140 mg/kg body weight (1 male/1 female at
70 mg/kg body weight and 15 males/6 females at The available in vitro and in vivo genotoxicity
140 mg/kg body weight); these were usually preceded by studies on 2- and 4-nitrophenol are summarized in
clinical signs, including pale appearance, languid behav- Table 3.
iour, prostration, wheezing, and dyspnoea, shortly after
dosing. The histopathological examination of these 2-Nitrophenol showed no mutagenicity in several
animals revealed minimal to moderately severe conges- limited bacterial assays. From the available data, it is not
tion in the lung, liver, kidney, adrenal cortex, and pitui- possible to draw any conclusions regarding its mutagen-
tary; in surviving animals, no treatment-related changes icity.
compared with controls were reported. A statement
concerning altered methaemoglobin values cannot be For 4-nitrophenol, positive results were obtained in
given owing to a non-reliable analytical method (about in vitro tests for chromosomal aberrations in mammalian
13% in controls at week 7) (Hazleton Lab., 1989). cells. However, apart from one well-documented study
Therefore, only a provisional NO(A)EL (changes in liver, published by NTP (1993), the other available assays
kidneys, and lungs) of 25 mg/kg body weight can be were inadequately reported. 4-Nitrophenol was shown to
derived from this study. The NO(A)EL based on the be mutagenic in some but not all of the bacterial assays,
formation of methaemoglobin may be lower. whereas other studies (i.e., host-mediated bacterial
assay, mouse lymphoma assay, unscheduled DNA
The dermal application of 4-nitrophenol to Swiss- synthesis assay [apparently in vitro ], sister chromatid
Webster mice (10 per sex and dose group; given 0, 22, exchange assay, sex-linked recessive lethal [SLRL] assay
44, 88, 175, or 350 mg/kg body weight in acetone, 3 times in Drosophila) gave negative results. In the absence of
per week over 13 weeks) resulted in dose-dependent any in vivo mutagenicity studies in mammals, it is not
mortality as well as skin irritation/inflammation and possible to conclude whether or not the mutagenic
necrosis at $175 mg/kg body weight.1 potential of 4-nitrophenol is expressed in vivo.
8.4.2 Chronic exposure and carcinogenicity 8.6 Reproductive and developmental

toxicity
In a long-term study with Swiss-Webster mice (50
per sex per dose group), 4-nitrophenol in acetone was 8.6.1 Reproductive toxicity
applied to the interscapular skin at doses of 0, 40, 80, or
160 mg/kg body weight, 3 days/week for 78 weeks. At In a valid two-generation study with groups of
termination of the study, the survival rates were 29/60, 24 female and 12 male Sprague-Dawley rats carried out
17/60, 26/60, and 24/60 for males and 35/60, 26/60, 33/60, by Angerhofer (1985), 4-nitrophenol dissolved in ethanol
and 27/60 for females. The increased mortality after 60 was applied dermally at doses of 0, 50, 100, or 250 mg/kg
weeks was due to a generalized amyloidosis (the severity body weight per day, 5 days/week. The F0 generation
of the amyloidosis was similar among dosed and control was exposed over a period of 140 days before mating.
animals) and secondary kidney failure. The final mean Dosing of the F0 females continued throughout
body weights of the dosed animals were similar to those breeding, gestation, and lactation. Groups of 26 females
of the controls. NTP (1993) stated that there were no and 13 males of the F1 generation were then exposed for
substance-related neoplastic or non-neoplastic effects 168 days in the same manner as had been the F0 rats; the
associated with the dermal administration of 4-nitro- females were again exposed throughout breeding, gesta-
phenol and that there was no evidence of a carcinogenic tion, and lactation. Apart from dose-related signs of skin
activity of the substance in male or female mice. irritation (erythema, scaling, scabbing, and cracking) in
dosed animals, the gross and histopathological examina-
In another study, which had several procedural tions provided no indication of significant adverse
deficiencies (only the skin was examined; only 12 weeks effects. The calculated indices concerning fertility, gesta-
of exposure), no skin tumours were observed in tion, viability, and lactation were not different from those
31 female Sutter mice after dermal application of a 20% of controls. The testis to body weight ratios in the F0
solution (25 :l of solution applied twice weekly) of 2- or generation were not affected, and histological lesions
4-nitrophenol in dioxane (Boutwell & Bosch, 1959). 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.
1
Gulf South Research Institute, not dated; no further
information available; results cited from NTP (1993).
14
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
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
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.
8.6.2 Developmental toxicity overt malformations, and perinatal loss were recorded. In
dams, the mortality was increased at a dose level of
8.6.2.1 2-Nitrophenol $667 mg/kg body weight; at a dose level of $333 mg/kg
body weight, the litter size on postnatal days 1 and 6
In a range-finding study with Charles River COBS© was non-significantly decreased.
©
CD rats (five dams per group; application of 0, 50, 125,
250, 500, or 1000 mg/kg body weight via gavage from day 8.7 Immunological and neurological
6 to day 15 of gestation; uterine examination on day 20), effects
dose levels of 500 and 1000 mg/kg body weight caused
signs of maternal toxicity (transient but dose-related There are no studies available dealing specifically
decrease in weight gain early during treatment). One with immunological or neurological effects. There is an
high-dose animal died, but no cause of death could be indication from an in vitro study that 4-nitrophenol may
determined. Other clinical findings included darkly act as a suppressor of cell-mediated immune response
coloured urine at $250 mg/kg body weight and yellow (Pruett & Chambers, 1988). However, the biological
staining of haircoat (at the nose, mouth, anogenital area) significance is uncertain.
at $125 mg/kg body weight; the necropsy findings gave
no biologically meaningful differences in surviving 8.8 Methaemoglobin formation
dams. At the highest dose level of 1000 mg/kg body
weight, a slight but statistically significant (also com- Methaemoglobin formation by 2-nitrophenol and
pared with historical controls) increase in group mean 4-nitrophenol has been tested in several studies using
post-implantation losses (13.8% versus 8.2% in controls) different species, routes, and durations of applications.
and mean early resorptions (2.3 versus 1.2 in controls) An overview is given in Table 4.
was seen. No effects were observed on the number of
viable fetuses, implantations, or corpora lutea 2-Nitrophenol clearly leads to the formation of
(International Research and Developmental Corporation, methaemoglobin in a dose-dependent manner in cats
1983). (BASF AG, 1970), the most sensitive species. The lowest
dose tested, 50 mg/kg body weight, produced increased
8.6.2.2 4-Nitrophenol methaemoglobin levels. In inhalation experiments in rats,
elevated methaemoglobin levels were observed at an
In both studies cited below, a complete examina- exposure level of 5 mg/m3; methaemoglobin levels were
tion of the pups for possible teratogenic effects was not less elevated at exposure levels of 30 and 60 mg/m3
performed. In addition, owing to limitations of these (Hazelton Lab., 1984).
studies (i.e., use of only one dose group or exposure to a
mixture), reliable NO(A)EL values cannot be derived. 4-Nitrophenol, in contrast, did not lead to methae-
moglobin formation in cats at concentrations up to
In a study performed by Booth et al. (1983), groups 500 mg/kg body weight (BASF AG, 1969). In rats, at high
of 50 female CD-1 mice received daily oral doses of concentrations in inhalation experiments, the met-
400 mg 4-nitrophenol/kg body weight via gavage from haemoglobin-forming capacity seemed to be very low
day 7 to day 14 of gestation. The survival rate in (1.5% at 2470 mg/m3). In conclusion, 4-nitrophenol may
pregnant mice (n = 36) was 81% versus 100% in controls, induce methaemoglobin formation, but the effect seems
and dosed animals showed less maternal weight gain. No to be rather weak, without clear dose–response.
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 9. EFFECTS ON HUMANS
abnormalities.
Kavlock (1990) studied the developmental toxicity

Naniwa (1979) performed patch tests with 4-
of 4-nitrophenol in Sprague-Dawley rats. The substance
nitrophenol, 4-aminophenol, 2-amino-4-chlorophenol, 3'-
(dissolved in a mixture of water, Tween 20, propylene
chlorodiphenylamine-2-carboxylic acid, and 4-dichloro-
glycol, and ethanol [4:4:1:1]) was applied via gavage to
nitrobenzene (0.1, 0.5, or 1% in petrolatum) on
groups of 12–13 animals at doses of 0, 100, 333, 667, or
31 employees probably exposed to these chemicals in a
1000 mg/kg body weight on day 11 of gestation. End-
chemical factory and on 5 control persons. In four
points concerning maternal toxicity included signs of
employees, a positive reaction to 4-nitrophenol was
toxicity, mortality, body weight gain, and the number of
observed, although none of these persons reacted
implantation scars in the uteri at weaning. In the off-
positively to all three tested concentrations. All four
spring, viability, body weight on postnatal days 1–6,
18
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- Experimental test results for the most sensitive
dinitrobenzene, no cross-sensitization due to 4-nitro- species are summarized in Table 5. Additional data on
phenol (1–2% in petrolatum) was observed. In addition, the toxicity of 2- and 4-nitrophenol to aquatic organisms
15 patients with a chloramphenicol allergy failed to react
to 4-nitrophenol (Eriksen, 1978).
19
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 10.2 Terrestrial environment
protozoan Entosiphon sulcatum and the green alga
Scenedesmus subspicatus proved to be most sensitive in The toxicity of 2- and 4-nitrophenol on higher
chronic cell multiplication inhibition tests with fresh- plants according to OECD Guideline 208 was tested in
water species. Daphnia magna exhibited a 21-day independent studies. After incubation of seeds with
lowest-observed-effect concentration (LOEC) of 1.0 mg different test substance concentrations, 14-day EC50
2-nitrophenol/litre in the Daphnia reproduction test values for reduced fresh weight of grown shoots were in
(Koerdel et al., 1984). The entoproct Barentsia the range of 52–420 mg 2-nitrophenol/kg soil (Broecker et
matsushimana was the most sensitive marine inverte- al., 1984; Koerdel et al., 1984) and 35–260 mg 4-
brate species tested, exhibiting a 49-day EC50 value of nitrophenol/kg soil (Ballhorn et al., 1984; Marquart et al.,
0.21 mg 4-nitrophenol/litre and a minimal effective 1984). The 14-day EC10 value for 2-nitrophenol was 10
concentration (ECm ) of 0.03 mg/litre (end-point: growth mg/kg soil for both species. Overall, turnip (Brassica
of germinated spores) (Scholz, 1986). Freshwater fish rapa) proved to be more sensitive than oat (Avena
showed less sensitivity. The lowest 96-h LC50 value of sativa).
3.8 mg 4-nitrophenol/litre was determined for rainbow
trout (Oncorhynchus mykiss) (Howe et al., 1994). The In tests conducted according to OECD Guideline
measured no-observed-effect concentration (NOEC) for 207, the adverse effects of 2- and 4-nitrophenol on
behavioural changes in a 28-day flow-through test with earthworms were examined in several independent
zebra fish was 2 mg 2-nitrophenol/litre (Broecker et al., studies. In the contact test, in which the animals are
1984). After prolonged exposure of zebra fish to 4- exposed on filter paper soaked with the test substance,
nitrophenol, minor morphological alterations of the liver, Neuhauser et al. (1985) established a 48-h LC50 value of
even at a concentration of 0.1 mg/litre, were observed. 5.9 :g/cm² for the toxicity of 2-nitrophenol on Eisenia
At 1 and 5 mg/litre, about 25% of the animals showed fetida. For 4-nitrophenol, the 48-h LC50 values were in
symptoms of degenerative transformation of the liver the range of 0.7–2.7 :g/cm², with Eisenia fetida and
tissue (Braunbeck et al., 1989). 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
Mononitrophenols
Koerdel et al., 1984), and 14-day LC50 values for 4- For 4-nitrophenol, irritating effects on skin and eye are
nitrophenol were in the range of 38–67 mg/kg soil, again assumed based on the studies performed according to
with Eisenia fetida and Eudrilus eugeniae as the most OECD/FDA guidelines; in addition, signs of irritation
sensitive species tested (Ballhorn et al., 1984; Marquart were reported after exposure by inhalation as well as
et al., 1984; Neuhauser et al., 1985, 1986). subchronic dermal exposure. In a guinea-pig maximiza-
tion test, 4-nitrophenol was considered to be sensitizing.
The environmental relevance, particularly of the Positive patch tests were recorded in humans exposed to
earthworm contact test, seems questionable. Critical 4-nitrophenol. Although this may have been due to
results from this test, as sole effect data on terrestrial cross-sensitization, sensitization to 4-nitrophenol in
organisms, should not justify a classification of tested humans cannot be excluded.
substances as highly toxic to earthworms or other soil
organisms. The available data on microorganisms and Only a few limited studies concerning repeated oral
plants indicate only a moderate toxicity potential in the exposure to 2- and 4-nitrophenol in experimental animals
terrestrial environment. 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-
11. EFFECTS EVALUATION tological examination, clinical chemistry, and
histopathological examination of the major organs and
tissues gave no indication for a substance-related toxic
11.1 Evaluation of health effects effect compared with controls. In rats dosed with 4-
nitrophenol, a focal fatty degeneration of the liver as well
11.1.1 Hazard identification and dose–response as congestion in several organs were the major
assessment histopathological findings. Other reported effects
included haematological changes, nephrosis, testicular
In general, there is only limited information con- atrophy, and follicular atresia in the ovaries. The
cerning the toxicological profiles of 2- and 4-nitrophenol. exposure by inhalation to 2-nitrophenol vapour caused
squamous metaplasia of the epithelium of the upper
In experimental animals given 4-nitrophenol orally, respiratory tract; with 4-nitrophenol dust (applied as
intravenously, or intraperitoneally, most of the applied sodium salt), haematological changes, increased met-
dose was excreted via the urine within 24–48 h as glucur- haemoglobin values, and differences in organ weights
onide and sulfate conjugates, while only very small were noted. For the effects given in these studies, it was
amounts were excreted via faeces or as unchanged 4- not possible to identify a clear dose–response or reliable
nitrophenol. In rabbits, after oral dosing, 4-nitrophenol NO(A)EL values.
undergoes reduction to 4-aminophenol as well as
glucuronidation and sulfation. In vivo and in vitro Insufficient data are available on 2-nitrophenol to
studies gave an indication for dermal uptake. For 2- allow any conclusions to be made about its possible
nitrophenol, the information is very limited. However, a mutagenicity. For 4-nitrophenol, more mutagenicity
comparable metabolic transformation is assumed based studies are available, and the substance was shown to
on the available data. Owing to their rapid metabolism be mutagenic in some but not all of the bacterial assays.
and excretion, bioaccumulation of 2- and 4-nitrophenol in In addition, positive results were obtained in in vitro
organisms is not to be expected. tests for chromosomal aberrations in mammalian cells;
however, apart from one well-documented study, the
With oral LD 50 values of 220–620 mg/kg body available assays were inadequately reported. In the
weight in rats and 380–470 mg/kg body weight in mice, 4- absence of any in vivo mutagenicity studies in mammals,
nitrophenol is harmful after oral uptake and was found to it is not possible to conclude whether or not the muta-
be more toxic than 2-nitrophenol. A dose-dependent genic potential of 4-nitrophenol is expressed in vivo.
increase in the formation of methaemoglobin was seen in
cats after oral exposure to 2-nitrophenol — but not after 4-Nitrophenol was not carcinogenic in male or
exposure to 4-nitrophenol — and in rats after exposure female mice after dermal application over 78 weeks. In a
by inhalation to 4-nitrophenol. limited study with female mice, no skin tumours were
seen after dermal application of 2- or 4-nitrophenol over
Most of the studies concerning skin- or eye- 12 weeks. No carcinogenicity studies using the oral or
irritating effects in experimental animals are limited as a inhalation routes were available for either of the isomers.
result of insufficient documentation. However, from the
available data, it can be concluded that 2-nitrophenol is No reproductive effects were observed in rats
slightly irritating to the skin but non-irritating to the eye, exposed to 4-nitrophenol in a two-generation study. For
and the substance proved to have no sensitizing effects. developmental toxicity, the available studies were inade-
21
quately performed (i.e., only one dose was applied, or accumulates in fog. From the mean measured level of 20
animals were dosed only on one day with a mixture). In :g/litre, the uptake of the substance by inhalation
an oral study with rats, 2-nitrophenol induced develop- (using the same assumptions as above) can be
mental effects in the offspring only at doses that also calculated to be about 8 ng during a 1-h exposure period
produced maternal toxicity. However, the fetuses were (i.e., 0.12 ng/kg body weight), assuming a maximum water
not examined for internal malformations. content of fog of 0.1 g/m3 (Pruppacher & Klett, 1978).
The uptake via drinking-water for 2- and 4-nitrophenol
Data on humans relevant for the assessment of can be calculated to be about 0.02 :g/kg body weight
potential adverse effects are limited to some patch tests per day, assuming a maximum concentration of 1 :g/litre
performed with 4-nitrophenol. drinking-water, a daily drinking-water consumption of 1.4
litres, and a mean body weight of 64 kg for males and
11.1.2 Criteria for setting guidance values for females.
2- and 4-nitrophenol
From these data, it can be concluded that exposure
As given in section 8, the database for 2-nitrophe- of the general population to the nitrophenol isomers is
nol is inadequate for calculating a tolerable daily intake mainly through ambient air and drinking-water.
(TDI) or a tolerable concentration (TC).
11.2 Evaluation of environmental effects
For 4-nitrophenol, the formation of methaemo-
globin was shown to be the most critical end-point after Releases of 2- and 4-nitrophenol into the environ-
exposure by inhalation and is assumed to be relevant for ment are primarily emissions into air, water, and soil from
oral exposure too. However, owing to the inaccuracy of diffuse sources, such as vehicle traffic and hydrolytic
the analytical method used in the 13-week study with and photolytic degradation of the respective pesticides.
oral application, a reliable NO(A)EL cannot be derived.
Therefore, at present, no TDI for 4-nitrophenol can be 2-Nitrophenol emitted to the troposphere will stay
developed owing to inadequacy of the database. predominantly in the gaseous phase and should be
rapidly removed by nitration. The major portion of
Longer-term toxicity studies concerning inhalation airborne 4-nitrophenol is expected to be particle bound
exposure were not identified in the literature, and the and can be washed out to surface waters and soil by wet
NO(A)EL values derived for 4-nitrophenol from short- and dry deposition. Because of their removal from air
term studies gave considerable differences (2-week and their insignificant volatility, nitrophenols are not
exposure: NO(A)EL of about 30 mg/m3; 4-week exposure: considered to contribute directly to the depletion of the
NO(A)EL of about 5 mg/m3). The NO(A)EL of 5 mg/m3 stratospheric ozone layer or to global warming. Mea-
was derived for local effects (cataracts), whereas the sured bioconcentration factors indicate a low potential
NO(A)EL for systemic effects (formation of for bioaccumulation.
methaemoglobin) may be lower. Therefore, a reliable TC
for exposure by inhalation cannot be calculated, as the Nitrophenols exhibit moderate to high toxicity to
formation of methaemoglobin is the critical end-point. aquatic organisms, with lowest effect concentrations
reported from chronic studies on algae, Daphnia, and
11.1.3 Sample risk characterization aquatic invertebrates. The lowest effect concentrations
found in chronic studies with freshwater organisms
As given in section 6.2, workers may be exposed to (Scenedesmus subspicatus, 96-h EC50: 0.39 mg 2-nitro-
2- and 4-nitrophenol via inhalation and skin contact phenol/litre; Entosiphon sulcatum, 72-h MIC: 0.83 mg 4-
during production and processing (mainly in the manu- nitrophenol/litre) were 40–50 times higher than maximum
facturing of pesticides). However, data on nitrophenol levels determined in a densely populated and highly
concentrations at the workplace were not identified. industrialized Asian river basin (0.0072 mg
2-nitrophenol/litre and 0.019 mg 4-nitrophenol/litre).
For the general population, an exposure to nitro- From these data, the safety margin between the LOEC
phenols via the environment cannot be excluded (see and maximum surface water concentrations is insufficient
also section 6.2). Assuming an ambient atmospheric to exclude any risk for sensitive aquatic organisms,
concentration of about 1 :g/m3, an inhalation uptake of particularly under surface water conditions not favour-
100%, a daily respiratory volume of 22 m3 for adults, a ing both elimination pathways. Taking into account the
mean body weight of 64 kg for males and females, and missing chronic effect data for fish, an uncertainty/
that 4 of 24 h are spent outdoors (IPCS, 1994), the uptake assessment factor of 100 has to be applied to derive a
by inhalation of nitrophenols is calculated to be 0.06 predicted no-effect concentration (PNEC) according to
:g/kg body weight per day. In addition, 4-nitrophenol standard procedures for environmental risk assessment.
22
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
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30
Mononitrophenols
APPENDIX 1 — 3-NITROPHENOL wastewater. From the available results, a slow mineralization of

3-nitrophenol under anaerobic conditions by adapted
microorganisms can be expected.
Identity and physical/chemical properties
A soil sorption coefficient (K oc) of 52.83, determined by
3-Nitrophenol (CAS No. 554-84-7; 3-hydroxy-1- Boyd (1982), and the n-octanol/water partition coefficient (log
nitrobenzene, m-nitrophenol) has the empirical formula C 6H5NO3. K ow) of 2.0, reported by Hansch & Leo (1979), indicate a low to
Its structural formula is shown below: 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); The oral LD50 of 3-nitrophenol is quoted to be $930
(3) HSDB (1998); (4) Hansch & Leo (1979) 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).
Environmental transport, distribution, and
transformation The available in vitro and in vivo genotoxicity studies on
3-nitrophenol are summarized in Table A-3. 3-Nitrophenol was
Data on the abiotic degradation of 3-nitrophenol were not shown to be mutagenic in a rec-assay and gave inconsistent
available. results in Salmonella/microsome assays. One study showed it to
be non-mutagenic in the Salmonella typhimurium TA98 and
Three studies on biotic degradation, summarized in TA100 strains, whereas another study showed mutagenicity in
Table A-2, indicate the isomer to be inherently biodegradable both of these strains in both the presence and absence of
in water under aerobic conditions. metabolic activation. In view of the conflicting results from
Salmonella/microsome assays and the absence of any data on
In tests on biotic degradation under anaerobic conditions clastogenicity, no conclusions can be made regarding the
using sewage sludge and sludge from the primary anaerobic mutagenicity of 3-nitrophenol.
stage of a municipal sewage treatment plant, respectively, initial
3-nitrophenol concentrations in the range of 96.5–579 mg/litre For 3-nitrophenol, there are no studies available
were not degraded at all within 7–60 days (Wagner & concerning irritating or sensitizing effects, repeated exposure,
Braeutigam, 1981; Battersby & Wilson, 1989). Boyd et al. reproductive and developmental toxicity, or effects on humans.
(1983), however, found complete anaerobic removal of 50
mg/litre within 1 week of incubation. In this test, mineralization Effects on aquatic species
was demonstrated only if the incubation period was extended to
10 weeks. Anaerobic degradation, even of high initial In tests performed on the toxicity of 3-nitrophenol to
nitrophenol concentrations, was found by Tseng & Lin (1994), various aquatic organisms (see Table A-4), 3-nitrophenol
who observed 90% removal of 3-nitrophenol (350–650 mg/litre) exhibited a moderate to high toxicity.
in a biological fluidized bed reactor with three different kinds of
31
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- The draft CICAD on mononitrophenols was sent for review
to institutions and organizations identified by IPCS after contact
Nitrophenol. Beratergremium fuer
with IPCS national Contact Points and Participating Institutions,
Umweltrelevante Altstoffe. Weinheim, VCH as well as to identified experts. Comments were received from:
VerlagsGmbH (Report No. 75; February 1992)
Federal Institute for Health Protection of Consumers &
For the BUA review process, the company that is in charge Veterinary Medicine, Berlin, Germany
of writing the report (usually the largest producer in Germany)
prepares a draft report using literature from an extensive Gesellschaft Deutscher Chemiker, Frankfurt, Germany
literature search as well as internal company studies. This draft is
subject to a peer review during several readings of a working Institute of Occupational Medicine, Chinese Academy of
group consisting of representatives from government agencies, Preventive Medicine, Ministry of Health, Beijing, People’s
the scientific community, and industry. Republic of China
The English translation of BUA Report No. 75 (BUA Institute of Terrestrial Ecology, Huntingdon, United
Report 2- and 4-Nitrophenol. GDCh-Advisory Committee on Kingdom
Existing Chemicals of Environmental Relevance. Stuttgart,
Hirzel Verlag [February 1992]) was released in 1993. 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, National Institute of Public Health, Prague, Czech
US Department of Health and Human Services, Republic
Public Health Service, Agency for Toxic
United States Department of Health and Human Services
Substances and Disease Registry (Report No. (National Institute of Environmental Health Sciences,
TP-91/23) 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
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)
Dr M. Baril, Institut de Recherches en Santé et Sécurité du
Mr R. Cary, Toxicology Unit, Health Directorate, Health and Travail du Québec (IRSST), Montreal, Quebec, Canada
Safety Executive, Bootle, Merseyside, United Kingdom
(Rapporteur) 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 Dr R.G. Liteplo, Environmental Health Directorate, Health
Registry, Centers for Disease Control and Prevention, Atlanta, Canada, Ottawa, Ontario, Canada
GA, USA
Ms L. Regis, Programme for the Promotion of Chemical Safety,
Dr G. Foureman, National Center for Environmental Assessment, World Health Organization, Geneva, Switzerland
US Environmental Protection Agency, Research Triangle Park,
NC, USA Mr A. Strawson, Health and Safety Executive, London, United
Kingdom
Dr H. Gibb, National Center for Environmental Assessment, US
Environmental Protection Agency, Washington, DC, USA Dr P. Toft, Programme for the Promotion of Chemical Safety,
(Chairperson) 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
Mononitrophenols
RÉSUMÉ D’ORIENTATION 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
Ce CICAD relatif aux isomères en position 2-, 3- et
aqueuse des nuages; en revanche, dans la phase
4- du nitrophénol a été préparé par l’Institut Fraunhofer gazeuse, la proportion de 4-nitrophénol est plus
de recherche en toxicologie et sur les aérosols de importante qu’on pourrait le penser en fonction des
Hanovre (Allemagne). Il est basé sur des mises au point données physico-chimiques, par suite d’une importante
rédigées par le Comité consultatif allemand sur les fixation du composé sur les particules. Compte tenu de
produits chimiques qui posent un problème écologique leur solubilité dans l’eau et de leur concentration dans la
(BUA, 1992) et par l’US Agency for Toxic Substances phase gazeuse, on peut s’attendre à ce que les
and Disease Registry (ATSDR, 1992) afin d’évaluer les nitrophénols présents dans l’atmosphère se déposent
effets potentiels du 2- et du 4-nitrophénol sur
par voie humide sur la surface du sol et de l’eau. La
l’environnement et la santé humaine. Les données prises
principale voie de transformation du 2-nitrophénol
en compte dans ces mises au point vont jusqu’en 1992.
présent dans l’atmosphère est vraisemblablement sa
Une recherche bibliographique exhaustive a été effectuée nitration rapide en 2,4-dinitrophénol, le 4-nitrophénol
en 1998 sur plusieurs bases de données afin de relever étant quant à lui en majeure partie fixé aux particules
les références intéressantes sur le 2- et le 4-nitrophénol aéroportées et donc disponible en petites quantités
publiées après celles qui figurent dans les documents de seulement pour des réactions photochimiques. La
base et d’obtenir toutes celles qui contiennent des majeure partie du 4-nitrophénol devrait d’ailleurs
données utiles sur le 3-nitrophénol. On a trouvé très peu disparaître de l’atmosphère en se déposant soit par voie
de données sur cet isomère, ce qui rend impossible une sèche, soit par voie humide. Il ne semble pas que les
véritable évaluation. Les données concernant cet nitrophénols contribuent directement à la dégradation de
isomère sont donc récapitulées à l’appendice 1. On la couche d’ozone stratosphérique ni au réchauffement
trouvera à l’appendice 2 des indications sur le mode général de la planète. Soumis à une photodécomposition
d’examen par des pairs ainsi que sur les sources
en milieu aqueux, le 4-nitrophénol a une demi-vie qui
documentaires utilisées. Les renseignements concernant
peut aller de 2,8 à 13,7 jours selon les mesures. Les
l’examen du CICAD par des pairs font l’objet de l’appen-
nombreuses études consacrées à la biodégradation du 2-
dice 3. Ce CICAD a été approuvé en tant qu’évaluation et du 4-nitrophénol montrent que ces deux isomères sont
internationale lors de la réunion du Comité d’évaluation intrinsèquement biodégradables dans l’eau en aérobiose.
finale qui s’est tenue à Washington du 8 au 11 décembre La minéralisation des nitrophénols en anaérobiose exige
1998. La liste des participants à cette réunion figure à à l’évidence une importante adaptation des populations
l’appendice 4. La fiche d’information internationale sur la microbiennes.
sécurité chimique (ICSC No 1342) relative au mélange
d’isomères du nitrophénol, établie par le Programme La valeur du coefficient de sorption par les
international sur la sécurité chimique (IPCS, 1998) est particules du sol (K oc), qui se situe entre 44 et 530,
également reproduite dans ce document. indique que le potentiel de sorption est faible à modéré.
Les nitrophénols qui passent dans le sol vont vraisem-
Les isomères du nitrophénol sont des solides
blablement subir une biodégradation aérobie. Il ne
solubles dans l’eau qui sont légèrement acides dans ce
devrait y avoir infiltration dans les eaux souterraines que
solvant par suite de leur dissociation. Les isomères 2- et lorsque les conditions ne sont pas favorables à une bio-
4- sont utilisés comme intermédiaires dans la synthèse dégradation. Pour le 2- et le 4-nitrophénol, la mesure du
d’un certain nombre d’insecticides organophosphorés et facteur de bioconcentration donne des valeurs allant de
de composés à usage médical. Lorsqu’ils passent dans 11 à 76, ce qui indique un faible potentiel de bioconcen-
l’environnement, c’est principalement par suite tration.
d’émissions dans l’eau, l’air et le sol provenant de
sources diffuses comme la circulation automobile ou la On connaît plutôt mal le profil toxicologique du 2-
décomposition par photolyse ou hydrolyse de certains et du 4-nitrophénol. Lorsqu’il est administré à des
insecticides. Le dépôt par voie sèche ou humide de animaux de laboratoire par voie orale, intraveineuse ou
nitrophénols présents dans l’atmosphère constitue un intrapéritonéale, le 4-nitrophénol est en majeure partie
apport supplémentaire dans l’hydrosphère et la géo-
excrété dans les urines en l’espace de 24 à 48 h sous
sphère. La formation photo-oxydative du 2- et du 4-
forme de glucuronide ou de sulfo-conjugué, une faible
nitrophénol dans l’atmosphère est encore débattue.
partie seulement passant dans les matières fécale ou
restant inchangée. On a montré que la proportion de
Les données disponibles montrent que le 2-nitro-
glucuronide et de sulfo-conjugués variait selon les
phénol ne devrait se volatiliser que lentement dans espèces. Après administration par voie orale à des
35
lapins, le 4-nitrophénol est réduit en p-aminophénol et sur des mammifères, il n’est pas possible de savoir si le
subit aussi une transformation en glucuronide et sulfo- pouvoir mutagène de cet isomère peut s’exprimer in vivo.
conjugués. Les données tirées des études in vivo et in
vitro donnent une indication sur la résorption du 4- Chez la souris l’application cutanée de 4-nitro-
nitrophénol par la voie transcutanée. En revanche, les phénol pendant une durée de 78 semaines n’a pas donné
données concernant le 2-nitrophénol sont très limitées. d’indices d’effets cancérogènes. Dans une autre étude
Quoi qu'il en soit, on peut considérer, en se basant sur sur la souris, qui présentait toutefois un certain nombre
les données disponibles, que les deux isomères ont un d’insuffisances, on n’a pas non plus observé de tumeurs
métabolisme comparable. Le 2- et le 4-nitrophénol ne cutanées après application cutanée de ces deux isomères
devraient pas s’accumuler dans l’organisme en raison de pendant 12 semaines. Aucune étude de cancérogénicité
leur métabolisation et de leur excrétion rapides. utilisant la voie orale ou respiratoire n’était disponible.
Les études de toxicité aiguë montrent que le 4- Les données relatives au 4-nitrophénol ne révèlent
nitrophénol a un effet nocif après ingestion et qu’il est aucun effet indésirable sur la reproduction ou le
plus toxique que le 2-nitrophénol. Chez des chats, on a développement qui soit statistiquement significatif après
constaté une augmentation du taux de méthémoglobine exposition de rats et de souris par voie orale ou cutanée.
liée à la dose après ingestion de 2-nitrophénol; la même Après administration par voie orale de 2-nitrophénol à
constatation a été faite chez des rats après inhalation de des rats, on a constaté dans la progéniture des animaux
4-nitrophénol. Une exposition répétée à du 4-nitrophénol des effets indésirables sur le développement, mais
a montré que la formation de méthémoglobine est l’effet seulement aux doses toxiques pour les mères. On n’a
le plus déterminant d’une exposition par la voie toutefois pas recherché la présence de malformations
respiratoire et cela vaut sans doute aussi pour la voie internes.
orale. Parmi les autres effets observés, on peut citer un
moindre gain de poids, une modification du poids des La base de données relative au 2-nitrophénol est
organes, une dégénérescence graisseuse du foie et des extrêmement limitée et celle qui concerne le 4-nitrophénol
anomalies hématologiques. Il n’a pas été possible de est insuffisante pour qu’on puisse en tirer une valeur
dégager une véritable relation dose-réponse ni de fiable de la NO(A)EL. Il est donc impossible de fixer pour
déterminer de manière fiable la dose sans effet (nocif) l’instant une valeur pour la dose journalière tolérable
observable (NO(A)EL) correspondant à ces effets. (DJT) ou pour la concentration tolérable (CT) de ces
deux isomères.
Le 2-nitrophénol est légèrement irritant pour la
peau mais il n’irrite pas la muqueuse oculaire. Le test de D’après les résultats des études toxicologiques
Buehler montre que le composé n’a pas non plus d’effet valables effectuées sur divers organismes aquatiques ,
sensibilisateur. En s’appuyant sur des études valables on peut considérer que ces deux nitrophénols sont
effectuées sur l’animal, on peut conclure que le 4- modérément à fortement toxiques pour la vie aquatique.
nitrophénol a par contre une légère action irritante sur la La concentration sans effet la plus faible qui ait été
peau et les yeux. Un test de maximalisation sur le cobaye obtenue lors d’études de longue durée sur des
a montré que le 4-nitrophénol avait également une légère organismes d’eau douce (Scenedesmus subspicatus,
action sensibilisatrice. Chez l’homme, on ne peut exclure EC50 à 96 h : 0,39 mg de 2-nitrophénol/litre; Entosiphon
une légère sensibilisation après un contact avec le sulcatum, concentration minimale inhibitrice à 72 h ou
composé, d’autant plus que la pose d’un timbre cutané CMI : 0,83 mg de 4-nitrophénol/l) était 40 à 50 fois plus
chez des ouvriers pouvant avoir été en contact avec du forte que la valeur maximale obtenue dans un bassin
4-nitrophénol a permis de constater une telle fluvial d’Asie situé dans une zone très industrialisée et
sensibilisation. densément peuplée (respectivement 0,0072 mg/l et 0,019
mg/l). Par conséquent, malgré la biodégradation et la
Aucun des deux isomères n’a fait l’objet décomposition photochimique, les nitrophénols
d’épreuves de génotoxicité suffisamment complètes. déversés dans l’eau peuvent présenter un certain risque
S’agissant du 2-nitrophénol, les données sont insuf- pour les organismes aquatiques sensibles, notamment
fisantes pour que l’on puisse tirer la moindre conclusion dans des eaux superficielles où les conditions ne sont
concernant une mutagénicité éventuelle. Dans le cas du pas favorables à ces deux modes d’élimination.
4-nitrophénol, les études de mutagénicité sont plus Cependant, compte tenu de leurs usages et de leurs
nombreuses, mais le compte rendu en est parfois possibilités de libération dans l’environnement, ces deux
insuffisant. On est fondé à penser que ce composé est nitrophénols ne présentent qu’un risque mineur pour les
susceptible de provoquer des aberrations chromoso- organismes aquatiques.
miques in vitro . Faute d’études de mutagénicité in vivo
36
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
RESUMEN DE ORIENTACIÓN 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-
Preparó el presente CICAD sobre los isómeros 2-, nitrofenol se enriquece en la fase líquida de las nubes,
3- y 4-nitrofenol el Instituto Fraunhofer de Toxicología y mientras que es posible encontrar más 4-nitrofenol del
de Investigación sobre los Aerosoles de Hannover, previsto a partir de los datos fisicoquímicos en la fase
Alemania. Se basa en los exámenes compilados por el gaseosa de las nubes, debido a una amplia unión a
Comité Consultivo Alemán sobre las Sustancias partículas. Habida cuenta de la solubilidad en agua y la
Químicas Importantes para el Medio Ambiente (BUA, presencia prevista en la fase de vapor, cabe esperar una
1992) y la Agencia para el Registro de Sustancias deposición húmeda de nitrofenoles del aire en las aguas
Tóxicas y Enfermedades de los Estados Unidos superficiales y en el suelo. La vía principal de trans-
(ATSDR, 1992) para evaluar los efectos potenciales del formación del 2-nitrofenol emitido a la troposfera debe
2- y el 4-nitrofenol en el medio ambiente y en el ser ser la nitración rápida a 2,4-dinitrofenol, mientras que se
humano. En estos exámenes se incluyeron los datos supone que la mayor parte del 4-nitrofenol suspendido
identificados hasta 1992. En 1998 se realizó una en el aire se encuentra unido a partículas y, por con-
búsqueda bibliográfica amplia de varias bases de datos siguiente, disponible solamente en menor cantidad para
para identificar todas las referencias importantes reacciones fotoquímicas. La mayor parte del 4-nitrofenol
relativas al 2- y el 4-nitrofenol publicadas con del aire debe precipitar por deposición húmeda y seca.
posterioridad a las que figuran en los documentos No se considera que los nitrofenoles contribuyan
originales y para conocer todas las referencias con datos directamente al agotamiento de la capa de ozono
pertinentes sobre el isómero 3-nitrofenol. La información estratosférico o al calentamiento mundial. La semivida
obtenida sobre el 3-nitrofenol fue muy escasa, lo que medida para la descomposición fotoquímica del 4-
impide una evaluación válida. En consecuencia, los nitrofenol en agua osciló entre 2,8 y 13,7 días. Numero-
datos sobre este isómero se resumen en el apéndice 1. La sos estudios sobre la biodegradación del 2- y el 4-
información relativa al carácter del examen colegiado y a nitrofenol indican que los isómeros son inherentemente
la disponibilidad de los documentos originales figura en biodegradables en agua en condiciones aerobias. La
el apéndice 2. La información sobre el examen colegiado mineralización de los nitrofenoles en condiciones
de este CICAD se presenta en el apéndice 3. Este CICAD anaerobias requiere evidentemente una amplia adap-
se aprobó como evaluación internacional en una reunión tación de las comunidades microbianas.
de la Junta de Evaluación Final celebrada en
Washington, DC, Estados Unidos, los días 8-11 de Los coeficientes de sorción en el suelo (K oc)
diciembre de 1998. La lista de participantes en esta medidos del orden de 44-530 indican un potencial de
reunión figura en el apéndice 4. La Ficha internacional de bajo a moderado para la sorción en el suelo. Los
seguridad química (ICSC 1342) para las mezclas de nitrofenoles liberados al suelo se deben biodescomponer
isómeros de nitrofenoles, preparada por el Programa en condiciones aerobias. Cabe prever filtración hacia el
Internacional de Seguridad de las Sustancias Químicas agua freática sólo en condiciones desfavorables para la
(IPCS, 1998), también se reproduce en el presente biodegradación. Para el 2- y el 4-nitrofenol, los factores
documento. de bioconcentración medidos de 11 a 76 ponen de
manifiesto un potencial bajo de bioacumulación.
Los isómeros del nitrofenol son sólidos hidro-
solubles con una acidez moderada en agua debido a la Se dispone sólo de información limitada relativa a
disociación. El 2-nitrofenol y el 4-nitrofenol se utilizan los perfiles toxicológicos del 2- y el 4-nitrofenol. Los
como intermediarios en la síntesis de diversos animales experimentales a los que se administró 4-
plaguicidas órganofosforados y algunos productos nitrofenol por vía oral, intravenosa o intraperitoneal
médicos. La liberación en el medio ambiente se produce excretaron la mayor parte de la dosis aplicada por vía
fundamentalmente por emisiones en el aire, el agua y el urinaria en un plazo de 24-48 horas en forma de conju-
suelo a partir de fuentes difusas, como el tráfico de gados de glucurónidos y sulfatos, mientras que por las
vehículos y la degradación hidrolítica y fotolítica de los heces se excretaron solamente cantidades muy
respectivos plaguicidas. También se produce liberación pequeñas, o bien como 4-nitrofenol inalterado. Se
en la hidrosfera y la geosfera a partir de la atmósfera observó que los porcentajes de conjugados de
debido a la deposición seca y húmeda de nitrofenoles glucurónidos y sulfatos eran dependientes de la especie
suspendidos en el aire. La formación fotooxidativa de 2- y de la dosis. Tras la administración oral a conejos, el 4-
y 4-nitrofenol en la atmósfera es todavía objeto de nitrofenol sufre una reducción a p-aminofenol, así como
estudio. una glucuronización y sulfatación. Los datos
disponibles de estudios in vivo e in vitro dan una idea
38
Mononitrophenols
de la absorción cutánea del 4-nitrofenol. Los datos para carcinogénicos. En otro estudio con ratones, que tiene
el 2-nitrofenol son muy limitados. Sin embargo, teniendo varias limitaciones, no se detectaron tumores cutáneos
cuenta los datos disponibles, se supone que se produce tras la aplicación en la piel de 2- ó 4-nitrofenol durante 12
una transformación metabólica comparable. No cabe semanas. Para ninguno de los isómeros había estudios
prever bioacumulación de 2- y 4-nitrofenol en los de carcinogenicidad utilizando la vía oral o la inhalación.
organismos debido a la rapidez de su metabolismo y
excreción. Los datos disponibles para el 4-nitrofenol no
pusieron de manifiesto efectos específicos o estadística-
En estudios de toxicidad aguda, el 4-nitrofenol es mente significativos de toxicidad reproductiva o del
perjudicial tras la absorción oral, y se observó que era desarrollo tras la administración cutánea u oral a ratas y
más tóxico que el 2-nitrofenol. Se detectó un aumento en ratones. En un estudio de administración por vía oral a
la formación de metahemoglobina dependiente de la ratas, el 2-nitrofenol indujo efectos en el desarrollo de la
dosis en gatos tras la exposición oral al 2-nitrofenol y en camada sólo con dosis que también producían toxicidad
ratas tras la exposición por inhalación al 4-nitrofenol. materna. Sin embargo, en estos estudios no se examin-
Después de una exposición repetida al 4-nitrofenol, se aron los fetos para investigar malformaciones internas.
observó la formación de metahemoglobina como el
efecto final más importante de la exposición por La base de datos para el 2-nitrofenol es
inhalación, y se considera que esto es aplicable también enormemente limitada y la relativa al 4-nitrofenol es
a la exposición oral. Otros efectos observados fueron la insuficiente para deducir valores fidedignos de la
reducción del aumento del peso corporal, diferencias en (NO(A)EL). Por consiguiente, es imposible determinar en
el peso de los órganos, degeneración adiposa focal del este momento la ingesta diaria tolerable o las
hígado y cambios hematológicos. Para esos efectos no concentraciones tolerables para el 2- ó el 4-nitrofenol.
fue posible determinar una relación clara dosis-respuesta
o concentraciones sin efectos (adversos) observados De los resultados disponibles de pruebas válidas
(NO(A)EL) fidedignas. sobre la toxicidad del 2-y el 4-nitrofenol para diversos
organismos acuáticos, los nitrofenoles se pueden
El 2-nitrofenol es ligeramente irritante para la piel, clasificar como sustancias con una toxicidad entre
pero no para los ojos. En una prueba de Buehler no se moderada y alta en el compartimento acuático. Las
observó efecto sensibilizador. Tomando como base los concentraciones más bajas con efectos obtenidas en
estudios válidos con animales experimentales, se supone estudios crónicos con organismos de agua dulce
que el 4-nitrofenol tiene efectos irritantes en la piel y los (Scenedesmus subspicatus, CE50: 0,39 mg de 2-nitro-
ojos. En una prueba de maximización en cobayas, se fenol/litro a las 96 h; Entosiphon sulcatum, concentra-
observó que el 4-nitrofenol era ligeramente sensibili- ción inhibitoria mínima a las 72 horas: 83 mg de 4-
zante. En el ser humano no se puede excluir una posible nitrofenol/litro) fueron 40-50 veces superiores a los
sensibilización tras el contacto con 4-nitrofenol, niveles máximos determinados en una cuenca fluvial
especialmente teniendo en cuenta que se ha observado asiática densamente poblada y muy industrializada
sensibilización cutánea en pruebas de parche en (0,0072 mg de 2-nitrofenol/litro y 0,019 mg de 4-nitro-
trabajadores de fábricas que podían haber estado fenol/litro). Por consiguiente, a pesar de la descomposi-
expuestos al 4-nitrofenol. ción biótica y fotoquímica, los nitrofenoles emitidos al
agua pueden representar algún peligro para los organis-
No se ha sometido a pruebas completas de mos acuáticos sensibles, particularmente en las condici-
genotoxicidad ninguno de los dos isómeros del ones de las aguas superficiales que no favorecen ambas
nitrofenol. Los datos disponibles sobre el 2-nitrofenol vías de eliminación. Habida cuenta de sus pautas de uso
son insuficientes para poder sacar conclusiones acerca y sus características de liberación, probablemente los
de su posible mutagenicidad. Hay más estudios de nitrofenoles plantean sólo un pequeño riesgo para los
mutagenicidad para el 4-nitrofenol, aunque algunos se organismos acuáticos.
notificaron de manera inadecuada. Hay pruebas que
parecen indicar que el 4-nitrofenol puede producir Los datos disponibles indican solamente una
aberraciones cromosómicas in vitro . En ausencia de toxicidad potencial moderada de los nitrofenoles en el
estudios de mutagenicidad in vivo en mamíferos, no es medio ambiente terrestre. A partir de los cálculos de la
posible llegar a la conclusión de si se expresa o no in razón exposición-toxicidad de los nitrofenoles a partir de
vivo el potencial mutagénico del 4-nitrofenol. la degradación de plaguicidas, sólo cabe esperar un
pequeño riesgo para los organismos en este comparti-
Tras la aplicación cutánea de 4-nitrofenol a mento, incluso en el peor de los casos.
ratones durante 78 semanas no se observaron efectos
39

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

Concise International Chemical Assessment Document 20

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

World Health Organization

WHO Library Cataloguing-in-Publication Data

(Concise international chemical assessment document ; 20)

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

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

©World Health Organization 2000

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

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

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

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND

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

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

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

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

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

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

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

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

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

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

FOREWORD While every effort is made to ensure that CICADs

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY

PRIMARY REVIEW BY IPCS

REVIEW BY IPCS CONTACT POINTS/

FINAL REVIEW BOARD 2

APPROVAL BY DIRECTOR, IPCS

1 Taking into account the comments from reviewers.

industry. They are selected because of their expertise in

Board members, authors, reviewers, consultants,

1. EXECUTIVE SUMMARY phase, wet deposition of nitrophenols from air to surface

In mice, the dermal application of 4-nitrophenol for

Water solubility 1.26 12.4

The nitrophenol isomers are usually determined by

Table 2: Biotic degradation of nitrophenols under aerobic conditions.

Concentration Additional Test duration Removal

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)

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)

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

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)

Tests on inherent biodegradability

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

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