N-PHENYL-1-NAPHTHYLAMINE

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 9
N-PHENYL-1-NAPHTHYLAMINE
First draft prepared by Dr G. Koennecker, Dr I. Mangelsdorf, and Dr A. Wibbertmann,
Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany
Please note that the layout and pagination of this pdf file are not identical to the printed
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, 1998
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WHO Library Cataloguing in Publication Data
N-phenyl-1-naphthylamine.
(Concise international chemical assessment document ; 9)
First draft prepared by G. Koennecker, I. Mangelsdorf and
A. Wibbertmann.
1.1-Naphthylamine – adverse effects 2.1-Naphthylamine –
toxicity 3.Environmental exposure I.Koennecker, G. II.Series
ISBN 92 4 153009 X
ISSN 1020-6167
(NLM Classification: QD 305.A8)
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TABLE OF CONTENTS
FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.
EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.
IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.
ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.
SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.
ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . 6
6.
ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
6.1
6.2
Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
7.
COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND
HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
8.
EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . 8
8.1
8.2
8.3
8.4
8.5
8.6
8.7
9.
EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
9.1
9.2
10.
Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
11.1
11.2
12.
Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . 13
10.1
10.2
11.
Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8.4.1
Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8.4.2
Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.2 Criteria for setting guidance values for N-phenyl-1-naphthylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
13
14
14
14
PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
iii
Concise International Chemical Assessment Document 9
13.
HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
13.1
13.2
13.3
14.
Human health hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Advice to physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Spillage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
APPENDIX 1 — SOURCE DOCUMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
iv
N-Phenyl-1-naphthylamine
FOREWORD
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–
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1
International Programme on Chemical Safety (1994)
Assessing human health risks of chemicals: derivation of
guidance values for health-based exposure limits. Geneva,
World Health Organization (Environmental Health Criteria
170).
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1
Concise International Chemical Assessment Document 9
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NATIONAL/REGIONAL
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OF SECOND DRAFT 1
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EDITING
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PUBLICATION
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3 Includes any revisions requested by the Final Review Board.
2
N-Phenyl-1-naphthylamine
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3
Concise International Chemical Assessment Document 9
1. EXECUTIVE SUMMARY
amount of N-phenyl-1-naphthylamine released into the
environment is expected to be low.
This CICAD on N-phenyl-1-naphthylamine was
based principally on a review prepared by the
Fraunhofer Institute for Toxicology and Aerosol
Research, Hanover, Germany, for the German Advisory
Committee on Existing Chemicals of Environmental
Relevance (BUA, 1993). This review assesses the
potential effects of N-phenyl-1-naphthylamine on the
environment and on human health. Data identified up to
1992 were considered in the BUA report. A
comprehensive literature search of several on-line
databases was conducted in 1997 to identify any
relevant references published subsequent to those
incorporated in the BUA report. Information on the
preparation and peer review of the source document is
presented in Appendix 1. Information on the peer review
of this CICAD is presented in Appendix 2. This CICAD
was approved as an international assessment at a
meeting of the Final Review Board, held in Berlin,
Germany, on 26-28 November 1997. Participants at the
Final Review Board meeting are listed in Appendix 3.
The International Chemical Safety Card (ICSC 1113) for
N-phenyl-1-naphthylamine, produced by the
International Programme on Chemical Safety (IPCS,
1993), has also been reproduced in this document.
Laboratory studies yielded half-lives for the
photochemical degradation of N-phenyl-1naphthylamine in water of 8.4 and 5.7 min. Photolysis
may lead to the preliminary breakdown of N-phenyl-1naphthylamine under favourable environmental
conditions, but further degradation is unlikely. The
substance is stable to hydrolysis under environmental
conditions, and removal by biodegradation in water and
soil is slow. Owing to its moderate to high potential for
sorption to organic soil constituents and its limited
mineralization in soil, N-phenyl-1-naphthylamine is
presumed to have geoaccumulation potential. The
probability of infiltration into groundwater is low. Based
upon studies with Daphnia and fish and its measured
log Kow of 4.2, N-phenyl-1-naphthylamine is expected to
have a moderate potential for bioaccumulation.
Nevertheless, secondary poisoning of higher trophic
levels via the aquatic food-chain seems unlikely in view
of the chemical's metabolism and extensive excretion.
The acute toxicity of N-phenyl-1-naphthylamine in fish
and Daphnia is high, with lowest reported no-observedeffect concentrations (NOECs) of 0.11 mg/litre (192 h)
and 0.02 mg/litre (21 days), respectively. Despite limited
hydrolytic or biotic degradation, the bioavailability of
this chemical in water is expected to be considerably
reduced by sorption and photochemical degradation.
N-Phenyl-1-naphthylamine (CAS no. 90-30-2) is a
lipophilic crystalline solid that is used as an antioxidant
in various lubrication oils and as a protective agent and
antioxidant in rubber and rubber mixtures for various
products, including tyres. Between 1986 and 1990, the
estimated worldwide production capacity of N-phenyl-1naphthylamine was 3000 tonnes per year. One German
company is the sole producer of N-phenyl-1naphthylamine within the European Union.
Identified data on concentrations of N-phenyl-1naphthylamine in environmental media were limited to
older studies from the USA, in which the chemical was
detected in river water (2-7 µg/litre) and sediment (1-5
mg/kg) near a small speciality chemicals manufacturing
plant. Available data were inadequate to allow the
assessment of human exposure or the prediction of
concentrations using fugacity modelling.
Based upon its physical/chemical properties, the
distribution of N-phenyl-1-naphthylamine in the
environment, predicted on the basis of a Level II
fugacity model, was approximately 36% to soil, 34% to
sediment, 29% to water, and less than 1% each to air,
suspended sediment, and biota. Quantitative data on
releases of N-phenyl-1-naphthylamine into the
environment from production, processing, and use are
not available. Indirect discharges to soil and surface
waters from the leakage of lubrication oils or leaching
from decaying tyres and rubber products may occur;
however, quantitative data are not available. Although
data were not identified, N-phenyl-1-naphthylamine may
be emitted to the atmosphere in exhaust gases during its
production and processing and during the vulcanization
of rubber mixtures. The use of N-phenyl-1naphthylamine-containing lubrication oils should not
result in the introduction of this substance into the
atmosphere, as these oils are applied in closed systems.
Overall, owing to its limited production capacity and the
application of emission reduction techniques, the
Based upon studies conducted with laboratory
animals, N-phenyl-1-naphthylamine is well absorbed and
extensively excreted after ingestion. Following ingestion
by rats, 60% of the administered dose was excreted in
the faeces and 35% in the urine within 72 h. Several
unidentified metabolites of N-phenyl-1-naphthylamine
have been detected in the urine of exposed rats. On the
basis of in vitro studies, metabolism likely occurs
primarily via hydroxylation.
The acute oral toxicity of N-phenyl-1-naphthylamine
in laboratory animals is low. In standard tests with
rabbits, N-phenyl-1-naphthylamine was reported to be
neither a skin irritant nor an eye irritant. However, the
skin sensitizing properties of N-phenyl-1-naphthylamine
were revealed in the guinea-pig maximization test as well
as in humans exposed to greases or rubber materials
containing this chemical.
4
N-Phenyl-1-naphthylamine
Limited data indicate that the kidneys and liver are
the main target organs following ingestion. Adequate
studies with which to derive putative effect levels were
not identified. The potential carcinogenicity of Nphenyl-1-naphthylamine could not be fully evaluated, as
none of the available studies was performed according
to currently accepted standard protocols.
International Chemical Safety Card reproduced in this
document. N-Phenyl-1-naphthylamine decomposes
upon heating or burning, producing irritating or toxic
fumes or gases (nitrogen oxides). The conversion for Nphenyl-1-naphthylamine is 1 ppm = 9.114 mg/m3 (at 101.3
kPa and 20°C). The structural formula for N-phenyl-1naphthylamine is:
N-Phenyl-1-naphthylamine was not mutagenic in
bacterial cells, nor were the frequencies of gene mutation
(mouse lymphoma assay) or chromosomal aberrations
(in vitro metaphase analysis in Chinese hamster ovary
cells or Chinese hamster lung cells) increased in these
cell types exposed in vitro. A marginally positive result
in a sister chromatid exchange assay conducted with
Chinese hamster ovary cells in the presence of metabolic
activation has been reported. Unscheduled DNA
synthesis was increased in exposed human lung (WI-38)
cells; however, the effects were not clearly
concentration dependent. N-Phenyl-1-naphthylamine
was negative in a dominant lethal test conducted in
mice. Based upon the available data, N-phenyl-1naphthylamine does not appear to be genotoxic. Data
on the reproductive/developmental toxicity and on
immunological or neurological effects of N-phenyl-1naphthylamine were not identified.
NH
The commercial product has a typical purity of >99%.
Named impurities from three manufacturers are 1naphthylamine (<100-500 mg/kg), 2-naphthylamine (<350 mg/kg), aniline (<100-2500 mg/kg), 1-naphthol (<5000
mg/kg), 1,1-dinaphthylamine (<1000 mg/kg), and Nphenyl-2-naphthylamine (500-<5000 mg/kg) (BUA, 1993;
Union Carbide, 1996).
3. ANALYTICAL METHODS
An increased rate of cancer was observed in one
epidemiological study of N-phenyl-1-naphthylamineexposed workers; however, owing to the small number of
excess deaths and concomitant exposure to other
substances, it is not possible to attribute this effect
solely to N-phenyl-1-naphthylamine. Although data are
inadequate to allow a more detailed characterization of
the potential health risks of N-phenyl-1-naphthylamine,
dermal contact with the chemical should be avoided
because of its sensitizing properties.
N-Phenyl-1-naphthylamine is quantified in
environmental media either by high-performance liquid
chromatography in combination with ultraviolet
absorption or by gas chromatography combined with
thermionic or mass spectrometric detection, flame
ionization detection, or electron capture detection. A
method for the determination of secondary amines in air
is suitable for the detection of N-phenyl-1naphthylamine.
The following enrichment techniques are used for
various types of samples: solid-phase adsorption (silica
gel, silica gel/glass fibre) with liquid extraction (ethanol,
acetic acid/2-propanol) for samples of air (NIOSH,
1984a,b); liquid/liquid extraction (acetonitrile, diethyl
ether), stripping with helium, and solid adsorption
(Tenax GC) or alkaline extraction (dichloromethane) for
samples of water (Jungclaus et al., 1978; Lopez-Avila &
Hites, 1980; Sikka et al., 1981; Rosenberg, 1983); liquid
extraction (isopropanol) for sediment (Jungclaus et al.,
1978; Lopez-Avila & Hites, 1980); and liquid extraction
(methanol) for fish, tissue, and serum (Sikka et al., 1981).
Detection limits range from 0.1 to 1 µg/litre for water and
from 50 to 100 µg/kg for sediment; detection limits for
biological materials were not identified.
2. IDENTITY AND PHYSICAL/CHEMICAL
PROPERTIES
N-Phenyl-1-naphthylamine (CAS no. 90-30-2;
C16H13N; 1-anilinonaphthaline; phenyl-[naphthyl-(1)]
amine; phenyl-"-naphthylamine) in its pure form
crystallizes into lemon yellow prisms or needles (melting
point 62-63°C). The chemical is marketed in the form of
brown to dark violet crystals or light brown to light
violet granules. The vapour pressure (1.06 × 10-6 kPa)
and the water solubility of N-phenyl-1-naphthylamine at
20°C (3.0 mg/litre) are quite low. With a measured noctanol/water partition coefficient (log Kow) of 4.2, Nphenyl-1-naphthylamine is characterized as a lipophilic
substance. Additional properties are presented in the
5
Concise International Chemical Assessment Document 9
4. SOURCES OF HUMAN AND
ENVIRONMENTAL EXPOSURE
emission reduction techniques are applied, and releases
of N-phenyl-1-naphthylamine are therefore presumed to
be low (<25 kg per year). Data on levels of N-phenyl-1naphthylamine in exhaust gases from vulcanization
processes are not available. The use of N-phenyl-1naphthylamine-containing lubrication oils should not
result in the introduction of the substance into the
atmosphere, as the oils are applied in closed systems
(BUA, 1993).
There are no known natural sources of N-phenyl-1naphthylamine. Other than the information derived from
the national source document, additional data on the
production, use patterns, and release of this chemical
were not identified.
Data on releases of N-phenyl-1-naphthylamine in
effluents from production and processing facilities were
not identified. Indirect discharges from leaching or the
decay of tyres and other rubber products are to be
expected in the long term; however, estimation of
amounts was not possible (BUA, 1993). The release of
N-phenyl-1-naphthylamine into the geosphere from the
leakage of lubrication oils and discarded rubber products
and tyres in landfill sites may occur; however, estimation
of the amounts was not possible with the available data
(BUA, 1993). Information on the occurrence of Nphenyl-1-naphthylamine in plants or animals was not
identified.
Within the European Union, one German company is
the sole producer of N-phenyl-1-naphthylamine.
Between 1986 and 1990, the estimated worldwide
production capacity of N-phenyl-1-naphthylamine was
3000 tonnes per year. Over the same period, estimated
production capacities in Western Europe, the People's
Republic of China, the USA, and Japan were
approximately 1000-1500 tonnes per year, 1000 tonnes
per year, 500 tonnes per year, and 300 tonnes per year,
respectively. Between 1986 and 1990, the consumption
of N-phenyl-1-naphthylamine in Germany was estimated
to be approximately 300-450 tonnes per year, although
its use is now declining. Approximately 50-100 tonnes
were covered by imports; exports amounted to
approximately 750-1150 tonnes per year (BUA, 1993).
5. ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, AND TRANSFORMATION
N-Phenyl-1-naphthylamine is used as an antioxidant
in gear, hydraulic, lubrication, and bearing oils and as a
protective agent and antioxidant in rubbers and rubber
mixtures. In Germany, N-phenyl-1-naphthylamine
consumption is divided equally among these two uses.
In these products, the chemical acts as a radical
scavenger in the auto-oxidation of polymers and mineral
lubricants. Average concentrations of N-phenyl-1naphthylamine in the final products are <1% w/w (BUA,
1993). In the rubber industry, approximately 75% of the
N-phenyl-1-naphthylamine is used in products such as
drums, buffers, conveyor belts, flexible tubes, gaskets,
and footwear components. The remaining 25% is used
in tyres (sidewalls or carcass, but not treads) (BUA,
1993).
Based on its physical/chemical properties, the
distribution of N-phenyl-1-naphthylamine in the
environment was predicted, using a Level II fugacity
model (Mackay, 1991), to be 36.3% to soil, 33.9% to
sediment, 28.9% to water, 0.8% to air, 0.06% to
suspended sediment, and 0.02% to biota. Input data for
the Level II fugacity model were as follows: temperature,
298°K; atmospheric volume, 6 x 109 m3; soil density, 1.5
g/cm3; density of biota, 1 g/cm3; carbon content of soil,
2%; carbon content of sediment, 4%; water depth, 1000
cm; water portion, 70%; soil depth, 15 cm; sediment
depth, 3 cm; suspended sediment portion, 5 ppm; biota
portion, 1 ppm; molar mass, 219 g/mol; water solubility, 3
mg/litre; vapour pressure, 1.06 mPa; n-octanol/water
partition coefficient, 15 850; soil sorption coefficient,
6510; bioaccumulation factor, 760; half-lives (days) in air
(0), water (365), soil (29.2), sediment (29.2), suspended
sediment (29.2), and biota (0). Owing to the lack of
relevant data, it was not possible to predict the
concentrations of N-phenyl-1-naphthylamine in various
media using a Level III fugacity model. Based on its
calculated Henry's law constant (7.748 x 10-2 Pa.m3/mol;
20°C) and other information (Thomas, 1990), the
volatility of N-phenyl-1-naphthylamine from aqueous
solution is expected to be low.
In Germany, N-phenyl-1-naphthylamine-containing
distillation residues from production facilities
(approximately 20 tonnes per year), like most gear and
hydraulic oil, are disposed of in chemical/physical/
biological treatment plants or hazardous waste
incinerators (BUA, 1993). About 30% of used tyres are
disposed of in landfill sites, approximately 37% are used
for the production of energy in the cement industry, an
estimated 22% are recycled, and approximately 11% are
exported (BUA, 1993). Exhaust gases may be emitted
during the production and processing of N-phenyl-1naphthylamine and during the vulcanization of rubber
mixtures at elevated temperatures; in Germany, however,
6
N-Phenyl-1-naphthylamine
Based on its ultraviolet absorption spectrum, direct
photochemical degradation of N-phenyl-1naphthylamine in air is expected (BUA, 1993). Data
concerning the photo-oxidative degradation of Nphenyl-1-naphthylamine in air are not available.
Measured half-lives for the photochemical degradation
of the chemical in water have been reported at 8.4 and
5.7 min (Sikka et al., 1981). In this experiment, sealed
tubes containing aqueous solutions of N-phenyl-1naphthylamine at approximately 1 mg/litre (water
unspecified but assumed to be distilled) were exposed to
sunlight. The experiment was conducted in May and
repeated in June in Syracuse, NY (USA); no information
was provided on light intensity. A further experiment
using a lamp at 300 nm (Rayonette Model RNR-400 mini
photochemical reactor; no information provided on
intensity) demonstrated that the photodegradation
product was produced rapidly and was itself
photostable. Given the lack of detail in the report, the
importance of photodegradation in the environment is
difficult to assess. There is also insufficient information
to allow the photodegradation product to be fully
characterized, but the authors suggest that it
incorporates the basic phenylnaphthylamine skeleton. It
can therefore be concluded that photolysis may lead to
preliminary breakdown of N-phenyl-1-naphthylamine
under favourable environmental conditions, but that
further degradation is unlikely. From experiments
conducted in aqueous solution, hydrolysis of N-phenyl1-naphthylamine under environmental conditions is
expected to be of limited importance (Sikka et al., 1981).
reflect reduced bioavailability of the N-phenyl-1naphthylamine (Rosenberg, 1983). Measured soil
sorption coefficients (Koc) are not available. Using the
regression equations of Kenaga (1980) and Kenaga &
Goring (1980), Koc values of 2400 and 4600, respectively,
were calculated for N-phenyl-1-naphthylamine. Thus,
soil sorption is predicted to be moderate to high. From
this expected sorption to organic soil constituents and
its limited mineralization in soil, N-phenyl-1naphthylamine is presumed to have geoaccumulation
potential. The probability of infiltration into
groundwater is low (BUA, 1993).
Considering its measured log Kow of 4.2 (Ozeki &
Tejima, 1979) and data from laboratory tests with
Daphnia and freshwater fish, N-phenyl-1-naphthylamine
is classified as a substance with moderate
bioaccumulation potential (Sikka et al., 1981; CITI, 1992).
For Daphnia magna, a mean bioconcentration factor
(related to radioactivity) of 637 was calculated following
exposure to [14C] N-phenyl-1-naphthylamine in a static
test (solubilizer: acetone; steady state after 12 h). About
50% of the accumulated radioactivity had been
eliminated after 53 h in clean water (Sikka et al., 1981).
Bioconcentration factors ranging from 432 to 1285
(related to radioactivity) and from 233 to 694 (related to
N-phenyl-1-naphthylamine) were determined in a flowthrough system (sublethal N-phenyl-1-naphthylamine
concentration) for the bluegill sunfish (Lepomis
macrochirus) at steady state. Depuration was biphasic,
with an elimination of [14C] N-phenyl-1-naphthylamine of
>90% after 8 days; radioactivity could still be detected
32 days after treatment (Sikka et al., 1981).
Bioconcentration factors for N-phenyl-1-naphthylamine
in common carp (Cyprinus carpio), measured in a flowthrough system after 8 weeks, were on the same order of
magnitude (427-2730) (CITI, 1992). N-Phenyl-1naphthylamine is metabolized by terrestrial and aquatic
microorganisms and by fish to at least two or three
unidentified metabolites (Sikka et al., 1981; Rosenberg,
1983).
Two standard tests on biodegradation performed
according to guideline 301C of the Organisation for
Economic Co-operation and Development (OECD)
(modified MITI-I test) reported no degradation of Nphenyl-1-naphthylamine (100 mg/litre initial
concentration) within 14 and 28 days, using nonadapted activated sludge (Bayer AG, 1990; CITI, 1992).
In tests with conditions favouring biodegradation, Nphenyl-1-naphthylamine was degraded with a half-life
ranging from 4 to 11 days (inocula: domestic sewage and
lake water, respectively). Additional substrates
accelerated degradation (Sikka et al., 1981; Rosenberg,
1983). Laboratory results indicate that N-phenyl-1naphthylamine is inherently biodegradable in the aquatic
compartment.
6. ENVIRONMENTAL LEVELS AND
HUMAN EXPOSURE
6.1
Mineralization of N-phenyl-1-naphthylamine
(measured by the evolution of [14C]carbon dioxide) was
17% in soil and 35% in a soil suspension in buffered salt
solution. In contrast to the aquatic studies, the addition
of degradable substrates reduced rather than accelerated
degradation. It was suggested that the organic materials
increased sorption of the N-phenyl-1-naphthylamine.
The reported lower degradation in soil may therefore
Environmental levels
In older studies from the USA, N-phenyl-1naphthylamine was detected in river water (2-7 µg/litre)
and sediment (1-5 mg/kg) near a small speciality
chemicals manufacturing plant (Jungclaus et al., 1978;
Lopez-Avila & Hites, 1980). Additional data on levels of
N-phenyl-1-naphthylamine in environmental media were
not identified. Based upon the use patterns of Nphenyl-1-naphthylamine, the presence of this substance
7
Concise International Chemical Assessment Document 9
in soil and sediment in some source-dominated areas
appears possible; however, quantitative data are not
available.
6.2
within 48 h; 95% was excreted within 72 h (60% in the
faeces and 35% in the urine). In the ether extract of the
urine, at least five radioactive metabolites were detected
but not identified. The elimination half-lives were
reported as 1.68 h for the fast elimination and 33 h for the
slow elimination (Sikka et al., 1981).
Human exposure
In a study in which male rats were administered Nphenyl-1-naphthylamine orally, only small quantities of
unchanged N-phenyl-1-naphthylamine were excreted in
the faeces and urine (0.4 and 0.01% of the applied dose,
respectively). Large amounts of glucuronide and sulfate
conjugates, which were not identified further, were
detected in the urine. Small quantities of N-phenyl-1naphthylamine were distributed in fatty tissue after
single or multiple (6 day) oral administration, whereas the
distribution of unchanged N-phenyl-1-naphthylamine in
liver, kidneys, spleen, heart, and lung was extremely low
(Miyazaki et al., 1987).
Owing to its low vapour pressure and use patterns,
the ingestion or inhalation of N-phenyl-1naphthylamine is expected to be minor. Dermal contact
with oils and rubber articles containing N-phenyl-1naphthylamine may occur in the workplace. Data on
occupational exposure were not available from industries
in Germany involved in the manufacture or use of Nphenyl-1-naphthylamine.2 Dermal contact may also be a
source of exposure for the general population, although
this should be of minor importance because of the small
quantities of N-phenyl-1-naphthylamine produced and
present in various products. Data on concentrations of
N-phenyl-1-naphthylamine in media relevant to
assessing exposure of the general population were not
identified. Moreover, available data were insufficient to
allow an estimation of human exposure based upon
concentrations predicted from fugacity modelling.
Mono- and dihydroxy-derivatives of N-phenyl-1naphthylamine have been identified in in vitro metabolic
studies conducted with rat liver microsomes (Sikka et al.,
1981; Xuanxian & Wolff, 1992). Sikka et al. (1981)
suggested that the hydroxyl group in the mono-hydroxy
derivative is in the naphthalene moiety at a para-position
to the amino group, whereas at least one hydroxyl group
in the dihydroxy-derivative is at the available paraposition in the naphthyl ring. Pretreatment of male rats
with phenobarbital or 3-methylcholanthrene increased
the rate of microsomal metabolism, indicating that more
than one P-450 enzyme is involved in the metabolism of
N-phenyl-1-naphthylamine (Xuanxian & Wolff, 1992).
7. COMPARATIVE KINETICS AND
METABOLISM IN LABORATORY ANIMALS
AND HUMANS
Studies providing quantitative information on the
absorption or distribution of N-phenyl-1-naphthylamine
in humans were not identified. From the limited
information available from studies conducted with
laboratory animals, it can be concluded that N-phenyl-1naphthylamine is well absorbed after ingestion and is
readily excreted. In vitro studies have demonstrated
that the metabolism of N-phenyl-1-naphthylamine
occurs primarily via hydroxylation.
In studies conducted with human volunteers or
laboratory animals, the isomer N-phenyl-2naphthylamine (CAS no. 135-88-6) was partially
metabolized to the known human carcinogen 2naphthylamine following ingestion or inhalation (NIOSH,
1976). Although data concerning the formation of this
metabolite are not available for N-phenyl-1naphthylamine, it should be noted that, based on its
chemical structure, it is unlikely that N-phenyl-1naphthylamine is metabolized to 2-naphthylamine.
In male Sprague-Dawley rats administered a single
oral dose of 160 mg [14C] N-phenyl-1-naphthylamine/kg
body weight, the chemical was well absorbed,
metabolized almost completely, and excreted primarily in
the faeces. Radioactivity was detected in plasma within
60 min, with the maximum concentration measured after 4
h. After 24 h, 20% of the radioactivity was found in the
gastrointestinal tract (including contents), 2.4% in fatty
tissue, 0.4% in the liver, and 0.1% in the kidneys. Ninety
per cent of the administered radioactivity was excreted
8. EFFECTS ON LABORATORY
MAMMALS AND IN VITRO TEST SYSTEMS
In most of the toxicity studies, information on the
purity of N-phenyl-1-naphthylamine was not provided.
As discussed in section 2, N-phenyl-1-naphthylamine
with a typical purity of >99% contains numerous
contaminants, and therefore the observed effects may
not be solely attributable to N-phenyl-1-naphthylamine.
Owing to the limited available toxicity data on
2
Personal communications concerning 1) BUA report on
N-phenyl-1-naphthylamine, Heidelberg,
Berufsgenossenschaft der chemischen Industrie (BG
Chemie), 27 August 1992; and 2) exposure data for Nphenyl-1-naphthylamine, Bundesanstalt für
Arbeitsschutz, Dortmund, 1992.
8
N-Phenyl-1-naphthylamine
N-phenyl-1-naphthylamine, information on the isomer
N-phenyl-2-naphthylamine (a known contaminant of
commercially available N-phenyl-1-naphthylamine) has
been included to aid in the identification of potential
target organs. There is limited evidence to suggest that
the kidneys and liver are the main target organs
following ingestion of N-phenyl-1-naphthylamine; this
has also been demonstrated for the isomer N-phenyl-2naphthylamine.
8.1
N-phenyl-1-naphthylamine to be an eye irritant. The
observed effects in some animals (slight conjunctivitis or
swelling of the eyelid) were reversible within a maximum
of 10 days (van Beek, 1977; Ciba-Geigy Corp., 1987a).
In a guinea-pig maximization test (Magnusson &
Kligman, 1970) and in a test performed according to
OECD guideline 406, N-phenyl-1-naphthylamine was
shown to be a strong sensitizer (positive reaction in
15/20 and 18/20 animals, respectively) (Boman et al.,
1980; Ciba-Geigy Corp., 1987c). In the modified
Landsteiner's guinea-pig sensitization test (no further
information available), which is not a standard method,
N-phenyl-1-naphthylamine did not exhibit sensitizing
potential (MacEwen & Vernot, 1974).
Single exposure
The acute oral toxicity of N-phenyl-1-naphthylamine
is low. Studies performed according to standard
protocols yielded LD50s in male and female Wistar rats of
>5000 mg/kg body weight (Bayer AG, 1978a,b). LD50s
for male CFE rats and male CF-1 mice are >1625 mg/kg
body weight (MacEwen & Vernot, 1974; Vernot et al.,
1977) and 1231 mg/kg body weight (MacEwen & Vernot,
1974), respectively. No specific signs of toxicity were
reported.
8.3
In five female Sprague-Dawley rats (two untreated
controls), no adverse clinical signs or effects on body
weight gain were noted after daily oral (gavage)
administration of 2000 mg N-phenyl-1-naphthylamine/kg
body weight, 5 days per week for 2 weeks. Data
concerning the purity of the test substance or the
formulation administered were not provided. Gross
morphological observations (no histopathological
examination) made at necropsy revealed no evidence of
exposure-related effects (Mobil Oil Corp., 1989).
Slight fatty degeneration in the liver of rabbits was
observed 3 months after a single subcutaneous injection
of 200 mg N-phenyl-1-naphthylamine/kg body weight
(Bayer AG, 1931). Like other aromatic amines, Nphenyl-1-naphthylamine induces the formation of
methaemoglobin. In mice, a slightly increased
methaemoglobin level (4.1% versus 0.4% in controls)
was noted within 10 min of a single intraperitoneal
administration; the increase was still detectable up to 24
h later (Nomura, 1977). Mice are less sensitive than
humans to methaemoglobin induction, and this small
increase in methaemoglobin level may be of importance
to human health. Data on effects related to acute
exposure to N-phenyl-1-naphthylamine via the
inhalation route were not identified.
8.2
Short-term exposure
Older studies (Bayer AG, 1931) performed with small
numbers of rabbits, although inadequate to serve as a
basis for the determination of putative effect levels, may
provide some useful information on toxicity and target
organs. The oral administration of 200 mg N-phenyl-1naphthylamine/kg body weight per day, 5 days per week
for 6 weeks, resulted in diarrhoea, proteinuria, slight
irritation of the kidneys, and a fatty degeneration of the
liver. After the subcutaneous administration (42 times in
7 weeks) of 50 or 200 mg N-phenyl-1-naphthylamine/kg
body weight per day, a fatty degeneration of the liver
and single proliferation of connective tissue were noted
3 months after the cessation of exposure. Dermal
application of a 5% solution of N-phenyl-1naphthylamine to the ear (28 times within 5 weeks)
produced slight skin erythema, proteinuria, and anorexia.
Death occurred 5 days after the 27th application, and
necropsy revealed fatty degeneration of the liver (Bayer
AG, 1931).
Irritation and sensitization
Three studies assessed skin irritation by N-phenyl-1naphthylamine using the Draize method in rabbits. In
one study, no effects were observed within 72 h of
application (no further information was reported)
(MacEwen & Vernot, 1974). In a study performed
according to US Food and Drug Administration (FDA)
standards, N-phenyl-1-naphthylamine was classified as
a very slight skin irritant (3/6 animals with intact skin and
2/6 animals with abraded skin showed a slight positive
reaction) (van Beek, 1977). In a test conducted
according to OECD guideline 404, N-phenyl-1naphthylamine was not considered to be a skin irritant.
Slight erythema and oedema reactions in 1/3 rabbits were
observed 1 h after removal of the test substance,
whereas no effects were noted after 24 or 72 h (CibaGeigy Corp., 1987b). Studies conducted according to US
FDA standards or OECD guideline 405 did not consider
In mice (sex and number not specified), the
intraperitoneal administration of 219 mg N-phenyl-1naphthylamine/kg body weight for 3 days resulted in
increased methaemoglobin levels (1.6% versus 0.4% in
controls) 48 h after treatment; methaemoglobin
concentrations were not elevated after intraperitoneal
administration of 109 mg/kg body weight for 9 days
(Nomura, 1977).
9
Concise International Chemical Assessment Document 9
8.4
Long-term exposure
8.4.1
Subchronic exposure
significant (p < 0.05) increase in the incidence of kidney
haemangiosarcomas (4/23 versus 0/24 in controls); the
numbers of animals with lung carcinoma were 3/23 and
0/24 in the exposed and control groups, respectively.
The administration of 5.3 mg purified N-phenyl-1naphthylamine per animal, 27 times over 9 weeks (total
dose 143 mg per animal), produced a significant (p <
0.05) increase in the number of animals with lung
carcinomas (6/25 versus 0/24 in controls). The incidence
of kidney haemangiosarcomas was not elevated (1/25
and 0/24 in the exposed and control groups,
respectively); however, there was a significant increase
(p < 0.05) in the combined incidence of kidney and lung
haemangiosarcomas (4/25 versus 0/24 in the controls).
All animals in the study were sacrificed after 10 months.
There are no studies available concerning
subchronic exposure to N-phenyl-1-naphthylamine. In
an oral 13-week study with the isomer N-phenyl-2naphthylamine (approximately 98% pure, containing <1
mg 2-naphthylamine/kg), relative liver weight in F344/N
rats and B6C3F1 mice increased in a dose-dependent
fashion. A chemical-related nephropathy was observed
in rats, characterized by renal tubular epithelial
degeneration and hyperplasia (NTP, 1988).
8.4.2
Chronic exposure and carcinogenicity
In TA-1 mice administered a total dose of 328 mg
technical-grade N-phenyl-1-naphthylamine per animal
subcutaneously over a period of 12 weeks (48 mg
peranimal over 3 weeks, followed by 280 mg per animal
over 9 weeks), there was a significant increase (p < 0.05)
in the incidence of kidney haemangiosarcomas (7/19
compared with 0/18 in unexposed controls). The
incidence of renal tumours was also significantly (p <
0.05) elevated in unilaterally nephrectomized TA-1 mice
(one kidney was removed 1 week prior to treatment)
subcutaneously administered a total dose of 328 mg of
either purified or technical-grade N-phenyl-1naphthylamine per animal over a period of 12 weeks (48
mg per animal over 3 weeks, followed by 280 mg per
animal over 9 weeks). The incidence of kidney
haemangiosarcomas in controls and the unilaterally
nephrectomized animals administered either the pure or
technical-grade material was 0/18, 12/16, and 13/13,
respectively (Wang et al., 1984). Evaluation of this
report is difficult owing to the number of individual
experiments. These studies are characterized by the use
of small numbers of animals of a single sex, limited dose
groups, the absence of data on mortality and morbidity,
use of a non-physiologically relevant route of exposure,
and insufficient characterization of the substance tested.
Long-term toxicity or carcinogenicity studies
performed according to currently accepted standard
protocols using physiologically relevant routes of
exposure were not identified. The inhalation exposure of
four rabbits (number of controls not provided,
approximate dose 100 mg/day) for several months (no
additional information provided) resulted in progressive
anaemia, leucopenia, lymphocytosis, pneumonia,
nephritis, nephrosis, formation of lung abscesses, fatty
degeneration of the liver after 3-5 months, and death
within 6-24 months (Schär, 1930). This study is
characterized by the limited number of animals,
methodological deficiencies, and insufficient
documentation of results.
Bladder tumours were not observed in a long-term
study in which three dogs were orally administered 290
mg N-phenyl-1-naphthylamine 5 days per week for up to
3.5 years (DuPont, 1945; Gehrmann et al., 1948; Haskell
Laboratory, 1971). Owing to the limited number of
animals and the examination for tumours only in the
bladder, this study is inadequate for evaluation of the
carcinogenic potential of N-phenyl-1-naphthylamine
following oral administration.
Wang et al. (1984) observed an increased incidence
of malignant tumours in male ICR and TA-1 mice
following repeated subcutaneous administration of Nphenyl-1-naphthylamine (technical grade or pure; no
additional data provided). In ICR mice, there was a
statistically significant increase (p < 0.05) in the
incidence of lung carcinoma (5/30 versus 0/24 in controls
administered vehicle alone) after the administration of 16
mg technical-grade N-phenyl-1-naphthylamine per
animal 27 times over 9 weeks (total dose 432 mg per
animal). The incidence of kidney haemangiosarcomas
was 1/30 and 0/24 in the exposed and control groups,
respectively; however, the combined incidence of liver,
kidney, and lung haemangiosarcomas was significantly
(p < 0.05) increased in the exposed animals (5/30 versus
0/24 in unexposed controls). The same dosing regimen
using purified N-phenyl-1-naphthylamine produced a
N-Phenyl-2-naphthylamine, which had effects
comparable to those of N-phenyl-1-naphthylamine in
the above-mentioned study by Wang et al. (1984), has
been tested in a 2-year carcinogenicity bioassay (NTP,
1988). There was no evidence of carcinogenic activity in
male or female F344/N rats administered diets containing
2500 or 5000 ppm (mg/kg) N-phenyl-2-naphthylamine
(estimated daily intakes of 100 and 225 mg/kg body
weight for males and 120 and 260 mg/kg body weight for
females, respectively). The lack of carcinogenicity in
rats may be related to an inability to metabolize Nphenyl-2-naphthylamine to the known animal and human
carcinogen 2-naphthylamine (NTP, 1988). There was no
evidence of carcinogenic activity in male B6C3F1 mice
administered diets containing 2500 or 5000 ppm (mg/kg)
N-phenyl-2-naphthylamine (estimated daily intakes of
10
N-Phenyl-1-naphthylamine
500 or 1000 mg/kg body weight, respectively). However,
in female mice receiving these diets (estimated daily
intakes of 450 or 900 mg/kg body weight, respectively),
there was equivocal evidence of carcinogenic activity,
based upon the occurrence of rare kidney neoplasms in
two high-dose animals (one tubular cell adenoma and
one tubular cell adenocarcinoma). For non-neoplastic
effects, the kidney was the principal target organ.
Mineralization, necrosis of the renal papilla, epithelial
hyperplasia, calculi of the kidney pelvis,
hydronephrosis, atrophy, fibrosis, and chronic focal
inflammation of the kidney were observed in the highdose female rats. In male rats of both dose groups and
in the high-dose female rats, cysts and acute
suppurative inflammation of the kidney were also noted.
Nuclear enlargement of renal tubular epithelial cells and
nephropathy were observed in the high-dose female
mice (NTP, 1988).
mg N-phenyl-1-naphthylamine/kg body weight per day
for 5 consecutive days followed by 2 days without
exposure. Each male was then caged with two virgin
females 5 days per week, and the sequence was repeated
weekly with two new females each week for 8 weeks.
Examination of females 14 days from the mid-week in
which they were caged with the males yielded negative
results (Brusick & Matheson, 1976, 1977).
8.6
Data on the reproductive and developmental toxicity
of N-phenyl-1-naphthylamine were not identified.
8.7
Immunological and neurological effects
Data on immunological and neurological effects of Nphenyl-1-naphthylamine in laboratory animals were not
identified.
In a dermal carcinogenicity study, approximately 0.75
mg N-phenyl-1-naphthylamine/kg body weight
(dissolved in 50 µl toluene) was applied to the skin of 50
male C3H mice twice per week for 80 weeks. Data
concerning the purity of the test substance or the
formulation applied were not provided. No adverse
effects on survival or increased incidence of skin
tumours were observed; however, pigmentation,
fibrosis, scar formation, acanthosis, and hyperkeratosis
were noted. Histopathological examinations of organs
other than the skin were not performed (Mobil Oil Corp.,
1985).
8.5
Reproductive and developmental toxicity
9. EFFECTS ON HUMANS
9.1
Case reports
N-Phenyl-1-naphthylamine, mixed with oil (Bayer AG,
1931) or water (Haskell Laboratory, 1971), was not
irritating when applied to the skin of volunteers (no data
on concentrations available). Skin eczema in workers
has been attributed to repeated exposure to high levels
of N-phenyl-1-naphthylamine, possibly in combination
with other substances. Reportedly, the content of Nphenyl-1-naphthylamine in a special antirust oil had to
be lowered from 2% to 0.5% because of skin problems.
Workers, who did not wear gloves, were exposed during
the packaging of bearing rings covered with antirust-oil
containing N-phenyl-1-naphthylamine (Järvholm &
Lavenius, 1981).
Genotoxicity and related end-points
The results of experiments on the genotoxicity of Nphenyl-1-naphthylamine are summarized in Table 1. NPhenyl-1-naphthylamine was not mutagenic in bacterial
tests conducted in the presence or absence of metabolic
activation. In mammalian cells, neither gene mutations
(mouse lymphoma assay) nor chromosomal aberrations
(in vitro metaphase analysis in Chinese hamster ovary
cells or Chinese hamster lung cells) were induced by Nphenyl-1-naphthylamine. A sister chromatid exchange
assay in Chinese hamster ovary cells was marginally
positive in the presence of metabolic activation. An
unscheduled DNA synthesis assay with human lung
(WI-38) cells yielded positive results, although the
effects were not clearly concentration dependent. A
number of non-validated short-term tests yielded
conflicting results on the transforming potential of Nphenyl-1-naphthylamine (BUA, 1993). Based upon the
weight of evidence from in vitro studies, N-phenyl-1naphthylamine does not appear to be genotoxic.
N-Phenyl-1-naphthylamine was also reported to have
sensitizing properties in humans. Case-studies on
patients with contact dermatitis, potentially associated
with occupational exposure to N-phenyl-1naphthylamine in greases or oils, have been identified.
The majority of these patients also had a positive
reaction to other substances in the test series, such as
mercaptobenzothiazole or p-phenylenediamine. Lower
incidences were reported in patients with past exposure
to rubber materials (Blank & Miller, 1952; Schultheiss,
1959; Nater, 1975; Te Lintum & Nater, 1979; Boman et al.,
1980; Järvholm & Lavenius, 1981; Kantoh et al., 1985;
No in vivo somatic cell mutation tests were
identified. In a dominant lethal test, 10 male ICR mice
were intraperitoneally administered 0, 50, 166, or 500
11
Concise International Chemical Assessment Document 9
Table 1: In vitro genotoxicity studies on N-phenyl-1-naphthylamine
Cell type
(end-point)
Test
concentration
Resulta
(with/ without
metabolic
activation)
Remarks
References
Salmonella typhimurium
TA98, TA100, TA1535,
TA1537,TA1538;
Escherichia coli WP2uvrA(gene mutation)
0.5-500 µl/plate with and
without metabolic activation
-/-
Brusick &
Matheseon 1976,
1977
S. typhimurium TA98,
TA100, TA1535, TA1537;
E. coli WP2
(gene mutation)
0.01-1000 µl/plate with and
without metabolic activation
-/-
Baden et al., 1978
S. typhimurium TA97,
TA98, TA100, TA1535,
TA1537
(gene mutation)
0.3-666 µl/plate with and
without metabolic activation
-/-
Zeiger et al., 1988
S. typhimurium TA98,
TA100, TA1537, TA1538
(gene mutation)
0.2-1000 µl/plate with and
without metabolic activation
-/-
JETOC, 1996
E. coli WP2uvrA
(gene mutation)
20-5000 µl/plate with and
without metabolic activation
-/-
JETOC, 1996
S. typhimurium TA98,
TA100, TA1535, TA1537,
TA1538
(gene mutation)
Not provided
-/-
Rannug et al., 1984
Saccharomyces cerevisiae D4
(gene mutation)
0.5-500 µl/plate with and
without metabolic activation
-/-
Brusick &
Matheseon 1976,
1977
Mouse lymphomna
(L5178Y) cells
(gene mutation)
0.005-0.1 µl/plate with
metabolic activation
0.5-25 µl/plate without
metabolic activation
-/-
Brusick &
Matheseon 1976,
1977
Human lung (WI-38) cells
(DNA repair[unscheduled
DNA synthesis])
5, 10, or 50 µl/ml with
metabolic activation
10, 50, or 100 µl/ml
without metabolic activation
- / (+)
Weak positive response at
50 µg/ml and toxic at 100
µg/ml without metabolic
activation; effects not clearly
concentration related
Brusick &
Matheseon 1976,
1977
Human lung (WI-38) cells
(DNA repair[unscheduled
DNA synthesis])
5, 10, or 50 µl/ml with and
without metabolic activation
(+) / (+)
Positive response at 10
µg/ml and toxic at 100
µg/ml with metabolic
activation; positive response
at 5 and 50 µg/ml without
metabolic activation; effects
not clearly concentration
related
Brusick &
Matheseon 1976,
1977
Chinese hamster ovary cells
(sister chromatid exchange)
0.6-19,9 µl/ml with
metabolic activation
1.8-18,2 µl/ml without
metabolic activation
(+) / -
Marginally positive with
metabolic activation
NTP, 1987;
Loveday et aö.,
1990
Chinese hamster ovary cells
(chromosomal aberrations)
1,49-19,9 µl/ml with
metabolic activation
2,99-29,9 µl/ml without
metabolic activation
-/-
NTP, 1987;
Loveday et al.,
1990
Chinese hamster lung cells
(chromosomal aberrations)
15,6 µl/ml with metabolic
activation
30 µl/plate without
metabolic activation
-/-
Sofuni et al., 1990
a - = negative result; (+) = weak positive result
12
N-Phenyl-1-naphthylamine
Kalimo et al., 1989; Carmichael & Foulds, 1990). Because
of the chemical's incorporation into the polymer matrix,
exposure to N-phenyl-1-naphthylamine in rubber
materials is assumed to be lower than exposure from
greases or oils.
9.2
lowest reported NOEC was 0.02 mg/litre (nominal
concentration; solubilizer: ethanol) (Sikka et al., 1981).
Acute toxicity tests in semi-static (daily renewal of
test medium) and flow-through systems yielded 96-h
LC50s in the range of 0.44-0.74 mg N-phenyl-1naphthylamine/litre for rainbow trout (Oncorhynchus
mykiss) and >0.57-0.82 mg/litre for bluegill sunfish
(solubilizers: ethanol and acetone, respectively; nominal
concentrations); the lowest reported NOEC (192 h) was
0.11 mg/litre (Sikka et al., 1981). Sublethal N-phenyl-1naphthylamine concentrations of approximately 5.2 and
5.6 mg/litre had teratogenic effects on embryos and
larvae, respectively, of the clawed frog (Xenopus laevis).
Concentrations above 6.2 mg/litre were lethal (100%
death of larvae within 24 h) for both (Greenhouse,
1976a,b). During neurulation, an EC50 of 4.57 mg/litre for
teratogenic effects was established. For larvae, a 48-h
LC50 of 2.3 mg/litre was determined (Greenhouse, 1977).
For larvae of the leopard frog (Rana pipiens), a 48-h
LC100 of 5 mg/litre was reported; no effects occurred after
24 h of exposure (Greenhouse, 1976b).
Epidemiological studies
An increased occurrence of cancers in a small
packaging unit in a Swedish engineering company was
reported in a cohort study (Järvholm & Lavenius, 1981).
Between 1954 and 1957, a special anticorrosive oil, which
contained 0.5% N-phenyl-1-naphthylamine in addition
to other chemicals, had been used in this unit. In 12 of
78 women in this unit (group A: 78 women/20 men),
cancers were diagnosed between 1964 and 1973 in
several organs (predominantly the uterus and ovary).
The staff performing the actual packaging, and thus in
contact with the oil, were mainly women. Morbidity and
mortality from cancer were 3.1- and 3.5-fold higher,
respectively, than expected, based upon age-specific
and sex-specific data from the Swedish Cancer Register
(the standard cancer rates for the period 1974-1976 were
estimated on the basis of the 1973 rate). In the males of
group A, no significant differences were established. In
another unit (reference group B: 25 women/8 men) where
anticorrosive oil without N-phenyl-1-naphthylamine had
been used, morbidity and mortality from cancer were not
elevated. This was also true for reference group C (8
women/23 men), from units that had been in contact with
N-phenyl-1-naphthylamine-containing anticorrosive oil
for a short period of time only, because they had
demonstrated allergic reactions. The authors concluded
that, apart from exposure to N-phenyl-1-naphthylamine,
the formation of N-nitroso- N-phenyl-1-naphthylamine
from sodium nitrite originating from the packaging paper
used may be a possible explanation for the increased
frequency of cancer in group A.
Data on chronic effects of N-phenyl-1naphthylamine in the aquatic environment are not
available.
10.2
Data on toxic effects of N-phenyl-1-naphthylamine
on terrestrial microorganisms, plants, animals, and
ecosystems are not available.
11. EFFECTS EVALUATION
11.1
10. EFFECTS ON OTHER ORGANISMS IN
THE LABORATORY AND FIELD
10.1
Terrestrial environment
Evaluation of health effects
11.1.1 Hazard identification and
dose–response assessment
Aquatic environment
N-Phenyl-1-naphthylamine is well absorbed and
readily excreted following ingestion; accumulation in the
body is not expected. The acute oral toxicity of Nphenyl-1-naphthylamine in laboratory animals is low.
Based on the results of tests performed according to
OECD guidelines, the substance is not considered to be
a skin or eye irritant. N-Phenyl-1-naphthylamine has
been observed to be a skin sensitizer in laboratory
animals and humans.
Valid results from laboratory tests with ciliates,
Daphnia, and fish indicate that N-phenyl-1naphthylamine is highly toxic to aquatic species. An
EC50 (48 h) of 2 mg N-phenyl-1-naphthylamine/litre
(nominal concentration; static; solubilizer: acetone) was
measured for the inhibition of cell proliferation of
freshwater ciliates (Tetrahymena pyriformis) (Epstein et
al., 1967). Forty-eight-hour LC50s from static and semistatic acute toxicity tests with young and adult
Daphnia magna were in the range of 0.30-0.68 mg Nphenyl-1-naphthylamine/litre (nominal concentration;
solubilizer: ethanol). The lowest reported 21-day LC50
from long-term semi-static tests was 0.06 mg/litre; the
A no-observed-effect level could not be derived from
the available toxicological studies. There is limited
evidence to suggest that the kidneys and liver are the
main target organs following oral exposure to N-phenyl1-naphthylamine, a finding comparable to that observed
13
Concise International Chemical Assessment Document 9
for its isomer, N-phenyl-2-naphthylamine. As indicated
above, useful data on the toxicity of N-phenyl-1naphthylamine are limited, and therefore additional data
on its isomer, N-phenyl-2-naphthylamine, have been
included to assist in the identification of potential target
organs. Available carcinogenicity studies on N-phenyl1-naphthylamine have not been performed according to
currently accepted standard protocols, and therefore the
potential carcinogenicity of this chemical cannot be fully
evaluated. However, in a 2-year carcinogenicity
bioassay conducted with N-phenyl-2-naphthylamine in
cannot be excluded. Although quantitative information
on the leaching of N-phenyl-1-naphthylamine from
rubber products is not available, the extent of such
leaching is expected to be low. Any leached material is
expected to be degraded faster than it is leached.
Indirect exposure of humans to N-phenyl-1naphthylamine leached from rubber products into the
soil is unlikely.
11.2
rats and mice, there was no evidence of carcinogenic
activity in male or female rats or male mice and equivocal
evidence of carcinogenic activity in female mice.
Overall, releases of N-phenyl-1-naphthylamine to the
environment from production and processing (e.g.
vulcanization of rubber mixtures) are expected to be small
in view of the chemical's low production. Based upon
the chemical's physical and chemical properties, it is
predicted that soil and sediment will be affected
indirectly by the leaching of N-phenyl-1-naphthylamine
from decaying tyres and rubber products; however, the
amounts of N-phenyl-1-naphthylamine introduced into
the environment via this route could not be quantified.
Data on the occurrence of N-phenyl-1-naphthylamine in
environmental media were available only from some
older studies for highly polluted river water and
sediment samples; recent measurements on levels in
water, soil, or biota were not identified. Data on
geoaccumulation or on the toxic effects of N-phenyl-1naphthylamine on terrestrial microorganisms, plants,
animals, and ecosystems were unavailable.
N-Phenyl-1-naphthylamine was not mutagenic in
bacterial test systems. In tests with mammalian cells,
some investigations yielded marginally positive or
questionably positive results. Based upon the available
evidence, N-phenyl-1-naphthylamine does not appear to
be genotoxic. It is worth noting, however, that several
aromatic amines (the chemical class to which N-phenyl1-naphthylamine belongs), while yielding negative or
weakly positive results in mutagenicity assays, are
carcinogenic.
An increased occurrence of cancers was observed in
one limited epidemiological study of occupationally
exposed individuals; however, because of the small
number of excess deaths and concomitant exposure to
other chemicals, it is not possible to attribute this
finding solely to N-phenyl-1-naphthylamine.
Information on the reproductive or developmental
toxicity of N-phenyl-1-naphthylamine was not available.
11.1.2
As data on effect levels for terrestrial organisms or
on current concentrations in environmental media were
not available, a quantitative risk assessment for the main
target compartments, water and soil, could not be carried
out; however, some qualitative statements can be made.
Owing to its moderate to high potential for sorption to
organic soil constituents and its limited mineralization in
soil, N-phenyl-1-naphthylamine released to this
environmental compartment is presumed to have
geoaccumulation potential. The probability of its
infiltration into groundwater is low. In laboratory
experiments, the acute toxicity of N-phenyl-1naphthylamine in fish and Daphnia was high, with
lowest reported NOECs of 0.11 mg/litre (192 h) and 0.02
mg/litre (21 days), respectively. Although considerable
bioconcentration factors were measured in fish and
Daphnia, biomagnification and secondary poisoning of
higher trophic levels via the aquatic food-chain seem
unlikely in view of the metabolism and extensive
excretion of N-phenyl-1-naphthylamine. Biodegradation
is expected to be the predominant route of environmental
breakdown; in water, it is aided by the presence of other
degradable substrates, but it is reduced in soil by
sorption. Available N-phenyl-1-naphthylamine is likely
to be biodegraded in both compartments with half-lives
of days to weeks. Photolysis may lead to initial
degradation under favourable conditions but is not
Criteria for setting guidance values for
N-phenyl-1-naphthylamine
Data are inadequate to allow the derivation of a noobserved-effect level or the performance of a risk
estimation for carcinogenicity. Dermal contact with Nphenyl-1-naphthylamine should be avoided because of
its sensitizing properties.
11.1.3
Evaluation of environmental effects
Sample risk characterization
Owing to the lack of available data with which to
derive a suitable guidance value as well as the lack of
information on exposure, a sample quantitative risk
characterization could not be performed. At the
workplace, there is a risk of dermal sensitization from
exposure to greases and antirust oils containing Nphenyl-1-naphthylamine. The risk from exposure to
rubber materials may be much lower, owing to the low
concentrations of N-phenyl-1-naphthylamine in such
materials; a risk to the general population from exposure
to products containing N-phenyl-1-naphthylamine
14
N-Phenyl-1-naphthylamine
considered important in the mineralization of N-phenyl1-naphthylamine. Hydrolysis is of very limited or no
importance in the environment.
12. PREVIOUS EVALUATIONS BY
INTERNATIONAL BODIES
Previous evaluations of N-phenyl-1-naphthylamine
by international bodies were not identified. Information
on international hazard classification and labelling is
included in the International Chemical Safety Card
reproduced in this document.
13. HUMAN HEALTH PROTECTION AND
EMERGENCY ACTION
Human health hazards, together with preventative
and protective measures and first aid recommendations,
are presented in the International Chemical Safety Card
(ICSC ) reproduced in this document.
13.1
Human health hazards
N-Phenyl-1-naphthylamine has sensitizing
properties.
13.2
Advice to physicians
In case of intoxication, the treatment is supportive.
Some chemicals of this class induce
methaemoglobinaemia.
13.3
Spillage
Because N-phenyl-1-naphthylamine is classified as a
sensitizer, emergency crews need to wear proper
equipment to prevent contact with the skin.
14. CURRENT REGULATIONS,
GUIDELINES, AND STANDARDS
Information on national regulations, guidelines, and
standards can be found in the International Register of
Potentially Toxic Chemicals (IRPTC), available from
UNEP Chemicals (IRPTC), Geneva.
The reader should be aware that regulatory decisions
about chemicals taken in a certain country can be fully
understood only in the framework of the legislation of
that country. The regulations and guidelines of all
countries are subject to change and should always be
verified with appropriate regulatory authorities before
application.
15
N-PHENYL-1-NAPHTHYLAMINE
1113
March 1998
CAS No: 90-30-2
RTECS No: QM4500000
UN No:
EC No:
TYPES OF
HAZARD/
EXPOSURE
FIRE
N-(1-Naphthyl)aniline
N-Phenyl-alpha-naphthylamine
C16H13N / C10H7NHC6H5
Molecular mass: 219.30
ACUTE HAZARDS/SYMPTOMS
PREVENTION
FIRST AID/FIRE FIGHTING
Combustible. Gives off irritating or
toxic fumes (or gases) in a fire.
NO open flames.
Powder, water spray, foam, carbon
dioxide.
In case of fire: keep drums, etc.,
cool by spraying with water.
EXPLOSION
EXPOSURE
AVOID ALL CONTACT!
Inhalation
Blue lips or finger nails. Blue skin.
Confusion. Convulsions.
Dizziness. Headache. Nausea.
Unconsciousness.
Local exhaust or breathing
protection.
Fresh air, rest. Refer for medical
attention.
Skin
MAY BE ABSORBED!
Protective gloves. Protective
clothing.
Remove contaminated clothes.
Rinse skin with plenty of water or
shower.
Face shield.
First rinse with plenty of water for
several minutes (remove contact
lenses if easily possible), then take
to a doctor.
Do not eat, drink, or smoke during
work. Wash hands before eating.
Rinse mouth. Refer for medical
attention.
Eyes
Ingestion
(See Inhalation).
SPILLAGE DISPOSAL
PACKAGING & LABELLING
Sweep spilled substance into sealable containers.
Carefully collect remainder, then remove to safe
place. Do NOT let this chemical enter the
environment (extra personal protection: P2 filter
respirator for harmful particles).
Symbol
R:
S:
UN Hazard Class:
UN Pack Group:
EMERGENCY RESPONSE
STORAGE
Well closed.
IPCS
International
Programme on
Chemical Safety
Prepared in the context of cooperation between the International
Programme on Chemical Safety and the European Commission
© IPCS 1999
SEE IMPORTANT INFORMATION ON THE BACK.
1113
N-PHENYL-1-NAPHTHYLAMINE
IMPORTANT DATA
Physical State; Appearance
WHITE TO SLIGHT YELLOWISH CRYSTALS.
Routes of Exposure
The substance can be absorbed into the body by inhalation of
its aerosol, through the skin and by ingestion.
Chemical Dangers
The substance decomposes on burning producing toxic fumes
including nitrogen oxides.
Occupational Exposure Limits
TLV not established.
Inhalation Risk
No indication can be given about the rate in which a harmful
concentration in the air is reached on evaporation of this
substance at 20C.
Effects of Short-term Exposure
The substance may cause effects on the blood, resulting in
formation of methaemoglobin. The effects may be delayed.
Medical observation is indicated.
Effects of Long-term or Repeated Exposure
Repeated or prolonged contact may cause skin sensitization.
PHYSICAL PROPERTIES
Melting point: 62-63C
Relative density (water = 1): 1.2
Solubility in water: none
Octanol/water partition coefficient as log Pow: 4.2
ENVIRONMENTAL DATA
The substance is very toxic to aquatic organisms. In the food chain important to humans, bioaccumulation takes place, specifically
in fish.
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
LEGAL NOTICE
Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible
for the use which might be made of this information
© IPCS 1999
Concise International Chemical Assessment Document 9
REFERENCES
Gehrmann GH, Foulger JH, Fleming AJ (1948) Occupational
tumours of the bladder. Proceedings of the 9th international congress
on industrial medicine (Chairperson: JM MacAlpine), Tudor Room,
Caxton Hall, pp. 472-475.
Baden JM, Kelley M, Simmon VF, Rice SA, Mazze RI (1978)
Fluroxene mutagenicity. Mutation research, 58:183-191.
Bayer AG (1931) Physiologische Eigenschaften von Phenyl-alphanaphthylamin und Phenyl-œ-naphthylamin. Ludwigshafen, I.G. Farben
(not available in print).
Greenhouse GA (1976a) The evaluation of toxic effects of
chemicals in fresh water by using frog embryos and larvae.
Environmental pollution, 11:303-315.
Bayer AG (1978a) Akute orale Toxizität von Additin 30 (Phenylalpha-naphthylamin) bei weiblichen Wistar Ratten. Wuppertal, Bayer AG
(not available in print).
Greenhouse G (1976b) Effects of pollutants on eggs, embryos and
larvae of amphibian species. Wright-Patterson Air Force Base, OH,
Aerospace Medical Research Laboratory, 24 pp. (Report No. AMRL-TR76-31).
Bayer AG (1978b) Akute orale Toxizität von Additin 30 (Phenylalpha-naphthylamin) bei männlichen Wistar Ratten. Wuppertal, Bayer AG
(not available in print).
Greenhouse GA (1977) Toxicity of N-phenyl-alpha-naphthylamine
and hydrazine to Xenopus laevis embryos and larvae. Bulletin of
environmental contamination and toxicology, 18:503-511.
Bayer AG (1990) Biologischer Abbau von Vulkanox PAN (OECD
Guideline 301C; modifiziert). Prüfbericht vom 05.12.1990. Leverkusen,
Bayer AG (not available in print).
Haskell Laboratory (1971) Memorandum to customers. Wilmington,
DE, E.I. DuPont de Nemours & Co. [cited in McCormick WE (undated),
Environmental health control for the rubber industry, Part II, p. 634.]
Blank IH, Miller OG (1952) A study of rubber adhesives in shoes as
the cause of dermatitis of the feet. Journal of the American Medical
Association, 149:1371-1374.
IPCS (1993) International Chemical Safety Card - N-phenyl-1naphthylamine. Geneva, World Health Organization, International
Programme on Chemical Safety (No. 1113).
Boman A, Hagelthorn G, Jeansson I, Karlberg A-T, Rystedt I,
Wahlberg JE (1980) Phenyl-alpha-naphthylamine - case report and
guinea pig studies. Contact dermatitis, 6:299-300.
Järvholm B, Lavenius B (1981) A cohort study on cancer among
workers exposed to an antirust oil. Scandinavian journal of work,
environment & health, 7:179-184.
Brusick D, Matheson DW (1976) Mutagen and oncogen study on
N-phenyl-alpha-naphthylamine - final report (Litton Bionetics, Inc.,
Kensington, MD). Wright-Patterson Air Force Base, OH, Aerospace
Medical Research Laboratory (Report No. AMRL-TR-76-79).
JETOC (1996) Mutagenicity test data of existing chemical
substances based on the toxicity investigation system of the industrial
safety and health law. Tokyo, Japan Chemical Industry EcologyToxicology & Information Center.
Brusick D, Matheson D (1977) Mutagenic evaluation of 1,1dimethylhydrazine, methylhydrazine and N-phenyl-alpha-naphthylamine.
In: Proceedings of the 7th annual conference on environmental
toxicology, 13-15 October 1976. Wright-Patterson Air Force Base, OH,
Aerospace Medical Research Laboratory, pp. 108-129 (Report No.
AMRL-TR-76-125).
Jungclaus GA, Lopez-Avila V, Hites RA (1978) Organic compounds
in an industrial wastewater: a case study of their environmental impact.
Environmental science and technology, 12:88-96.
Kalimo K, Jolanki R, Estlander T, Kanerva L (1989) Contact allergy
to antioxidants in industrial greases. Contact dermatitis, 20:151-152.
BUA (1993) BUA-Stoffbericht N-phenyl-1-naphthylamin.
Beratergremium fuer Umweltrelevante Altstoffe. Weinheim, VCH
VerlagsGmbH (Report No. 113; April 1993).
Kantoh H, Ishihara M, Itoh M, Hosono K, Nishimura M (1985)
Allergens in rubber products. HIFU (Skin research), 27:501-509 (in
Japanese, with English summary).
Carmichael AJ, Foulds IS (1990) Isolated naphthylamine allergy to
phenyl-alpha-naphthylamine. Contact dermatitis, 22:298-299.
Kenaga EE (1980) Predicted bioconcentration factors and soil
sorption coefficients of pesticides and other chemicals. Ecotoxicology
and environmental safety, 4:26-38.
Ciba-Geigy Corp. (1987a) N-Phenyl-1-naphthylamine: Acute dermal
irritation/corrosion study in the rabbit (final report) - with cover letter
dated 10/02/91. Hawthorne, NY, US Environmental Protection Agency,
Office of Toxic Substances (EPA Report OTS 0533599; Doc. ID 86920000033).
Kenaga EE, Goring CAI (1980) Relationship between water
solubility, soil sorption, octanol-water partitioning, and concentration of
chemicals in biota. In: Eaten JG, Parrish PR, Hendricks AC, eds.
Aquatic toxicology. Philadelphia, PA, American Society for Testing and
Materials, pp. 78-115 (ASTM Special Technical Publication 707).
Ciba-Geigy Corp. (1987b) N-Phenyl-1-naphthylamine: Acute eye
irritation/corrosion study in the rabbit (final report) - with cover letter
dated 10/02/91. Hawthorne, NY, US Environmental Protection Agency,
Office of Toxic Substances (EPA Report OTS 0533600; Doc. ID 86920000034).
Lopez-Avila V, Hites RA (1980) Organic compounds in an industrial
wastewater. Their transport into sediments. Environmental science and
technology, 14:1382-1390.
Ciba-Geigy Corp. (1987c) N-Phenyl-1-naphthylamine: Skin
sensitization test in the guinea pig modified maximization test (final
report) - with cover letter dated 10/02/91. Hawthorne, NY, US
Environmental Protection Agency, Office of Toxic Substances (EPA
Report OTS 0533601; Doc. ID 86-920000035s).
Loveday KS, Anderson BE, Resnick MA, Zeiger E (1990)
Chromosome aberration and sister chromatid exchange tests in
Chinese hamster ovary cells in vitro. V: Results with 46 chemicals.
Environmental and molecular mutagenesis, 16:272-303.
CITI (1992) Biodegradation and bioaccumulation. Data of existing
chemicals based on the CSCL Japan. Tokyo, Japan Chemical Industry
Ecology-Toxicology & Information Center, Chemicals Inspection &
Testing Institute.
MacEwen JD, Vernot EH (1974) Toxic hazards research unit annual
technical report: 1974 (University of California). Wright-Patterson Air
Force Base, OH, Aerospace Medical Research Laboratory (Report No.
AMRL-TR-74-78).
DuPont (1945) Aniline tumours of the bladder. Studies of urinary
bladder tumours. Wilmington, DE, E.I. DuPont de Nemours & Co., 7 pp.
Mackay D (1991) Multimedia models: the fugacity approach.
Chelsea, MI, Lewis Publishers.
Epstein SS, Saporoschetz IB, Hutner SO (1967) Toxicity of
antioxidants to Tetrahymena pyriformis. Journal of protozoology, 14:238244.
Magnusson B, Kligman AM (1970) Allergic contact dermatitis in the
guinea pig. Identification of contact allergens. Springfield, IL, Charles C.
Thomas.
18
N-Phenyl-1-naphthylamine
Miyazaki K, Kawai S, Sasayama T, Iseki K, Arita T (1987)
Absorption, metabolism and excretion of N-phenyl-1-naphthylamine in
rat. Yakuzaigaku, 47:17-22 (in Japanese, with English summary).
Te Lintum JCA, Nater JP (1979) Allergic contact dermatitis caused
by rubber chemicals in dairy workers. Dermatologica, 148:42-44.
Mobil Oil Corp. (1985) Dermal carcinogenicity in mice - with cover
letter dated 12/17/91. Princeton, NJ, US Environmental Protection
Agency, Office of Toxic Substances (EPA Report OTS 0533828; Doc.
ID 86-920000547S).
Thomas RG (1990) Volatilization from water. In: Lyman WJ, Reehl
WF, Rosenblatt DH, eds. Handbook of chemical property estimation
methods. Environmental behavior of organic compounds. New York, NY,
McGraw-Hill Book Co., pp. 15-34.
Mobil Oil Corp. (1989) Two-week oral toxicity study in female rats
(final report) - with cover letter dated 12/17/91. Princeton, NJ, US
Environmental Protection Agency, Office of Toxic Substances (EPA
Report OTS 0533821; Doc. ID 86-920000540S).
Union Carbide (1996) Material safety data sheet from 2/22/96.
Union Carbide Corporation, South Charleston Plant (USA), 8 pp.
van Beek L (1977) Primary skin and eye irritation tests with the
compound WTR 10 in albino rabbits. Zeist, TNO Central Institute on
Nutrition and Food Research, 10 pp. (Report No. R 5468).
Nater JP (1975) Überempfindlichkeit gegen Gummi.
Berufsdermatosen, 23:161-168.
Vernot EH, MacEwen JD, Haun CC, Kinkead ER (1977) Acute
toxicity and skin corrosion data for some organic and inorganic
compounds and aqueous solutions. Toxicology and applied
pharmacology, 42:417-423.
NIOSH (1976) Metabolic precursors of a known human carcinogen,
beta-naphthylamine. Cincinnati, OH, US Department of Health and
Human Services, National Institute of Occupational Safety and Health
(Current Intelligence Bulletin 16; Publication No. 78-127).
Wang H, Wang D, Dzeng R (1984) Carcinogenicity of N-phenyl-1naphthylamine and N-phenyl-2-naphthylamine in mice. Cancer
research, 44:3098-3100.
NIOSH (1984a) NIOSH manual of analytical methods, 3rd ed. Vol.
1. Cincinnati, OH, US Department of Health and Human Services,
National Institute of Occupational Safety and Health, pp. 2002-1 2002-6 (Publication No. 84-100).
Xuanxian X, Wolff T (1992) Metabolism of N-phenyl-2naphthylamine and N-phenyl-1-naphthylamine by rat hepatic
microsomes and hepatocytes. Journal of environmental science, 4:7483.
NIOSH (1984b) NIOSH manual of analytical methods, 3rd ed. Vol.
2. Cincinnati, OH, US Department of Health and Human Services,
National Institute of Occupational Safety and Health, pp. 5518-1 5518-4 (Publication No. 84-100).
Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K (1988)
Salmonella mutagenicity tests: IV. Results from the testing of 300
chemicals. Environmental and molecular mutagenesis, 12:1-158.
Nomura A (1977) Studies of sulfhemoglobin formation by various
drugs. Folia Pharmacologica Japonica, 73:793-802 (in Japanese, with
English summary).
NTP (1987) National Toxicology Program, fiscal year 1987, annual
plan. Research Triangle Park, NC, US Department of Health and
Human Services, National Institutes of Health, National Toxicology
Program, p. 87.
NTP (1988) NTP technical report on the toxicology and
carcinogenesis studies of N-phenyl-2-naphthylamine (CAS no. 135-88-6)
in F344/N rats and B6C3F1 mice (feed studies). Research Triangle Park,
NC, US Department of Health and Human Services, National Institutes
of Health, National Toxicology Program, 4 pp. (NTP TR 333).
Ozeki S, Tejima K (1979) Drug interactions. V. Binding of basic
compounds to bovine serum albumin by fluorescent probe technique.
Chemical and pharmaceutical bulletin, 27:638-646.
Rannug A, Rannug U, Ramel C (1984) Genotoxic effects of
additives in synthetic elastomers with special consideration to the
mechanism of action of thiurames and dithiocarbamates. In: Industrial
hazards of plastics and synthetic elastomers. New York, NY, Alan R.
Liss Inc., pp. 407-419.
Rosenberg A (1983) Microbial metabolism of N-phenyl-1naphthylamine in soil, soil suspensions, and aquatic ecosystems.
Chemosphere, 12:1517-1523.
Schär W (1930) Experimentelle Erzeugung von Blasentumoren. Die
Wirkung langdauernder Inhalation von aromatischen
Aminoverbindungen. Deutsche Zeitschrift für Chirurgie, 226:81-97.
Schultheiss E (1959) Gummi und Ekzem (3. Mitteilung), Kasuistik.
Berufsdermatosen, 5:76-96.
Sikka HC, Pack EJ, Sugatt RH, Banerjee S, Rosenberg A,
Simpson BW (1981) Environmental fate and effects of N -phenyl-1naphthylamine and its disposition and metabolism in the rat. Syracuse,
NY, Syracuse Research Co., 106 pp. (Report No. AFOSR-TR-810703).
Sofuni T, Matsuoka A, Sawada M, Ishidate M, Zeiger E, Shelby MD
(1990) A comparison of chromosome aberration induction by 25
compounds tested by two hamster cell (CHL and CHO) systems in
culture. Mutation research, 241:175-213.
19
Concise International Chemical Assessment Document 9
APPENDIX 1 — SOURCE DOCUMENT
APPENDIX 2 — CICAD PEER REVIEW
BUA-Stoffbericht N-phenyl-1-naphthylamin.
Beratergremium fuer Umweltrelevante Altstoffe (Report No.
113; April 1993). VCH VerlagsGmbH, Weinheim
The draft CICAD on N-phenyl-1-naphthylamine was
sent for review to institutions and organizations identified by
IPCS after contact with IPCS national Contact Points and
Participating Institutions, as well as to identified experts.
Comments were received from:
For the BUA review process, the company that is in charge of
writing the report (usually the largest producer in Germany)
prepares a draft report using literature from an extensive
literature search as well as internal company studies. This draft
is subject to a peer review during several readings of a working
group consisting of representatives from government agencies,
the scientific community, and industry.
Department of Health, London, United Kingdom
Health and Safety Executive, Bootle, United Kingdom
Health Canada, Ottawa, Canada
The English translation of the BUA report (BUA Report Nphenyl-1-naphthylamine. GDCh-Advisory Committee on Existing
Chemicals of Environmental Relevance. VCH VerlagsGmbH,
Weinheim) was released in 1994.
National Chemicals Inspectorate (KEMI), Solna,
Sweden
National Institute for Working Life, Solna, Sweden
National Institute of Occupational Health, Budapest,
Hungary
National Institute of Public Health, Oslo, Norway
National Institute of Public Health and Environmental
Protection, Bilthoven, The Netherlands
United States Department of Health and Human
Services (National Institute for Occupational Safety
and Health, Cincinnati, USA; National Institute of
Environmental Health Sciences, Research Triangle
Park, USA)
20
N-Phenyl-1-naphthylamine
(representing ECETOC, the European Centre for Ecotoxicology
and Toxicology of Chemicals)
APPENDIX 3 — CICAD FINAL REVIEW
BOARD
Mr R. Green,1 International Federation of Chemical, Energy,
Mine and General Workers’ Unions, Brussels, Belgium
Berlin, Germany, 26–28 November 1997
Dr B. Hansen,1 European Chemicals Bureau, European
Commission, Ispra, Italy
Members
Dr J. Heuer, Federal Institute for Health Protection of
Consumers & Veterinary Medicine, Berlin, Germany
Dr H. Ahlers, Education and Information Division, National
Institute for Occupational Safety and Health, Cincinnati, OH,
USA
Mr T. Jacob,1 DuPont, Washington, DC, USA
Mr R. Cary, Health Directorate, Health and Safety Executive,
Bootle, United Kingdom
Ms L. Onyon, Environment Directorate, Organisation for
Economic Co-operation and Development, Paris, France
Dr S. Dobson, Institute of Terrestrial Ecology, Huntingdon,
United Kingdom
Dr H.J. Weideli, Ciba Speciality Chemicals Inc., Basel,
Switzerland (representing CEFIC, the European Chemical
Industry Council)
Dr R.F. Hertel, Federal Institute for Health Protection of
Consumers & Veterinary Medicine, Berlin, Germany
(Chairperson)
Secretariat
Mr J.R. Hickman, Health Protection Branch, Health Canada,
Ottawa, Ontario, Canada
Dr M. Baril, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr I. Mangelsdorf, Documentation and Assessment of
Chemicals, Fraunhofer Institute for Toxicology and Aerosol
Research, Hanover, Germany
Dr R.G. Liteplo, Health Canada, Ottawa, Ontario, Canada
Ms L. Regis, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Ms M.E. Meek, Environmental Health Directorate, Health
Canada, Ottawa, Ontario, Canada (Rapporteur)
Mr A. Strawson, Health and Safety Executive, London,
United Kingdom
Dr K. Paksy, Department of Reproductive Toxicology,
National Institute of Occupational Health, Budapest, Hungary
Dr P. Toft, Associate Director, International Programme on
Chemical Safety, World Health Organization, Geneva,
Switzerland
Mr V. Quarg, Ministry for the Environment, Nature
Conservation & Nuclear Safety, Bonn, Germany
Mr D. Renshaw, Department of Health, London, United
Kingdom
Dr J. Sekizawa, Division of Chemo-Bio Informatics, National
Institute of Health Sciences, Tokyo, Japan
Prof. S. Soliman, Department of Pesticide Chemistry,
Alexandria University, Alexandria, Egypt (Vice-Chairperson)
Dr M. Wallen, National Chemicals Inspectorate (KEMI),
Solna, Sweden
Ms D. Willcocks, Chemical Assessment Division, Worksafe
Australia, Camperdown, Australia
Dr M. Williams-Johnson, Division of Toxicology, Agency for
Toxic Substances and Disease Registry, Atlanta, GA, USA
Dr K. Ziegler-Skylakakis, Senatskommission der Deutschen
Forschungsgemeinschaft zuer Pruefung gesundheitsschaedlicher
Arbeitsstoffe, GSF-Institut fuer Toxikologie, Neuherberg,
Oberschleissheim, Germany
Observers
Mrs B. Dinham,1 The Pesticide Trust, London, United
Kingdom
Dr R. Ebert, KSU Ps-Toxicology, Huels AG, Marl, Germany
1
Invited but unable to attend.
21
Concise International Chemical Assessment Document 9
RÉSUMÉ D’ORIENTATION
caoutchouc, mais là encore, on ne dispose d’aucune
donnée. La présence de N-phényl-1-naphtylamine dans
les huiles de graissage ne devrait pas contribuer à sa
libération dans l’atmosphère, car ces huiles sont utilisées
en circuit fermé. Globalement, compte tenu des capacités
de production limitées et de l’application de techniques
de réduction des émissions, la quantité de Nphényl-1-naphtylamine libérée dans l’environnement
devrait être faible.
Ce CICAD relatif à la N-phényl-1-naphtylamine est
fondé principalement sur une étude menée par l’Institut
Fraunhofer de Toxicologie et de Recherche sur les
Aérosols de Hanovre (Allemagne) pour le compte du
Comité consultatif allemand sur les substances chimiques importantes pour l’environnement (BUA, 1993).
Cette étude évalue les effets potentiels de la N-phényl1-naphtylamine sur l’environnement et la santé humaine.
Le rapport du BUA s’appuie sur les données disponibles
jusqu’en 1992. Une recherche bibliographique
approfondie a été menée en 1997 dans plusieurs bases
de données en ligne pour retrouver toutes les références
publiées postérieurement au rapport du BUA. Les
informations relatives à la préparation du document
initial et à son examen par les pairs figurent à l’appendice 1. Les renseignements concernant l’examen du
CICAD par les pairs font l’objet de l’appendice 2. Ce
CICAD a été approuvé en tant qu’évaluation internationale lors d’une réunion du Comité d’évaluation
finale qui s’est tenue à Berlin (Allemagne) du 26 au
28 novembre 1997. La liste des participants à cette
réunion figure à l’appendice 3. La fiche d’information
sur la sécurité chimique de la N-phényl-1-naphtylamine
(ICSC 1113), établie par le Programme international sur la
Sécurité chimique (IPCS, 1993), est également reproduite
dans le présent document.
Selon des études de laboratoire, la Nphényl-1-naphtylamine subit une dégradation
photochimique dans l’eau avec une demi-vie de 8,4 ou
5,7 minutes. La photolyse peut conduire à une
dégradation préliminaire dans des conditions favorables,
mais une dégradation ultérieure est peu probable. Dans
l’environnement, la substance résiste à l’hydrolyse et sa
biodégradation dans l’eau et le sol se fait lentement. En
raison d’un potentiel de sorption modéré à élevé sur les
constituants organiques du sol et d’une minéralisation
limitée dans le sol, on peut supposer que la
N-phényl-1-naphtylamine présente un potentiel de
géoaccumulation. La probabilité d’infiltration dans les
eaux souterraines est faible. Les résultats d’études
effectuées sur des daphnies et des poissons et un
log Ko/w de 4,2 laissent supposer que la
N-phényl-1-naphtylamine a un potentiel de bioaccumulation modéré. Néanmoins, une contamination secondaire des niveaux trophiques supérieurs par la chaîne
alimentaire aquatique semble peu probable compte tenu
du fait que la substance est métabolisée et excrétée dans
des proportions importantes. La N-phényl-1-naphtylamine est très toxique pour les poissons et les daphnies,
avec des concentrations sans effet observé (NOEC) de
0,11 mg/litre (192 h) et 0,02 mg/litre (21 jours), respectivement. En dépit d’une dégradation hydrolytique ou
biologique limitée, les mécanismes de sorption et de
dégradation photochimique devraient contribuer à
réduire considérablement la biodisponibilité de la
substance dans l’eau.
La N-phényl-1-naphtylamine (CAS No 90-30-2) est
un solide cristallin lipophile utilisé comme antioxygène
dans diverses huiles de graissage et comme agent
protecteur et antioxygène dans le caoutchouc et les
mélanges à base de caoutchouc servant à la fabrication
de différents produits, notamment les pneumatiques. De
1986 à 1990, la capacité mondiale de production de la
N-phényl-1-naphtylamine a été estimée à 3000 tonnes par
an. Une entreprise allemande est la seule à produire
cette substance dans l’Union européenne.
Compte tenu des propriétés physico-chimiques de
la N-phényl-1-naphtylamine, sa distribution dans l’environnement, prédite sur la base d’un modèle de fugacité
de niveau II est approximativement la suivante : 36 %
dans le sol, 34 % dans les sédiments, 29 % dans l’eau et
moins de 1 % dans l’air, les sédiments en suspension et
les biotes. Il n’existe pas de données quantitatives sur
les rejets de N-phényl-1-naphtylamine dans l’environnement lors de sa production, de sa transformation et de
son utilisation. Des rejets indirects sont possibles dans
le sol et les eaux de surface en cas de fuites d’huiles de
graissage ou par suite d’un relargage lors de la dégradation des pneus et des articles en caoutchouc, mais on ne
dispose pas de données quantitatives à ce sujet. La
N-phényl-1-naphtylamine peut être libérée dans l’atmosphère avec les gaz émis lors de sa production et de son
traitement ou à l’occasion de la vulcanisation du
Les données connues sur les niveaux de Nphényl-1-naphtylamine dans l’environnement se limitent
aux résultats d’études relativement anciennes menées
aux États-Unis d’Amérique, selon lesquelles la
substance a été détectée dans l’eau (2-7 µg/litre) et les
sédiments (1-5 mg/kg) des cours d’eau à proximité d’une
petite usine de fabrication de produits chimiques. Les
données disponibles n’ont pas permis d’évaluer
l’exposition humaine ni de prédire les concentrations à
l’aide d’un modèle de fugacité.
Selon des études menées sur des animaux
de laboratoire, la N-phényl-1-naphtylamine est bien
absorbée et facilement excrétée après ingestion. Chez le
rat, 60 % de la dose ingérée ont été excrétés dans les
fèces et 35 % dans l’urine au cours des 72 heures
suivantes. Plusieurs métabolites non identifiées ont été
22
N-Phenyl-1-naphthylamine
détectées dans l’urine de rats exposés à la substance.
D’après des études in vitro, il semble que le principal
mécanisme de métabolisation de la N-phényl-1-naphtylamine soit l’hydroxylation.
La toxicité aiguë par voie orale de la N-phényl-1naphtylamine chez les animaux de laboratoire est faible.
La substance a été soumise à des épreuves normalisées
chez le lapin, qui ont montré qu’elle n’était irritante ni
pour la peau ni pour l’œil. Toutefois, un test de
maximalisation sur cobayes a révélé que la N-phényl-1naphtylamine était un sensibilisant de la peau, ce qui a
été confirmé par des épreuves pratiquées sur des
personnes exposées à des graisses ou à des
caoutchoucs contenant cette substance.
Des données limitées montrent que les principaux
organes cibles après ingestion sont les reins et le foie.
On n’a trouvé aucune étude permettant de déterminer les
concentrations suivies d’un effet présumé. Le potentiel
cancérogène de la N-phényl-1-naphtylamine n’a pu être
pleinement évalué car aucune des études disponibles n’a
été menée conformément aux normes actuellement
reconnues.
La N-phényl-1-naphtylamine ne s’est pas révélée
mutagène sur des cellules bactériennes et il n’y a pas eu
augmentation de la fréquence des mutations géniques
(analyse des mutations du lymphome de la souris) ni des
aberrations chromosomiques (analyse in vitro de la
métaphase sur des cellules d’ovaires ou de poumons de
hamsters chinois) dans ce type de cellules à la suite
d’une exposition in vitro. On a signalé un résultat
faiblement positif dans une épreuve d’échange de
chromatides sœurs sur des cellules d’ovaires de
hamsters chinois avec activation métabolique. Il y a eu
augmentation de la synthèse non programmée d’ADN
dans des cellules de poumon humain exposé (WI-38);
toutefois, cet effet n’a pas semblé clairement lié à la
concentration. Un test de létalité dominante a donné un
résultat négatif chez la souris. D’après les données
disponibles, la N-phényl-1-naphtylamine ne semble pas
génotoxique. Aucune donnée n’a été trouvée sur la
toxicité pour la reproduction ou le développement ni sur
les effets immunologiques ou neurologiques de la Nphényl-1-naphtylamine.
Une étude épidémiologique a révélé une
augmentation du taux de cancers chez des ouvriers
exposés à la N-phényl-1-naphtylamine; toutefois, cet
effet n’a pu être attribué exclusivement à la N-phényl-1naphtylamine en raison du petit nombre de décès
supplémentaires et de l’exposition concomitante à
d’autres substances. Bien que les données disponibles
soient insuffisantes pour caractériser exactement les
risques potentiels pour la santé, il convient d’éviter le
contact de la N-phényl-1-naphtylamine avec la peau en
raison de ses propriétés sensibilisantes.
23
Concise International Chemical Assessment Document 9
RESUMEN DE ORIENTACIÓN
durante su producción y tratamiento y a partir de la
vulcanización de las mezclas de caucho. El uso de
aceites lubricantes con N-fenil-1-naftilamina no debería
contribuir a su liberación en la atmósfera, puesto que
estos aceites se aplican en sistemas cerrados. En
conjunto, teniendo en cuenta la capacidad de
producción limitada y la aplicación de técnicas de
reducción de las emisiones, la cantidad de N-fenil-1naftilamina liberada en el medio ambiente debería ser
baja.
Este CICAD relativo a la N-fenil-1-naftilamina se
basa fundamentalmente en un examen preparado por el
Instituto Fraunhofer de Toxicología y de Investigación
sobre los Aerosoles de Hannover, Alemania, para el
Comité Consultivo Alemán sobre las Sustancias
Químicas Importantes para el Medio Ambiente (BUA,
1993; versión inglesa: BUA, 1994). Este estudio evalúa
los efectos potenciales de la N-fenil-1-naftilamina en el
medio ambiente y la salud humana. El informe del BUA
se basa en los datos disponibles hasta 1992. En 1997 se
realizó una investigación bibliográfica amplia de varias
bases de datos en línea para encontrar todas las
referencias publicadas con posterioridad al informe del
BUA. La información sobre la preparación del
documento original y su examen colegiado figura en el
Apéndice 1. La información acerca del examen colegiado
de este CICAD se presenta en el Apéndice 2. Este
CICAD se aprobó como evaluación internacional en una
reunión de la Junta de Evaluación Final celebrada en
Berlín (Alemania) los días 26-28 de noviembre de 1997.
La lista de participantes en esta reunión figura en el
Apéndice 3. La Ficha internacional de seguridad
química (ICSC 1113) para la N-fenil-1-naftilamina,
preparada por el Programa Internacional de Seguridad de
las Sustancias Químicas (IPCS, 1993), también se
reproduce en el presente documento.
Según los estudios de laboratorio, la N-fenil-1naftilamina sufre una degradación fotoquímica en el agua
con una semivida de 8,4 y 5,7 minutos. La fotolisis
puede dar lugar a una degradación preliminar en
condiciones favorables, pero es poco probable que se
produzca una degradación ulterior. En el medio
ambiente, la sustancia resiste la hidrólisis, y la
eliminación por biodegradación en el agua y el suelo es
lenta. Habida cuenta de su potencial de sorción entre
moderado y alto en los constituyentes orgánicos del
suelo y de su mineralización limitada en el suelo, se
supone que la N-fenil-1-naftilamina tiene un potencial de
geoacumulación. La probabilidad de infiltración en el
agua fréatica es baja. Los resultados de los estudios
efectuados con Daphnia y con peces y el log Ko/w de
4,2 obtenido hacen suponer que la N-fenil-1-naftilamina
tiene un potencial de bioacumulación moderado. No
obstante, la contaminación secundaria de los niveles
tróficos superiores a través de la cadena alimentaria
acuática parece poco probable, teniendo en cuenta que
la sustancia se metaboliza y excreta en proporciones
importantes. La N-fenil-1-naftilamina es muy tóxica para
los peces y para Daphnia, siendo la concentración sin
efectos observados (NOEC) más que baja que se ha
notificado de 0,11 mg/litro (192 h) y de 0,02 mg/litro (21
días), respectivamente. A pesar de producirse una
degradación hidrolítica o biológica limitada, los
mecanismos de sorción y de degradación fotoquímica
deberían contribuir a reducir considerablemente la
disponibilidad de la sustancia en el agua.
La N-fenil-1-naftilamina (CAS Nº 90-30-2) es una
sustancia cristalina lipófila utilizada como antioxidante
en diversos aceites lubricantes y como agente protector
y antioxidante en el caucho y las mezclas a base de
caucho que se emplean en la fabricación de diferentes
productos, en particular los neumáticos. De 1986 a 1990,
la capacidad estimada de producción mundial de Nfenil-1-naftilamina fue de 3000 toneladas al año. Una
empresa alemana es la única productora de esta
sustancia en la Unión Europea.
Teniendo en cuenta las propiedades fisicoquímicas
de la N-fenil-1-naftilamina, su distribución en el medio
ambiente, prevista tomando como base el modelo de
fugacidad de nivel II, es la siguiente: 36% en el suelo,
34% en los sedimentos, 29% en el agua y menos del 1%
en el aire, los sedimentos en suspensión y la biota. No
existen datos cuantitativos de la liberación de N-fenil-1naftilamina en el medio ambiente a partir de su
producción, elaboración y uso. Se pueden producir
vertidos indirectos en el suelo y en las aguas
superficiales en caso de derrames de aceites lubricantes
o por lixiviación a partir de neumáticos o productos de
caucho en descomposición, pero no se dispone de datos
cuantitativos a este respecto. La N-fenil-1-naftilamina
se puede liberar en la atmósfera con los gases de escape
Los datos conocidos sobre los niveles de N-fenil-1naftilamina en el medio ambiente se limitan a los
resultados de estudios relativamente antiguos realizados
en los Estados Unidos, según los cuales la sustancia se
detectó en el agua (2-7 µg/litro) y en los sedimentos (1-5
mg/kg) de un río cerca de una pequeña fábrica de
productos químicos. Los datos disponibles no permiten
evaluar la exposición humana ni predecir las
concentraciones utilizando un modelo de fugacidad.
Según los estudios realizados en animales de
laboratorio, la N-fenil-1-naftilamina se absorbe bien y se
excreta en su mayor parte tras la ingestión. En el caso de
24
N-Phenyl-1-naphthylamine
la rata, el 60% de la dosis administrada se excretó con las
heces y el 35% con la orina en un plazo de 72 horas. En
la orina de ratas expuestas a la sustancia se han
detectado varios metabolitos no identificados. Teniendo
en cuenta los estudios in vitro, parece que el
mecanismo principal de metabolización de la N-fenil-1naftilamina es la hidroxilación.
fallecimientos y a la exposición concomitante a otras
sustancias. Aunque los datos disponibles sean
inadecuados para caracterizar exactamente los riesgos
potenciales para la salud, conviene evitar el contacto
cutáneo con la N-fenil-1-naftilamina, debido a sus
propiedades sensibilizantes.
La toxicidad aguda por vía oral de la N-fenil-1naftilamina en animales de laboratorio es baja. En
pruebas normalizadas realizadas con conejos, se puso de
manifiesto que la sustancia no era irritante de la piel ni
de los ojos. Sin embargo, en una prueba de
maximización realizada con cobayas se observó que la
N-fenil-1-naftilamina tenía propiedades de sensibilizante
cutáneo, y también en seres humanos expuestos a
grasas o a materiales de caucho que contenían esta
sustancia.
Hay datos limitados que indican que los principales
órganos destinatarios tras la ingestión son los riñones y
el hígado. No se ha encontrado ningún estudio
adecuado que permita establecer posibles niveles de
efectos. No se ha podido evaluar completamente la
posible carcinogenicidad de la N-fenil-1-naftilamina,
puesto que ninguno de los estudios disponibles se
realizó de acuerdo con los protocolos normalizados
aceptados actualmente.
La N-fenil-1-naftilamina no fue mutagénica en células
bacterianas, ni produjo un aumento de la frecuencia de
mutaciones génicas (análisis de las mutaciones del
linfoma de ratón) ni de las aberraciones cromosómicas
(análisis in vitro de la metafase en células de los ovarios
y de los pulmones de hámster chino) en este tipo de
células tras la exposición in vitro. Se ha notificado un
resultado débilmente positivo en un ensayo de
intercambio de cromátidas hermanas en células de ovario
de hámster chino con activación metabólica. Se observó
un aumento de síntesis no programada de ADN en
células de pulmón humano expuestas (WI-38); sin
embargo, estos efectos no parecían depender de la
concentración. El resultado de un ensayo de letalidad
dominante realizado con N-fenil-1-naftilamina en ratones
fue negativo. Según los datos disponibles, esta
sustancia no parece ser genotóxica. No se han
encontrado datos acerca de la toxicidad reproductiva y
en el desarrollo y de los efectos inmunológicos o
neurológicos de la N-fenil-1-naftilamina.
En un estudio epidemiológico se observó un
aumento de la frecuencia de cáncer en los trabajadores
expuestos a la N-fenil-1-naftilamina; sin embargo, este
efecto no se puede atribuir exclusivamente a la N-fenil-1naftilamina, debido al pequeño aumento en el número de
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