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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 74






    DIAMINOTOLUENES







    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.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1987


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DIAMINOTOLUENES

 1. SUMMARY AND CONCLUSIONS

     1.1. Summary
          1.1.1. Identity and analytical methods
          1.1.2. Production, uses, and sources of exposure
          1.1.3. Kinetics
                 1.1.3.1  Animal studies
                 1.1.3.2  Human studies
          1.1.4. Effects on organisms in the environment
          1.1.5. Effects on experimental animals
          1.1.6. Effects on human beings
     1.2. Conclusions

 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

     2.1. Identity
     2.2. Physical and chemical properties
     2.3. Conversion factors
     2.4. Analytical methods

 3. SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT AND 
     DISTRIBUTION

     3.1. Natural occurrence
     3.2. Production
     3.3. Uses
     3.4. Release into the environment, distribution, and 
          transformation

 4. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

     4.1. Environmental levels
     4.2. General population exposure
     4.3. Occupational exposure

 5. KINETICS AND METABOLISM

     5.1. Studies on experimental animals
          5.1.1. Absorption and retention
          5.1.2. Distribution and reaction with body components
          5.1.3. Metabolism
          5.1.4. Excretion
     5.2. Human studies

 6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

 7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

     7.1. Single exposures
     7.2. Short-term exposures
     7.3. Long-term exposure

     7.4. Reproduction and teratogenicity
          7.4.1. Reproduction
          7.4.2. Teratogenicity
     7.5. Mutagenicity and related end-points
          7.5.1. DNA damage
          7.5.2. Mutation
          7.5.3. Cell transformation
          7.5.4. Chromosomal effects
     7.6. Carcinogenicity

 8. EFFECTS ON MAN

     8.1. Single and short-term exposures
     8.2. Long-term occupational exposure - epidemiological studies

 9. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE 
     ENVIRONMENT

     9.1. Evaluation of human health risks
          9.1.1. General considerations
          9.1.2. Assessment of exposure
          9.1.3. Single and short-term exposures
          9.1.4. Long-term exposure
                 9.1.4.1  Carcinogenicity and mutagenicity
                 9.1.4.2  Reproduction and teratogenicity
     9.2. Evaluation of effects on the environment
     9.3. Conclusions

10. RECOMMENDATIONS

11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

WHO TASK GROUP ON DIAMINOTOLUENES

 Members

Dr X. Baur, Pulmonary Section, Klinikum Grosshaden, University of 
   Munich, Munich, Federal Republic of Germany 

Dr L. Belin, Department of Medicine, Sahlgren's Hospital, Goteborg, 
   Sweden 

Ms Andrea Blaschka, Office of Toxic Substances, US Environmental
   Protection Agency, Washington DC, USA  (Co-Rapporteur)

Dr M. Dieter, US National Institute for Environmental Health 
   Sciences, Research Triangle Park, North Carolina, USA 
    (Co-Rapporteur)

Dr M. Greenberg, Department of Health and Social Security, London, 
   United Kingdom 

Dr I. Gut, Institute of Hygiene and Epidemiology, Prague,
   Czechoslovakia  (Chairman)

Dr M. Mann, Bayer AG, Leverkusen, Bayerwerk, Federal Republic of 
   Germany 

Dr C. Rosenburg, Institute of Occupational Health, Department of 
   Industrial Hygiene and Toxicology, Helsinki, Finland 

Professor H. Sakurai, School of Medicine, Keio University, Tokyo, 
   Japan 

 Secretariat

Dr G.C. Becking, International Programme on Chemical Safety,
   Interregional Research Unit, World Health Organization,
   Research Triangle Park, North Carolina, USA  (Secretary)

Mr A.C. Fletcher, International Agency for Research on Cancer,
   Lyons, France

NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors that may have occurred to the 
Manager of the International Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 



                       *    *    *



    A detailed data profile and a legal file can be obtained from 
the International Register of Potentially Toxic Chemicals, Palais 
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 - 
985850). 

ENVIRONMENTAL HEALTH CRITERIA FOR DIAMINOTOLUENES

    A WHO Task Group on Environmental Health Criteria for 
Diaminotoluenes met at the Monitoring and Assessment Research 
Centre, London, United Kingdom, from 20 to 25 October 1986. 
Professor P.J. Petersen welcomed the participants on behalf of the 
host Institution, and Dr G.C. Becking opened the meeting on behalf 
of the three co-sponsoring organizations of the IPCS 
(ILO/UNEP/WHO).  The Task Group reviewed and revised the draft 
criteria document and made an evaluation of the health risks of 
exposure to diaminotoluenes. 

    The efforts of MS ANDREA BLASCHKA, US ENVIRONMENTAL PROTECTION 
AGENCY, Washington DC, USA, in the preparation of the draft, and of 
all others who helped in the preparation and finalization of the 
document are gratefully acknowledged. 



                          * * *



    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO Collaborating Centre for Environmental 
Health Effects.  The United Kingdom Department of Health and Social 
Security generously supported the cost of printing. 

1.  SUMMARY AND CONCLUSIONS

1.1.  Summary

1.1.1.  Identity and analytical methods

    Diaminotoluenes are synthetic aromatic amines (total of 6 
isomers).  The isolated, purified isomers are colourless crystals, 
while the commercial isomeric mixtures are light yellow to tan 
(Meta-diaminotoluene), or light grey to purple (Ortho-diamino-
toluene) solids.  Diaminotoluenes are soluble in hot water, 
alcohol, ether, and hot benzene.  When heated, they emit toxic 
fumes of nitrogen oxides. 

    Several qualitative and quantitative procedures for the 
determination of diaminotoluenes have been developed using thin-
layer, high-performance-liquid, or gas chromatography, methods.  
Detection limits in air samples range from 0.1 to 10 g/m3.  The
isomeric ratios in technical grade mixtures have been determined by 
nuclear magnetic resonance and infra-red spectrometry. 

1.1.2.  Production, uses, and sources of exposure

    Diaminotoluenes are produced from dinitrotoluenes through a 
catalytic hydrogenation procedure, or by the reaction of iron and 
hydrochloric acid with dinitrotoluenes.  Diaminotoluenes are large-
volume intermediates used in the production of a wide variety of 
industrial and consumer products.  The mixture of 2,4- and 2,6-
isomers is used predominantly as an intermediate in the manufacture 
of toluene diisocyanate.  Commercial mixtures of 2,3- and 3,4-
isomers, as well as the 2,4- and 2,6-isomers, are used as co-
reactants or as raw materials in the manufacture of urethane 
products, dyes, corrosion inhibitors, and rubber antioxidants.  
Diaminotoluene isomers have relatively limited use as epoxy curing 
agents and as photographic developers.  The most commonly marketed 
isomers and isomer mixtures are 2,4-diaminotoluene (2,4-DAT), 3,4-
DAT, Meta-DAT (an 80:20 or 65:35 mixture of the 2,4- and 2,6-
isomers), and Ortho-DAT (3,4-, 2,3-isomers, as 60:40 mixture); 2,5-
diaminotoluene is also marketed in small quantities.  These isomers 
and their mixtures are reviewed together, because any single 
commercial product will contain various levels of the other 
isomers. 

    The major sources of environmental pollution are the 
manufacture of diaminotoluenes and their products.  Over 50% of the 
losses into the environment are through industrial wastes deposited 
in landfills.  Diaminotoluenes are soluble in water; therefore, 
leakage from landfills or storage sites, and spillage during 
shipping and handling may also represent sources of surface and 
groundwater contamination. 

    Despite the wide use and the water solubility of diamino-
toluenes, there is a lack of information concerning their levels in 
the environment, as well as data on their transport and their fate 
in the ecosystem. 

    Data are not available on the exposure of the general 
population to diaminotoluenes and there is a paucity of data on the 
exposure of workers to diaminotoluenes, though work-place air 
levels ranging up to 0.44 mg/m3, with occasional excursions up to 
11 mg/m3, have been reported. 

1.1.3.  Kinetics

1.1.3.1.  Animal studies

    Diaminotoluenes have been absorbed via all exposure routes 
tested.  Skin penetration by diaminotoluenes is affected by the 
type of vehicle and site of application.  The greatest absorption 
of 2,4-diaminotoluene (approximately 50%) resulted when the test 
material was dissolved in acetone and applied to the abdominal skin 
of monkeys.  Following intraperitoneal injection of [14C]-2,4-
diaminotoluene, absorption was rapid and peak concentrations in rat 
and mouse blood and plasma occurred within 1 h and decreased 
rapidly for 7 h. 

    Distribution varies with different species.  However, data 
indicate that, in most species, the organs with the highest 
concentrations are the liver, kidneys, and adrenal glands.  High 
concentrations are also observed in the gastrointestinal tract, 
while the lowest levels are found in the heart, gonads, brain, and 
blood.  A dose-dependent binding of the 2,4-isomer to hepatic and 
renal proteins has been demonstrated. 

    The acetylation of amino groups, oxidation of methyl groups, 
and ring hydroxylation appear to be the major metabolic steps.  
Phenolic metabolites and trace amounts of unchanged diaminotoluenes 
are excreted in the urine of experimental animals.  Elimination of 
diaminotoluene metabolites takes place via both urine and faeces.  
However, the primary route and rate of elimination varies with 
different species, e.g., urinary elimination is faster and more 
complete in mice (2 days) than in rats (6 days). 

1.1.3.2.  Human studies

    Data are not available on the kinetics and metabolism of 
diaminotoluenes after oral or inhalation exposure.  The results of 
skin penetration studies correspond with those from experimental 
animal studies.  After 40 min of dermal contact, the highest rate 
of urinary excretion occurred 4 - 8 h after exposure.  During 24 h 
of dermal contact, the highest absorption of 2,4-diaminotoluene 
resulted when test material was dissolved in acetone and applied to 
the skin of the forearm (23.7%).  Data from studies on human 
volunteers showed that, after subcutaneous injection of 5.5 mg 2,5-
diaminotoluene, 47.6% of the dose was excreted in the urine as 
 N,N'-diacetyl-2,5-diaminotoluene. 

1.1.4.  Effects on organisms in the environment

    Diaminotoluenes are toxic for aquatic species.   Daphnia, the 
most sensitive species of those tested, was adversely affected at 
concentrations of 2 - 5 mg/litre.  At higher concentrations, 

diaminotoluenes were toxic for ostracods, fish, and algae, the 
algal species tested being the most tolerant.  No data are 
available on other non-mammalian species in the environment. 

1.1.5.  Effects on experimental animals

    2,4- and 2,5-Diaminotoluenes are ocular and dermal irritants.  
Instillation of 100 g 2,4-diaminotoluene in the rabbit eye caused 
severe eye irritation within 24 h.  In rabbits, irritation and 
blisters developed after 24-h dermal contact with 500 mg 2,4-
diaminotoluene or 12.5 mg 2,5-diaminotoluene. 

    Dermal contact with 1 - 10% solutions of 2,5-diaminotoluene 
resulted in the development of severe irritation and leukocyte 
infiltration in 25 - 50% of exposed guinea-pigs.  In addition, 35% 
of the exposed animals were sensitized to the test compound.  
Dermal contact was for 24 h/day for 2 periods of 5 days, separated 
by 2 days free of exposure. 

    Diaminotoluenes are mild cumulative poisons, and their toxicity 
in different species varies considerably.  The acute oral LD50 of 
Meta-diaminotoluene for the mouse was 350 mg/kg body weight; for 
the rat, it ranged from 270 to 300 mg/kg body weight.  The acute 
oral LD50 of Ortho-diaminotoluene for the rat was 810 mg/kg (range, 
590 - 1120 mg/kg body weight).  The dermal LD50 of Meta-
diaminotoluene for the rat was 1200 mg/kg body weight, while the 
dermal LD50 of Ortho-diaminotoluene for the rabbit was 1120 mg/kg 
(range, 650 - 2040 mg/kg body weight). 

    At extremely high exposure levels, diaminotoluenes are toxic 
for the central nervous system, produce jaundice, and induce 
anaemia by destruction of the red blood cells after methaemoglobin 
formation. 

    In short-term studies, the toxic effects of 2,4-diaminotoluene 
are characterized by a decrease in body weight and an increase in 
the liver:body weight ratio.  Following a 5-day oral treatment of 
male F-344 rats with 70 mg 2,4-diaminotoluene/kg body weight, per 
day, the activities of microsomal cytochrome P-450-dependent 
enzymes were depressed, while that of epoxide hydrolase was 
markedly elevated (3 - 8 times that in controls).  2,4-
Diaminotoluene or one of its metabolites has been shown to bind 
irreversibly to hepatic and renal proteins and to liver ribosomal 
RNA.  Oral ingestion of 2,4-diaminotoluene at 50 or 100 mg/kg for 2 
years accelerated the development of chronic renal disease in F-344 
rats, an effect that contributed to a marked decrease in survival. 

    The reproductive and teratogenic effects of diaminotoluenes 
depend on the route of administration, the isomer studied, and the 
species of the experimental animal.  Results of recent studies have 
shown that 2,4-diaminotoluene (98% pure) is a potent reproductive 
toxin in the male rat.  At a level of 0.3 g/kg diet for 10 weeks 
(~ 15 mg/kg body weight per day), this agent produced marked toxic 
effects on spermatogenesis (66% reduction) associated with a 

significant reduction in the weights of the seminal vesicles and 
epididymides, as well as a diminished level of circulating 
testosterone, and an elevation of serum-luteinizing hormone. 

    The 2,6-isomer, but not the 2,4-isomer, is embryotoxic in the 
rat and rabbit and has been reported to cause malformation in the 
rat.  The no-observed-adverse-effect level for 2,6-diaminotoluene 
was 10 mg/kg body weight in the rat, and 30 mg/kg body weight in 
the rabbit.  Ortho-diaminotoluene (2,3-, 3,4-isomer mixture) is 
toxic for the treated dams, their embryos, and fetuses.  The no-
observed-adverse-effect level is 30 mg/kg body weight in both the 
rat and rabbit. 

    Diaminotoluenes have been shown to be mutagenic in several  in 
 vitro assays and in  Drosophila, but the results in several  in vivo  
mammalian assays were negative. 

    2,4-Diaminotoluene is the only isomer that has been reported to 
produce an increased incidence of tumours in rodents.  This isomer 
produces hepatocellular, subcutaneous, and mammary gland tumours in 
rats and hepatocellular and vascular tumours in mice, when present 
in the diet at levels > 79 mg/kg.  On the other hand, it was 
reported that the 2,6-isomer was not carcinogenic for rodents.  
Tumours in the same organs as those affected by 2,4-diaminotoluene 
were found after administration of 2,6-diaminotoluene at > 250 
mg/kg for 103 weeks, but they were considered not significant after 
extensive statistical evaluation. 

1.1.6.  Effects on human beings

    Diaminotoluenes are irritant to the eyes and the skin.  Local 
actions include severe dermatitis, blistering, and urticaria, and, 
in the eye, lachrymation, corneal opacities, and permanent 
blindness, if untreated.  In the case of inhalation of fumes, 
coughing, dyspnoea, and respiratory distress may result. 

    The epidemiological assessment of the reproductive hazards for 
males exposed to DAT (in most cases, together with dinitrotoluene) 
revealed inconclusive findings suggesting adverse effects on sperm 
production and on the viability of pregnancies in women whose 
husbands have been exposed.  Sperm samples from workers in 3 DAT 
production plants showed a reduced sperm count in one plant (with 
the smallest study group and an unusually high sperm count in the 
control group), but also a reduced proportion of large 
morphological sperm.  Studies of the reproductive history of the 
wives of workers in 3 plants (in 2 of which semen analysis was also 
carried out) revealed excess miscarriage rates, which are related 
to DAT exposure in two populations, though both suffered from 
limited size and the risk of some self selection of volunteers who 
participated in the study.  Given the animal evidence of adverse 
effects on spermatogenesis, these findings are of concern. 

1.2.  Conclusions

    Diaminotoluenes are highly irritating to the skin and eyes, and 
the fumes are irritating to the respiratory tract.  Diaminotoluenes 
are readily absorbed through the skin, and exposure may result in 
methaemoglobinaemia.  Renal toxicity after oral administration of 
2,4-diaminotoluene has been reported in experimental animals.  2,4-
Diaminotoluene has been shown to be carcinogenic for animals, but 
there is inadequate evidence to evaluate the carcinogenic potential 
of 2,5- and 2,6-diaminotoluene.  All three of these isomers have 
been shown to be mutagenic.  They are reproductive toxins in 
experimental animals, but human reproduction data are limited. 

    Diaminotoluenes should be handled as hazardous chemicals. 
Preventive measures should be taken to avoid exposure of workers 
and to prevent environmental pollution. 

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

    Diaminotoluenes are synthetic aromatic amines (total of 6 
isomers) with two amino groups and a methyl group attached to a 
benzene ring (Table 1).  The molecular formula is C7H10N2 and the 
relative molecular mass, 122.17. 

Table 1.  Identity of diaminotoluene isomersa
-----------------------------------------------
Diaminotoluenes   CAS         RTECS
                  registry    accession number
                  number      index
-----------------------------------------------
 Isomers

2,3-DAT           2687-25-4   ---

2,4-DAT           95-80-7     XS9625000

2,5-DAT           95-70-5     XS9700000

2,6-DAT           823-40-5    XS9750000

3,4-DAT           496-72-0    XS9820000

3,5-DAT           108-71-4    ---

 Commercial mixture

Meta-DAT                     
(2,4-, 2,6-       95-80-7     ---
isomers mix)      823-40-5
(80:20)

Ortho-DAT         26787-25-4  ---
(2,3-, 3,4-       496-72-0
isomer mix)
(40:60)
-----------------------------------------------
a STRUCTURAL FORMULA:

Chemical Structure

    Commercial grades of diaminotoluenes are available; however, 
the most commonly marketed diaminotoluenes are:  (a) "crude" 
diaminotoluenes-mixture, containing all 6 isomers (Table 1); (b) 
Meta-diaminotoluene (Meta-DAT), containing approximately 80% 2,4- 
and 20% 2,6-isomers (also produced in smaller amounts as 65:35 
mixture); and (c) Ortho-diaminotoluene (Ortho-DAT), consisting of 
approximately 40% 2,3- and 60% 3,4-isomers.  All commercial grades 
contain traces of the other isomers; therefore, diaminotoluenes and 
their mixtures are reviewed together in this document. 

    Most of the common and trade names for commercial 
diaminotoluenes are listed in Table 2. 
Table 2.  Diaminotoluenes synonyms and trade names
----------------------------------------------------------------------------
A.   Commercial mixtures

    I.   Meta-Diaminotoluenes

Chemical abstract name            benzenediamine,ar-methyl- (9CI)

Other chemical names              benzenediamine,ar-methyl (RTECS: TDB);
                                  diaminotoluene (RTECS: TDB);
                                  phenylenediamine,ar-methyl- (TDB);
                                  Meta-diaminotoluene; Meta-toluene-
                                   diamine (MTD);
                                  toluene-ar,ar-diamine (8CI) (CAS: TDB);
                                  toluenediamine (RTECS: TDB, DOT);
                                  tolylenediamine (RTECS, TDB)

Common name                       diaminotoluene; toluenediamine; TDA

    II.   Ortho-Diaminotoluene

Chemical abstract name            benzenediamine,ar-methyl- (9CI)

Other chemical names              o-TDA

Common name                       Ortho-toluenediamine; OTD

B.   Diaminotoluene isomers

    I.   2,3-isomer

Chemical abstract name            1,2-benzenediamine,3-methyl- (9CI)

Other chemical names              toluene-2,3-diamine (8CI) (CAS: TDB);
                                  1-methyl-1,2,3-phenylenediamine (TDB);
                                  1,2-diamino-3-methylbenzene (TDB);
                                  2,3-diaminotoluene (TDB*);
                                  2,3-toluylenediamine (TDB);
                                  2,3-tolylenediamine (TDB);
                                  3-methyl-o-phenylenediamine (TDB);
                                  3-methyl-1,2-phenylenediamine (TDB)

Common names                      2,3-TDA

    II.   2,4-isomer

Chemical abstract name            1,3-benzenediamine,4-methyl- (9CI)
----------------------------------------------------------------------------

Table 2.  (contd.)
----------------------------------------------------------------------------
    II.   2,4-isomer (contd.)

Other chemical names               m-toluenediamine (RTECS);
                                   m-toluylendiamin (Czech, RTECS: TDB);
                                   m-toluylenediamine (RTECS: TDB);
                                   m-tolyenediamine (RTECS: TDB);
                                   m-tolylenediamine (RTECS);
                                  Meta-toluylene diamine (RTECS: TDB);
                                  toluene-2,4-diamine (8CI) (CAS, RTECS:
                                   TDB*);
                                  tolylene-2,4-diamine (RTECS: TDB);
                                  1,3-diamino-4-methylbenzene (RTECS: TDB);
                                  2,4-diamino-1-methylbenzene (RTECS: TDB);
                                  2,4-diamino-1-toluene (RTECS: TDB);
                                  2,4-diaminotoluen (Czech, RTECS: TDB);
                                  2,4-diaminotoluene (MESH, RTECS: TDB);
                                  2,4-diaminotoluol (RTECS: TDB);
                                  2,4-tolamine (RTECS: TDB);
                                  2,4-toluenediamine (MESH, RTECS: TDB);
                                  2,4-toluylenediamine (DOT, RTECS: TDB);
                                  2,4-tolylenediamine (RTECS: TDB);
                                  3-amino- p-toluidine (RTECS: TDB);
                                  4- m-tolylenediamine (RTECS: TDB);
                                  4-methyl- m-phenylenediamine (RTECS: TDB);
                                  4-methyl-1,3-benzenediamine (RTECS: TDB);
                                  5-amino- o-toluidine (RTECS: TDB)

Common names                      TDA; MTD; 2,4-TDA (CAS, RTECS: TDB)

Trade names                       Azogen Developer H; Benzofur MT;
                                  C.I. Oxidation Base (RTECS);
                                  C.I. Oxidation Base 20;
                                  C.I. Oxidation Base 35 (RTECS);
                                  C.I. Oxidation Base 200;
                                  Developer B (RTECS: TDB); Developer DB
                                   (RTECS: TDB);
                                  Developer DBJ (RTECS: TDB); Developer H;
                                  Developer MC (RTECS: TDB); Developer MT
                                   (RTECS: TDB);
                                  Developer MT-CF (RTECS: TDB);
                                  Developer MTD (RTECS; TDB);
                                  Developer T (RTECS: TDB); Developer 14;
                                  Eucanine GB (RTECS: TDB); Fouramine;
                                  Fouramine J (RTECS: TDB); Fourrine M
                                   (RTECS: TDB);
                                  Fourrine 94 (RTECS: TDB);
                                  Lekutherm-Haerter VP-KU 6546;
                                  Nako TMT (RTECS: TDB); NCI-C02302 (RTECS: 
                                   TDB);
----------------------------------------------------------------------------

Table 2.  (contd.)
----------------------------------------------------------------------------
Trade names (contd.)              Pelagol J (RTECS: TDB); Pelagol Grey J
                                   (RTECS: TDB);
                                  Pontamine Developer TN (RTECS: TDB);
                                  Renel MD (RTECS: TDB); Tertral G;
                                  Zoba GKE (RTECS: TDB);
                                  Zogen Developer H (RTECS: TDB).

Colour index number               76035

    III.   2,5-isomer

Chemical abstract name            1,4-benzenediamine,2-methyl-(9CI)

Other chemical names               p-toluenediamine (MESH, RTECS: TDB);
                                   p-toluylendiamine (RTECS: TDB);
                                   P,m-tolylenediamine (RTECS: TDB);
                                   para-meta-tolylenediamine;
                                   para-toluenediamine;
                                   para-toluylenediamine;
                                   para-tolylenediamine;
                                  toluene-2,5-diamine (8CI) (CAS, RTECS:
                                   TDB);
                                  toluylene-2,5-diamine (RTECS: TDB);
                                  2-methyl- p-phenylenediamine (RTECS: TDB);
                                  2-methyl-1,4-benzenediamine (RTECS: TDB*);
                                  2,5-diaminotoluene (MESH, RTECS: TDB);
                                  2,5-toluenediamine;
                                  4-amino-2-methylaniline (RTECS: TDB)

Common name                       2,5-TDA

Trade names                       Oxidation Base 4 (as sulfate)

Colour index number               C.I. 76042 (RTECS); 76043 (as sulfate)

    IV.   2,6-isomer

Chemical abstract name            1,3-benzenediamine,2-methyl- (9CI)

Other chemical names               m-phenylenediamine-2-methyl;
                                  toluene-2,6-diamine (8CI) (CAS, RTECS:
                                   TDB);
                                  tolylene-2,6-diamine;
                                  1,3-benzenediamine;
                                  2-methyl- m-phenylenediamine (TDB);
                                  2-methyl-1,3-benzenediamine (TDB);
                                  2-methyl-1,3-phenylenediamine (TDB);
                                  2,6-diamino-1-methylbenzene (TDB);
                                  2,6-diaminotoluene (MESH, RTECS: TDB*);
                                  2,6-toluenediamine;
                                  2,6-toluylenediamine (RTECS: TDB);
                                  2,6-tolylenediamine (RTECS: TDB)
----------------------------------------------------------------------------

Table 2.  (contd.)
----------------------------------------------------------------------------
    IV.   2,6-isomer (contd.)

Common names                      2,6-TDA

    V.   3,4-isomer

Chemical abstract names           1,2-benzenediamine,4-methyl- (9CI)

Other chemical names               o-toluenediamine;
                                  toluene-3,4-diamine (8CI) (CAS, RTECS:
                                   TDB);
                                  1,2-benzenediamine,4-methyl- (RTECS: TDB);
                                  1,2-diamino-4-methylbenzene (TDB);
                                  3,4-diamino-1-methylbenzene (TDB);
                                  3,4-diaminotoluene (RTECS: TDB);
                                  3,4-toluenediamine;
                                  3,4-toluylenediamine (RTECS);
                                  3,4-tolylenediamine (RTECS: TDB);
                                  4-methyl- o-phenylenediamine (TDB);
                                  4-methyl-1,2-benzenediamine (TDB);
                                  4-methyl-1,2-diaminobenzene (TDB);
                                  4-methyl-1,2-phenylenediamine (TDB)

Common name                       3,4-TDA

    VI.   3,5-isomer

Chemical abstract name            1,3-benzenediamine,5-methyl- (9CI)

Other chemical names              3,5-diaminotoluene;
                                  3,5-toluenediamine

Common name                       3,5-TDA
----------------------------------------------------------------------------
2.2.  Physical and Chemical Properties

    Diaminotoluenes are colourless crystals that are freely soluble 
in hot water, alcohol, ether, and hot benzene.  Some of the 
physical properties of the 6 isomers are listed in Table 3 (Buist, 
1970; CRC, 1975).  Diaminotoluenes are oxidized readily in neutral 
or alkaline solution to form dark-coloured products and tars.  The 
oxidation products have not been fully characterized.  When heated, 
diaminotoluenes emit toxic fumes of nitrogen oxides. 

    The composition and physical properties of the commercial 
mixtures vary considerably.  Some of the physical properties of the 
2 most widely-used commercial mixtures are summarized in Table 4. 

     Meta- and Ortho-diaminotoluenes are weakly basic and react with 
mineral acids to form water-soluble amine salts.  These salts are 
more resistant to oxidation than the parent amine. 

Table 3.  Physical properties of the diaminotoluene isomers
-------------------------------------------------------------------
Property                      Diaminotoluene isomers            
                    2,3-    2,4-   2,5-     2,6-  3,4-   3,5-
-------------------------------------------------------------------
Melting point (C)  63-64   99     64       105   88.5   -

Boiling point (C)  255     280    273-274  289b  265    283-285
                                                  (subl)

Vapour pressurea (kPa)

 at 150 C          1.20    1.47   -        2.13  -      -
 at 160 C          1.87    2.27   -        3.33  -      -
 at 180 C          2.67    4.80   -        7.60  -      -
-------------------------------------------------------------------
a To convert kPa to mmHg, divide by 0.133.
b Obtained by extrapolation from vapour pressure-temperature data 
  and Antoine constants. From: Willeboordse et al. (1968).


Table 4.  Physical and chemical properties of commercial grades of
diaminotoluene
----------------------------------------------------------------------
               Meta-DAT                     Ortho-DAT
               (80:20, 2,4-/2,6-isomers)    (60:40, 3,4-/2,3-isomers)
----------------------------------------------------------------------
Appearance     solid, light yellow to tan;  light grey to purple
               darkens on storage and       solid
               exposure to air

Odour          slight ammonia-like          slight ammonia-like

Melting range  80 - 90 C (176 - 194 F)    40 - 50 C (104 - 122 F)

Boiling point  283 C (541 F) at 760 mmHg  > 250 C (> 480 F)
                
Flash point    140 C (284 F)              > 110 C (> 230 F)

Autoignition   450 C (842 F)              540 C (1005 F)
temperature

Vapour         0.34 x 10-3 mmHg at 37.8 C  2.23 mmHg at 100 C
pressure       1 mmHg at 106.5 C           27.8 mmHg at 140 C
               100 mmHg at 212 C           43.5 mmHg at 160 C

Specific       -                            1.045 at 100 C
gravity

Density        0.086 kg/litre at 105 C     -

Solubility     in hot water, alcohol,       in hot water, alcohol,
               ether and many polar         ether and many polar
               organic solvents             organic solvents
----------------------------------------------------------------------

2.3.  Conversion Factors

    1 ppm in air = 5 mg/m3 at 25 C and 760 mmHg.

2.4.  Analytical Methods

    Analytical methods for the determination of diaminotoluenes in 
water, air, different consumer products, and biological fluids are 
listed in Table 5. 

    Diaminotoluenes may be analysed as free bases by reversed phase 
high-performance liquid chromatography using both ultraviolet (UV) 
and electrochemical detection (Purnell & Warwick, 1981; Purnell et 
al., 1982; Nieminen et al., 1983).  Gas chromatographic methods 
usually involve derivatization to facilitate separation and 
increase sensitivity (Olufsen, 1979; Skarping et al., 1983a,b).  
Detection limits in air samples range from 0.1 to 10 g/m3. 

    Diaminotoluenes and their derivatives have been studied in 
blood, urine, and liver cytosol preparations using thin-layer 
chromatography and gas chromatography/mass spectrometry (GC/MS) 
(Kiese & Rauscher, 1968; Kiese et al., 1968; Glinsukon et al., 
1975; Waring & Pheasant, 1976).  A high-performance liquid 
chromatographic method for the determination of diaminotoluenes in 
urine and plasma has been described by Unger & Friedman (1979).


Table 5.  Analytical methods for the determination of diaminotoluenes
------------------------------------------------------------------------------------------------------
Matrix        Analytical procedure             Determination         Detection     Reference
                                                                     limit
------------------------------------------------------------------------------------------------------
Water         high-performance liquid chrom-   2,4-, 2,5-, 2,6-,     0.2 - 0.7 ng  Riggin & Howard
              atography with ultraviolet and   3,4-isomers                         (1983)
              electrochemical detection

Air           gas-liquid chromatography/       2,4-isomer            3 g/m3       Becher (1981)
              nitrogen-phosphorus detector
              on glass capillary columns

              high-performance liquid chrom-                         0.1 -         Purnell et al.
              atography with ultraviolet                             10 g/m3      (1982)
              and electrochemical detection

              high-performance liquid chrom-   2,4-isomer            -             Nieminen et al.
              atography with ultraviolet                                           (1983)
              detection

              gas-liquid chromatography with   2,4- and 2,6-isomers  ~ 0.1 -       Skarping et al.
              electron capture detection on                          0.4 pg        (1983a)
              glass capillary column

              gas-liquid chromatography/       2,4- and 2,6-isomers  10 - 20 pg    Skarping et al.
              nitrogen-phosphorus detector                           amine         (1983b)
              on glass capillary columns

Hair dyes     gas-liquid chromatography/       2,5-isomer            5 mg/litre    Choudhary (1980)
              flame ionization detector

              thin-layer chromatography        2,4-, 2,5-, and       0.2 mg/litre  Kottemann (1966)
                                               3,4-isomer

              high-performance liquid chrom-   2,4-, 2,5-,           0.5 mg/litre  Johansson et al.
              atography/ultraviolet detection  and 2,6-isomers                     (1981)

              high-performance liquid chrom-   2,4-, 2,5-,           -             Liem & Rooselaar
              atography/ultraviolet detection  and 3,4-isomers                     (1981)

------------------------------------------------------------------------------------------------------
Table 5.  (contd.)
------------------------------------------------------------------------------------------------------
Matrix        Analytical procedure             Determination         Detection     Reference
                                                                     limit
------------------------------------------------------------------------------------------------------
Hair dyes     high-performance liquid chrom-   2,4- and 2,6-isomers  0.1 g/litre  Snyder et al.
(contd.)      atography/ultraviolet detection                                      (1982)
              gas-liquid chromatography/mass
              spectrometry

Polyurethane  thin-layer chromatography/       2,4- and 2,6-isomers  1 g/g        Guthrie &
foams         fluorimetry                                                          McKinney (1977)

Biological    high-performance liquid chrom-   2,4- and 2,6-isomers  2 mg/litre    Unger & Friedman
tissues and   atography/ultraviolet detection                                      (1979)
fluids

Isomeric      nuclear magnetic resonance       all isomers           -             Mathias (1966)
mixtures      spectrometry

              thin-layer chromatography        all isomers           -             Macke (1968)

              gas-liquid chromatography/       all isomers           -             Boufford (1968)
              flame ionization detector

              gas-liquid chromatography/       all isomers           -             Willeboordse et
              thermal detector                                                     al. (1968)

              infra-red spectroscopy           2,4- and 2,6-isomers  -             Biernacka et al.
                                                                                   (1974)
------------------------------------------------------------------------------------------------------

3.  SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT AND
DISTRIBUTION

3.1.  Natural Occurrence

    Diaminotoluenes are not known to occur as natural products. 

3.2.  Production

    Currently, diaminotoluenes are produced commercially through 
the catalytic hydrogenation of dinitrotoluenes.  This procedure, 
economic only for large-scale production, is used in the 
manufacture of toluene diisocyanates.  At dye plants, diamino-
toluenes are produced by the reaction of hydrochloric acid on 
dinitrotoluenes, in the presence of an iron catalyst (Austin, 
1974). 

    Most diaminotoluenes produced are used on site by the 
manufacturer; therefore, published production figures do not 
adequately reflect the true world production of diaminotoluenes. 

    Between 1972 and 1976, the average annual production of 
diaminotoluenes in the USA was 89 x 106 kg, ranging from 76 x 106 
kg in 1972 to 105 x 106 kg in 1976 (US ITC, 1977).  Thereafter, the 
production was estimated from the known production of toluene 
diisocyanates ranging between 305 x 106 kg annually in the period 
1977 - 81, and 360 x 106 kg in 1984 (US ITC, 1982, 1985). 

    Up to 1978, an estimated 180 - 200 x 106 kg of 2,4-DAT was 
produced annually in western Europe (IARC, 1978).  During 
1971 - 75, the the annual production of 2,4-DAT in Japan was 
approximately 210 x 103 kg; the compound was neither imported nor 
exported (IARC, l978).  However, in 1981, the production of 2,4-DAT 
in Japan was estimated to have declined to 50 x 103 kg (CIC Japan, 
1983). 

3.3.  Uses

    Diaminotoluenes are used extensively within the chemical 
industry as intermediates in the manufacture of widely different 
commercial products (Table 6).  Minor applications of diamino-
toluene isomers include their use as raw materials, co-reactants, 
and curing agents.  Toluene diisocyanates represent the largest 
end-use accounting for more than 90% of the total annual production 
of diaminotoluenes, largely a mixture of 2,4- and 2,6-isomers 
(Backus, 1974; Milligan & Gilbert, 1978). 

    Diaminotoluenes are intermediates in the synthesis of dyes used 
for textiles, furs, leathers, biological stains and indicators, 
spirit varnishes and wood stains, and pigments.  Previously used in 
hair-dyes, 2,4-DAT was removed from use by many countries after it 
was found to be a hepatocarcinogen in rats (Ito et al., 1969).  
Meta-DAT is used to produce diethyltoluenediamine (DETDA) for the 
manufacture of certain urethane elastomers (Milligan & Gilbert, 
1978).  Ortho-DAT is used to produce mercaptotoluimidazole (MTI) 
and its zinc salt, both of which are used primarily as specialty 
antioxidants in nitrile rubber elastomers (Gan et al., 1975). 

Table 6.  End-use application(s) of individual 
diaminotoluene isomers
------------------------------------------------------
Application              2,3-  2,6-  2,3-  3,4-  2,5-
------------------------------------------------------
Toluene diisocyanate     X     X
(> 90% of total use of
diaminotoluenes)

Urethane co-reactants    X     X     X     X
(DAT-initiated polyols)

DETDAa                   X     X

DYESb                    Xd    X                 d

Tolyltriazole                        X     X

Epoxy curing             X     X           X

Mercaptotoluimidazole                X     X

Photographic developer         X
------------------------------------------------------
a DETDA = Diethyltoluenediamine.
b DYES = Fur, leather, biological stains, indicators, 
  textiles, hair, spirit varnishes, wood stains, and 
  pigments.
c Use in hair dyes and cosmetics prohibited in USA 
  since 1971.
d Forbidden in Italy - 1978.

3.4.  Release into the Environment, Distribution, and Transformation

    Data are lacking on the extent of the global release of 
diaminotoluenes, as well as their transport, distribution, and 
degradation within the environment. 

    Releases of 2,4-DAT into the environment have been estimated in 
the USA, the largest contribution being over 6 x 106 kg dumped in 
authorized landfills.  Releases of 1.4 x 106 kg were estimated to 
occur from the production of diaminotoluenes, and 0.3 x 106 kg 
during dye production and usage; unknown quantities of DAT may 
derive from the hydrolysis of TDI released into the environment. 

    Information on the transport, distribution, and degradation of 
DAT isomers under conditions approaching those found in natural 
bodies of water have not been reported in the literature.  However, 
a bench-scale treatability study for 2,4-DAT using acclimated 
sludge from a treatment plant showed that the isomers are 
degradable.  The observed total organic carbon removal was 45% in 
4 h (Matsui et al., 1975). 

4.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

4.1.  Environmental Levels

    No information was available in the literature reviewed from 
which environmental levels could be calculated.  Two properties of 
the diaminotoluenes are relevant to this problem.  Since the vapour 
pressure is low (Tables 4 and 5), the risk of contaminating the 
environment through evaporation is minimal.  However, air emissions 
from inappropriately operated plants may pose a hazard.  Since the 
chemical is soluble in water, the potential for exposure through 
water contamination is of concern.  No data are available on levels 
of diaminotoluenes in surface and groundwater, in soil, and/or air. 

4.2.  General Population Exposure

    No information is available on the exposure of the general 
population to diaminotoluenes. 

4.3.  Occupational Exposure

    Filatova et al. (1970) reported concentrations of diamino-
toluenes in manufacturing plants of up to 0.2 mg/m3, with 
occasional excursions up to 11 mg/m3. 

    The results of studies conducted in 3 plants manufacturing 
diaminotoluenes in the USA showed that the work-place ambient air 
levels ranged from 0.005 to 0.44 mg/m3 (NIOSH, 1980, 1981, 1982).  
The highest level of diaminotoluenes (0.44 mg/m3) was found in the 
filter room at one plant (NIOSH, 1980).  A level of 0.39 mg 
diaminotoluenes/m3 was measured in a sample taken at the breathing 
zone of an operator in a second plant (NIOSH, 1981).  All values 
were calculated as time-weighted averages. 

5.  KINETICS AND METABOLISM

5.1.  Studies on Experimental Animals

5.1.1.  Absorption and retention

    Skin penetration by test materials varied amoung species 
(monkeys, swine), and was affected by vehicle and site of 
application.  In one study, [14C]-2,4-DAT (4 g/cm2), dissolved in 
acetone, methanol, or a skin lotion, was applied to 3 - 15 cm2 of 
the ventral forearm, abdomen, or back of 3 - 6 monkeys/group (9 
groups).  The material was removed after 24 h by washing with soap 
and water.  The greatest absorption (53.8  15.4%) resulted when 
[14C]-2,4-DAT in acetone was applied to the abdominal skin of 
monkeys (Marzulli et al., 1981).  The permeability of diamino-
toluenes across the epidermis was highly dependent on the 
formulation used.  When 1.4 g of 2,5-DAT was applied in a gel 
to the abdominal skin of dogs for a contact period of 3 h, 2.9% 
(40 mg) was absorbed.  Addition of hydrogen peroxide, similar to 
the formulation used in hair dye, reduced the amount absorbed 
to < 0.21% (Kiese et al., 1968) or < 0.13% (Hruby, 1977).  The 
hair in the exposed area retained 4% of the 14C activity, 5 days 
after application (Hruby, 1977). 

    Hruby (1977) studied the absorption of [14C]-2,5-DAT following 
oral and subcutaneous single-dose administrations to rats.  Five 
days following subcutaneous injection of 3 - 5 mg [14C]-2,5-DAT (in 
water), 6.9% of the dose was found in the total-body homogenate and 
1.7% remained at the injection site.  Five days after oral (gavage) 
administration of 10 mg [14C]-2,5-DAT (in water), the rat gastro-
intestinal tract retained 1.4% of the applied radioactivity and 
1.2% was found in the total body homogenate (Hruby, 1977). 

    No studies on uptake after inhalation were found. 

5.1.2.  Distribution and reaction with body components

    The distribution of diaminotoluenes and their reaction with 
body components have been investigated, mainly after 
intraperitoneal injection of radioactive labelled compounds.  No 
data on the distribution of diaminotoluenes and reaction with 
tissues after inhalation or oral ingestion were found in published 
reports. 

    Distribution of [14C]-2,4-DAT after intraperitoneal injection 
was rapid, and the peak concentration in rat and mouse blood and 
plasma occurred in 1 h, then decreased rapidly for 7 h.  On a 
comparative basis, all tissue concentrations of bound 14C were 
considerably lower in the male NIH-Swiss mice than in the male 
Fischer rats (Grantham et al., 1980). 

    Tissue distribution of [Me-14C]-2,4-DAT hydrochloride was 
studied in male B6C3F1 mice given a single intraperitoneal 
injection (1 Ci, 0.667 mg/kg body weight) (Unger et al., 1980).  
The highest concentrations, 1/2 h after dosing, were found in the 

kidneys, gonads, epididymis, lungs, muscle, and blood.  One hour 
after dosing, the liver contained the greatest amount, accounting 
for nearly 12% of the dose.  The concentration in the adrenal 
glands exceeded that in the kidney, 1 and 2 h after dosing.  High 
concentrations of radioactivity were also observed in the 
gastrointestinal tract. 

    Four hours after an intraperitoneal injection of 100 mg (0.8 
mmol/kg, ring-labelled [3H]-2,4-DAT) in male Wistar rats, 0.3 nmol 
was found covalently bound per mg liver protein.  A similar degree 
of binding was seen in the kidneys.  Subcellular fractionation of 
the liver showed that most of the bound material was in the 
microsomal fraction (Dybing et al., 1978).  No significant binding 
to DNA  in vitro or  in vivo could be demonstrated using [3H]-2,4-
DAT, whereas it was found to bind covalently to hepatic RNA  in 
 vivo.  These findings were confirmed by Aune et al. (1979). 

5.1.3.  Metabolism

    Glinsukon et al. (1975, 1976) found that the 2,4-isomer was 
selectively  N-acetylated at the  p-amino group by liver cytosol 
prepared from hamsters, guinea-pigs, rabbits, mice, and rats.  The 
cytosol from liver, kidney, intestinal mucosa, and lung of hamsters 
and rabbits was studied for  N-acetyl transferase activity using 
2,4-DAT and 4-acetylamino-2-amino-toluene as substrates.  All 
tissues showed marked species differences in enzyme activity.  
Tissues with high  N-acetyl transferase levels, such as liver, 
could produce both 4-acetylamino-2-aminotoluene and 2,4-
diacetylaminotoluene (Glinsukon et al., 1975).  There were also sex 
differences in the  N-acetylation capacity of the liver cytosol. 

    After a single ip injection of 2,4-DAT (77 mg/kg body weight) 
in male rats, 69.4% of the dose was eliminated in the urine and 
faeces after 24 h as a complex mixture of metabolites, indicating 
both free and conjugated derivatives.  The major urinary 
metabolites identified were 4-acetylamino-2-aminotoluene, 2,4-
diacetylaminotoluene, and 4-acetylamino-2-aminobenzoic acid.  In 
mice, oxidation of the methyl group to a benzoic acid was the major 
reaction and the major urinary metabolites in mice were 4-
acetylamino-2-aminobenzoic, 4-acetylamino-2-aminotoluene, and 2,4-
diacetylaminobenzoic acid (Grantham et al., 1980).  Waring & 
Pheasant (1976) investigated the metabolism of 2,4-DAT in female 
rabbits, rats, and guinea-pigs to determine whether the isomer gave 
rise to hydroxylamines or aminophenols, which might account for the 
observed toxic and carcinogenic effects.  After oral administration 
(gavage) of 2,4-DAT (50 mg/kg body weight), phenolic metabolites 
were excreted in the urine.  When free and conjugated metabolites 
were combined, 5-hydroxy-2,4-DAT was the major metabolite in all 3 
species (Table 7). 

Table 7.  Excretion of metabolites after dosing with 2,4-diamino-
toluene
-------------------------------------------------------------------
Metabolite                              Percentage dose excreteda   
                                        Rabbit   Rat    Guinea-pig
-------------------------------------------------------------------
2,4-DAT                                 trace    1.3    trace

3-hydroxy-2,4-DAT                       10       8      trace

5-hydroxy-2,4-DAT                       22       12     9

6-hydroxy-2,4-DAT ( m-aminophenol)       trace    5      trace

3-hydroxy-4-acetylamino-2-aminotoluene  10       18     trace

5-hydroxy-4-acetylamino-2-aminotoluene  6        14     17

glucuronide I, 3-hydroxy-DAT            10       16     15

glucuronide II, 5 hydroxy-DAT           32       12     46

glucuronide III, 6-hydroxy-DAT          2        6      4

unidentified phenolic compounds         0        trace  trace
-------------------------------------------------------------------
a Results are given as percentage dose, average of 10 studies, 
  standard deviation 6.4% for metabolites 1 - 5, and 12.8% for 
  metabolites 6 - 8.  Animals were dosed orally at 50 mg/kg; urine 
  was collected for 48 h.
  From:  Waring & Pheasant (1976).

    The levels of methaemoglobin found in the rabbit, rat, and 
guinea-pig correlated well with the total urinary excretion of 
aminophenol.  The methaemoglobin levels reached a peak 6 - 12 h 
after the administration of 2,4-DAT and then slowly declined.  The 
highest levels of aminophenols and of methaemoglobin were found in 
the rabbit (Waring & Pheasant, 1976). 

5.1.4.  Excretion

    During a 24-h period of dermal contact with [14C]-2,4-DAT, 14C 
urinary excretion in monkeys reached a peak at 8 - 12 h (Marzulli 
et al., 1981). 

    Data from studies on the rat, rabbit, mouse, guinea-pig, and 
dog exposed to diaminotoluenes (cutaneous, subcutaneous, 
intravenous, intraperitoneal, or oral by gavage) showed fast 
elimination rates (Kiese et al., 1968; Waring & Pheasant, 1976; 
Hruby, 1977; Grantham et al., 1980; Unger et al., 1980).  The 
elimination of radioactivity from various tissues in rodents 
followed a well-defined biphasic pattern.  Rapid elimination over 
7 h was followed by a rather slow decline in the isotopic contents 
of tissues (Grantham et al., 1980; Unger et al., 1980).  The half-
lives of tissue elimination during the fast phase were 0.89, 0.43, 

and 1.51 h for male mouse liver, kidneys, and blood, respectively.  
During the slow phase of elimination, the half-lives for liver, 
kidneys, and blood in male mice were 11.7, 9.1, and 12.6 h, 
respectively.  The half-lives of elimination of radioactivity, 
during the slow phase, were greater for muscle (23.9 h) and skin 
(29.2 h) than for any other tissue (Wagner, 1975; Unger et al., 
1980). 

    The primary route of elimination in rodents was via the kidneys 
during the first hour after exposure.  However, after 2 h, the 
predominant route shifted from urinary to faecal, probably a 
reflection of biliary excretion.  Only 1.25% of the administered 
radioactivity had been exhaled after 24 h (Unger et al., 1980).  On 
a comparative basis, faecal elimination was greater in rats than in 
mice, but the rate of urinary excretion was more rapid in mice than 
in rats.  Approximately 90% of a dose was eliminated in the urine 
of mice in 24 h compared with 74% in the urine of rats (Grantham et 
al., 1980).  Complete elimination was accomplished in 2 days in 
mice, while rats required 6 days. 

    Male and female rats, injected subcutaneously with 3 - 5 mg 
[14C]-2,5-DAT hydrochloride, eliminated 65% of the dose in the 
urine and 5% in faeces after 24 h.  The same pattern of elimination 
was found after oral administration of 10 mg of the labelled 
compound (Hruby, 1977). 

    When beagle dogs were intravenously injected with a dose of 
224 mg, infused over 3 h, the total amounts of radioactivity 
eliminated in the urine and faeces were 60% and 19%, respectively.  
After 4 days, elimination mainly occurred within the first 24 h.  
After a skin application of 1.4 g [14C]-2,4-DAT for 3 h (in 50 ml 
of a dye formulation), only 0.092 and 0.84% of the dose were 
eliminated, respectively, in the urine and faeces of beagle dogs 
over 4 days, reflecting the inhibitory effect of the dye 
formulation on the absorption of the 2,4-DAT (Hruby, 1977).  In 
another study on dogs, about 40 mg 2,5-diaminotoluene was absorbed 
through the skin from a gel containing 1.4 g of the material.  The 
addition of hydrogen peroxide to the gel reduced the amount 
absorbed to less than 3 mg.  The amount excreted unchanged in the 
urine was 60 - 70 g (Kiese et al., 1968). 

5.2.  Human Studies

    As only limited information is available on the absorption, 
distribution, metabolism, and excretion of diaminotoluenes in human 
beings, these aspects are discussed together, rather than in 
separate sections. 

    Although the high boiling point of diaminotoluenes makes 
absorption through the lungs unlikely under normal working 
conditions, inhalation may occur when hot vapours escape from 
stills.  Possible inhalation and dermal exposure to dusts may occur 
if diaminotoluenes are handled in a less than optimal manner.  
Since diaminotoluenes are soluble in water, absorption from the 

gastrointestinal tract could occur following ingestion.  However, 
no data were found on the kinetics and metabolism of diamino-
toluenes after oral or inhalation exposures. 

    Skin penetration by [14C]-2,4-DAT was measured in human beings 
(Marzulli et al., 1981).  When 4 g [14C]-2,4-DAT in acetone/cm2 
was applied to the skin of the forearm, the highest absorption of 
the chemical (23.7 %  16.1% of the applied dose) resulted after 
24 h of dermal contact.  Urinary excretion reached a peak after 
4 - 8 h of skin contact.  In a study by Kiese & Rauscher (1968), 
the hair of 5 human subjects was dyed (40 min) with a formula 
containing 2.5 g 2,5-DAT; absorption of approximately 0.2% of the 
applied material occurred.  No data were given on the retention and 
distribution of diaminotoluenes after this dermal contact. 

    Data from studies on 6 volunteers (3 males and 3 females) 
showed that, after subcutaneous injection of 5.54 mg 2,5-DAT, 47.6% 
of the dose was excreted in the urine as  N,N'-diacetyl-2,5-DAT.  
The rate of excretion was highest during the first 24 h, and only a 
trace appeared in the urine excreted on the third day, in one 
study.  When the compound was applied as a hair dye (40 min), the 
highest rate of excretion was observed during a period of 5 - 8 h 
after application.  On average, a total amount of 3.7 mg  N,N'-
diacetyl-2,5-DAT (i.e., 0.09% of the applied dose) was calculated 
to have been excreted in urine taken over 2 days from 5 subjects 
(Kiese & Rauscher, 1968). 

6.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    Little information is available on the effects of diamino-
toluenes on animal populations found in the environment.  The 
effects of 2,4-DAT at concentrations ranging from 1 to 1000 
mg/litre were observed for  Daphnia ( Daphnia magna Straus), 
ostracoda, guppies ( Lebistes reticulatus Peters), and channel 
seaweed  (Scenedesmus obliquus).  Daphnia was the most sensitive 
species; 5 mg/litre was lethal in 5 - 10 days, and prolonged 
exposure to 2 mg/litre caused a reduction in the number of 
offspring produced.  A concentration of 20 mg/litre was not lethal 
for ostracods after 10 days, but 50 mg/litre was lethal in 5 - 8 
days.  Fish survived for 10 days at 200 mg/litre, but a 
concentration of 500 mg/litre was lethal in 2 - 3 days.  The algae 
tested were the most resistant, surviving for 10 days at a 
concentration of 1000 mg/litre (Smirnova et al., 1967). 

7.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    The early literature (1881 - 1939) contains several reports on 
toxicological manifestations associated with the administration of 
diaminotoluenes in experimental animals.  Most of the papers are 
difficult to interpret and to use in the assessment of chemical 
hazards, because massive doses of chemicals of unknown purity and 
isomeric composition were used, and because of the experimental 
designs chosen.  The toxic effects were characterized by icterus, 
haemoglobinuria, disposition of haemosiderin in the spleen, bone 
marrow, and liver, respiratory and generalized central nervous 
system (CNS) depression, pulmonary and cerebral oedema, and 
increased bile acids in the liver, blood, and/or urine of exposed 
animals (Von Oettingen, 1941). 

7.1.  Single Exposures

    Diaminotoluenes are considered to be dermal and eye irritants.  
In studies on rabbits, 12.5 mg 2,5-DAT or 500 mg 2,4-DAT caused 
skin irritation, defined as erythema and oedema, after 24 h of 
dermal contact.  Instillation of 100 g of the 2,4-isomer into the 
rabbit eye caused severe eye irritation within 24 h.  Data showing 
the extent of the acute toxicity of diaminotoluenes in various 
laboratory animals are summarized in Tables 8 and 9. 

    The acute toxic effects of diaminotoluenes were characterized 
by marked central nervous system depression during exposure (e.g., 
decreased locomotor activity, piloerection, ptosis, ataxia, 
tremors) and production of methaemoglobin, 6 - 8 h after exposure. 

    Duodenal and glandular mucosal damage in the stomach were 
observed in fed, unrestrained rats, 24 h following a single 
subcutaneous dose of 3,4-DAT.  The optimal ulcerogenic dose of 3,4-
DAT (i.e., the dose causing a low mortality and a maximal incidence 
of duodenal damage within 24 h), was 350 mg/kg body weight (Perkins 
& Green, 1975). 

7.2.  Short-Term Exposures

    When guinea-pigs were treated with 1 - 10% 2,5-DAT (24 h/day 
for 5 days, 2 days without treatment, followed by exposure for 
another 5 days), sensitization was obtained in 35% of treated 
animals (Schfer et al., 1978). 

    Both the 2,4- and 3,4-isomers caused severe icterus in rats.  
In male and female rats, 3,4-DAT (unlike the 2,4-isomer), given 
orally or parenterally, produced a high incidence of perforating 
duodenal ulcers within a few days (Selye, 1973).  These effects 
were obtained in animals allowed to move freely with access to food 
and water during the period of observation.  A dose of 500 mg 
diaminotoluenes/kg body weight was administered in 2 ml water, 
twice daily. 


Table 8.  Lethality of diaminotoluenes
---------------------------------------------------------------------------
Species                     Exposure  LD50      Reference
                            route     (mg/kg
                                      body
                                      weight)
---------------------------------------------------------------------------
 Ortho-DAT (2,3-, 3,4- mix)

Rat                         oral      810       Carpenter et al. (1974)
Rabbit                      dermal    1120      Carpenter et al. (1974)

 Meta-DAT (2,4-, 2,6- mix)

Rat                         oral      300       Izmerov et al. (1982)
Rat (male)                  oral      270       Weisbrod & Stephan (1983)
Mouse (male)                oral      350       Weisbrod & Stephan (1983)
Rat (male)                  ip        230a      Weisbrod & Stephan (1983)
Mouse (male)                ip        240b      Weisbrod & Stephan (1983)
Rat (male)                  iv        350       Weisbrod & Stephan (1983)
Mouse (male)                iv        90-105    Weisbrod & Stephan (1983)
Rat                         dermal    1200      Izmerov et al. (1982)

 2,4-DAT (technical grade)

Fischer rat (male)          ip        325       Grantham et al. (1980)
NIH-Swiss mouse (male)      ip        480       Grantham et al. (1980)
HaM/ICR mouse (male)        ip        80        Weisburger et al. (1978)
HaM/ICR mouse (female)      ip        90        Weisburger et al. (1978)
---------------------------------------------------------------------------
a A methaemoglobin level of 8.4% was observed, 6 h after ip administration.
b A methaemoglobin level of 7.8% was observed, 6 h after ip treatment.

 Note:  No published data on the acute toxicity of the 2,3-isomer were
       available.
    The effects of 2,4-DAT on the liver microsomal mixed-function 
oxidase system, DT-diaphorase, and epoxide hydrolase were reported 
by Dent & Graichen (1982).  Following oral treatment with 2,4-DAT 
at 70 mg/kg body weight per day for 5 days, the activities of 
microsomal cytochrome P-450-dependent enzymes were depressed, while 
epoxide hydrolase activity was markedly elevated (3 - 8 times 
control) in male F-344 rats.  Under these experimental conditions, 
an increase in the liver to body weight ratio (3.2 - 4%), and in 
the liver microsomal protein concentration (19.3 - 27.4 g/kg) were 
induced by 2,4-DAT. 

7.3.  Long-Term Exposure

    Oral administration of 2,4-DAT (see Table 11, section 7.6, for 
doses) for 79 - 103 weeks accelerated the appearance of renal 
toxicity in male F-344 rats, associated with a high incidence of 
secondary hyperparathyroidism (NCI, 1979).  The chronic renal 
disease reported was believed to have decreased the longevity of 
the treated rats, either directly or through inhibition of the 
clearance of toxic metabolites (Cardy, 1979). 

Table 9.  Summary of some single-dose studies
--------------------------------------------------------------------------
Species     Route of  Dose     Effects                     Reference
            exposure  (mg/kg
                      body
                      weight)
--------------------------------------------------------------------------
 2,4-DAT (technical grade)

Wistar rat  oral      50       produced metHba; highest    Waring &
(male)                         amounts (5 - 6%) were       Pheasant (1976)
                               found 6 - 8 h after
                               exposure

                      > 50     toxic

Sprague     oral      500      developed icterus and       Selye (1973)
Dawley rat                     death
(male and
female)

NZW rabbit  oral      50       MetHb reached 18 - 20%      Waring &
                               level 6 - 8 h after         Pheasant (1976)
                               application

                      > 50     toxic

Dunkin-     oral      50       MetHb reached 3 - 4% level  Waring &
Harvey                         6 - 8 h after application   Pheasant (1976)
guinea-pig                     

                      > 50     toxic

 3,4-DAT (97% pure)

Sprague     subcut-   125-500  discrete, non-perforated    Perkins &
Dawley rat  aneous             duodenal lesions were       Green (1975)
(female)                       observed immediately
                               distal to the gastroduo-
                               denal junction 24 h
                               following the administra-
                               tion of a single dose
--------------------------------------------------------------------------
a metHb = methaemoglobin.

    No studies were found on the effects of diaminotoluenes on the 
nervous system or the immune system after long-term exposure. 

7.4.  Reproduction and Teratogenicity

7.4.1.  Reproduction

    There are 2 studies on experimental animals that evaluate the 
reproductive toxicity of diaminotoluenes.  Soares & Lock (1980) 
administered 2,4-DAT orally or ip at 40 mg/kg body weight for 

2 days to DBA/2J male mice.  Forty-eight hours after treatment, 
mating trials were conducted for 8 weeks.  There were no treatment-
related effects on sperm morphology or fertility, as measured by 
this dominant lethal assay.  However, in male Sprague Dawley rats, 
long-term exposure to 2,4-DAT in the feed impaired reproductive 
performance and capacity (Thysen et al., 1985a,b).  Dietary levels 
of 0.03% 2,4-DAT for 10 weeks (~ 15 mg/kg body weight per day) 
decreased fertility and exerted an inhibitory effect on sperm 
production in male rats.  Eleven weeks after treatment, the sperm 
count remained significantly depressed ( P < 0.001), suggesting 
irreversible damage to the germinal components in the testes.  Data 
from hormone analyses at the end of the 10 weeks of exposure, and 
at the end of 11 weeks after treatment, showed a significant 
decrease in serum-testosterone and an elevation of serum-luteinizing 
hormone concentrations, which were associated with a reduction in 
seminal vesicle weight.  Histological changes found in the 
reproductive organs from treated males were correlated with these 
physiological changes.  At a lower dose (0.01% or ~ 5 mg/kg body 
weight), 2,4-DAT did not cause any of these toxic responses. 

7.4.2.  Teratogenicity

    Studies on the teratogenic potential of diaminotoluenes are 
summarized in Table 10.  Skin application of 2,4-DAT induced a low 
incidence of skeletal changes in rats (Burnett et al., 1976).  Oral 
or intraperitoneal administration of this isomer did not produce 
any effects on the fertility or reproductive performance of male 
mice (Soares & Lock, 1980).  Subcutaneous or intraperitoneal 
injection of 2,5-DAT in mice on day 8 of gestation, at levels of 50 
or 75 mg/kg body weight, caused crainiofacial malformation and 
fused or distorted thoracic vertebrae associated with the absence 
of, or fused, ribs (Inouye & Murakami, 1976, 1977).  However, 2,5-
DAT sulfate, at levels of 16 - 64 mg/kg body weight per day 
administered subcutaneously on days 6 - 15 of gestation, did not 
cause any malformations in mice or rats (Marks et al., 1981). 

    The results of oral administration of 2,6-DAT to rats and 
rabbits, at doses of between 10 and 300 mg/kg body weight 
(Knickerbocker et al., 1980), showed that, in rats, doses of 
between 100 and 300 mg/kg body weight increased the occurrence of 
incomplete vertebrae and that the highest dose resulted in missing 
sternebrae and incomplete closure of the skull.  A no-observed-
adverse-effect level of 10 mg/kg body weight was reported in rats.  
No skeletal or soft-tissue abnormalities were observed in the 
offspring of rabbits, but, using fetal toxicity indices, a no-
observed-adverse-effect level of 30 mg/kg body weight was reported. 

    Becci et al. (1983) administered Ortho-DAT (2,3-, 3,4-isomer 
mixture) by gavage to rats and rabbits (Table 10).  Reduced body 
weight during gestation was noted at 300 mg/kg body weight in rats 
and 100 mg/kg body weight in rabbits.  An increased incidence of 
several skeletal variations in the fetuses was noted, probably due, 
in part, to the maternal toxicity.  The no-observed-adverse-effect 
level in both rats and rabbits was 30 mg/kg body weight. 


Table 10.  Teratogenicity studies with diaminotoluenes
-----------------------------------------------------------------------------------------------------------------
DAT        Species    Route of        Dose and duration     Effects                             Reference
isomer                administration
-----------------------------------------------------------------------------------------------------------------
2,4-       Charles    skin            2 ml/kg body weight   skeletal changes seen in 6/169      Burnett et al.
(3% in     River/CD                   on days 1, 4, 7, 10,  live fetuses ( P > 0.05)             (1976)
hair-dye   rat                        13, 16, and 19 of     
formula)   (female)                   gestation

2,5-       Charles    skin            2 ml/kg body weight   no increase in abnormalities in     Burnett et al.
(sulfate)  River/CD                   on days 1, 4, 7, 10,  treated groups                      (1976)
(3% in     rat                        13, 16, and 19 of
hair-dye                              gestation
formula)

2,5-       JCL:ddn    subcutaneous    50 mg/kg body weight  In groups treated sc or ip on day   Inouye & Murakami
dihydro-   mice       or intraper-    on one day of days    8 of gestation, there was evidence  (1976, 1977)
chloride   (female)   itoneal         7 - 14 of gestation   of craniofacial malformation:         
                      single dose     or 75 mg/kg on day    exencephaly, prosoposchisis, and
                                      8 of gestation or     hair lip with cleft palate, and
                                      50 mg/kg on day 8 of  high incidence of skeletal 
                                      gestation             malformation: fused or distorted
                                                            thoracic vertebrae associated with
                                                            absence of, or fused, ribs; no
                                                            such malformed fetuses were found
                                                            in groups treated on days 10 - 14
                                                            of gestation; only a very low
                                                            incidence of vertebral and rib 
                                                            anomalies followed treatment on
                                                            day 7 or 9; maternal toxicity was
                                                            reported at 75 mg/kg but not at
                                                            50 mg/kg

2,5-       CD-1 mice  subcutaneous    16, 32, 48, or 64     no teratogenic effects were noted;  Marks et al.
(sulfate)                             mg/kg body weight     maternal toxicity was evident at    (1981)
                                      per day on days       48 and 64 mg/kg; reduced fetal
                                      6 - 15 of gestation   weight was noted at > 32 mg/kg
-----------------------------------------------------------------------------------------------------------------
                                                            
Table 10.  (contd.)
-----------------------------------------------------------------------------------------------------------------
DAT        Species    Route of        Dose and duration     Effects                             Reference
isomer                administration
-----------------------------------------------------------------------------------------------------------------
2,5-       rat        oral (gavage)   10, 50, or 80 mg/kg   maternal toxicity and embryo-       Spengler et al.
(sulfate)                             body weight per       toxicity evident at 80 mg/kg; no    (1986)
                                      day on day 15 of      effects observed at lower doses
                                      gestation                  

           rabbit     oral (gavage)   10, 25, or 50 mg/kg   no effects observed
                                      body weight per day
                                      on days 6 - 18 of
                                      gestation

2,6-       Sprague    oral (gavage)   10, 30, 100, or 300   no effects on pregnancy, number     Knickerbocker et
           Dawley                     mg/kg body weight     of live fetuses, and resorption     al. (1980)
           rat                        per day on days       sites/dam; 300 mg/kg produced         
                                      6 - 15 of gestation   smaller body weight gain in the
                                                            dams; 30 - 300 mg/kg produced
                                                            increased haemorrhagic abdomens 
                                                            in the fetuses; 100 and 300 mg/kg
                                                            increased the occurrence of 
                                                            incomplete vertebrae, and 300 
                                                            mg/kg showed missing sternebrae 
                                                            and incomplete skull closure in
                                                            the fetuses; the no-observed-
                                                            adverse-effect dose was 10 mg/kg
                                                            per day

2,6        Dutch      oral (gavage)   3, 10, 30, or 100     100 mg/kg per day reduced dam       Knickerbocker et
           belted                     mg/kg body weight     weights, increased resorptions,     al. (1980)
           rabbit                     per day on days       decreased fetal weights, and       
           (female)                   6 - 18 of gestation   neonatal survival;

                      oral (gavage)   3, 10, 30, or 100     there were no differences in        Knickerbocker et
                                      mg/kg body weight     skeletal or soft-tissue             al. (1980)
                                      per day on days       abnormalities between treated      
                                      6 - 18 of gestation   animals and controls; the no-
                                                            observed-adverse-effect dose was
                                                            30 mg/kg per day
-----------------------------------------------------------------------------------------------------------------

Table 10.  (contd.)
-----------------------------------------------------------------------------------------------------------------
DAT        Species    Route of        Dose and duration     Effects                             Reference
isomer                administration
-----------------------------------------------------------------------------------------------------------------
 o-DAT     Sprague     oral            10, 30, 100, or 300   maternal toxicity was indicated     Becci et al.
(2,3-,    Dawley                      mg/kg body weight     at 300 mg/kg per day by reduced     (1983)
3,4-      rat                         per day on days       body weight gain during gestation;
isomer                                6 - 15 of gestation   No significant differences in
mix)                                                        numbers of live fetuses, 
                                                            implantation or resorption sites; 
                                                            fetal body weight was reduced at 
                                                            the highest dose ( P < 0.05); no
                                                            evidence of teratogenic effects
                                                            or effects on dams at doses < 30
                                                            mg/kg; no skeletal or soft-tissue
                                                            malformations that could be          
                                                            related to treatment; however, 
                                                            increased incidence of missing 
                                                            sternebrae at 300 mg/kg per day 
                                                            and incomplete ossified vertebrae 
                                                            at 100 and 300 mg/kg per day were 
                                                            noted compared with controls

 o-DAT     Dutch       oral            3, 10, 30, or 100     maternal toxicity at 100 mg/kg per  Becci et al.
(2,3-,    belted                      mg/kg body weight     day elicited by reduced body        (1983)
3,4-      rabbit                      per day on days       weight gain during pregnancy; no
isomer                                6 - 18 of gestation   significant difference in the
mix)                                                        number of implantations; at 100
                                                            mg/kg per day, fetal body weight
                                                            was reduced and the number of
                                                            resorption sites was increased;
                                                            no skeletal or soft-tissue
                                                            malformations that could be 
                                                            related to treatment were noted
-----------------------------------------------------------------------------------------------------------------
                                                              
7.5.  Mutagenicity and Related End-Points

7.5.1.  DNA damage

    At concentrations of 1 x 10-4 mol/litre and below, 2,4-DAT, but 
not 2,6-DAT, induced unscheduled DNA synthesis in primary cultures 
of rat hepatocytes (Bermudez et al., 1979).  2,4-DAT produced a 
significant elevation in unscheduled DNA synthesis at 2 and 12 h in 
the  in vivo/in vitro hepatocyte DNA repair assay (Mirsalis & 
Butterworth, 1982; Mirsalis et al., 1982).  2,5-DAT produced a 
positive response in a DNA-repair assay in rat hepatocytes and a 
weak positive response in hamster hepatocytes at 10-5 mol, the 
highest concentration that was not toxic to the cells that were 
tested (Kornbrust & Barfknecht, 1984). 

    Shooter & Venitt (1979) used continuous administration of 2,4-
DAT in the drinking-water to determine whether phosphotriesters 
could be detected in the DNA of the liver of treated rats.  
Positive results were obtained at 10 mg/litre.  A low, but 
significant, level of these lesions was produced.  Shooter & 
Venitt's studies on rodents indicated that methyl- and 
ethylphosphotriesters persist for many weeks in the DNA of certain 
organs (notably liver, kidney, and lung) and that such lesions are 
not eliminated by DNA repair. 

    The results of studies by Greene et al. (1981) showed that 
2,4-, 2,5-, 2,6-, and 3,4-isomers significantly inhibited the 
incorporation of [125I]-iododeoxyuridine into mouse testicular DNA 
and demonstrated dose-response characteristics.  The 2,4-, 2,5-, 
and 3,4-isomers were capable of reaching the testes and of passing 
target cell membranes at this site.  They concluded that the 3 
isomers may present a genetic health hazard for an intact animal.  
The inhibition induced by 2,6-DAT might have been caused by a 
chemically-induced decrease in body temperature (Greene et al., 
1981). 

    DNA damage was not found in human cultured fibroblasts after 
exposure to 100 mol 2,4-DAT alone (3.5  1.5 increase in percent 
single-strand DNA).  When the cells were incubated in the presence 
of 1 mg ram seminal vesicle microsomes/ml and 100 mol arachidonic 
acid, a significant increase in the fraction of single-strand DNA 
(21.3  3.7,  P < 0.001) was found in cells exposed to 2,4-DAT.  
DNA strand breaks were not induced when prostaglandin synthase 
(PGS) was inhibited by adding indomethacin (100 mol) or 
acetylsalicylic acid (1 mmol) (Nordenskjld et al., 1984).  These 
results, which suggest that 2,4-DAT may be activated by PGS to form 
products that cause DNA damage in cultured human fibroblasts, are 
in agreement with the findings of Rahimtula et al. (1982). 

7.5.2.  Mutation

    Several studies have shown that 2,4-, 2,6-, and 2,5-isomers can 
induce reverse mutations in  Salmonella typhimurium strains TA 1538 
and TA 98, in the presence of various metabolic activation systems 
(McCann et al., 1975; Dybing & Thorgeirsson, 1977; Dybing et al., 

1977; Pienta et al., 1977b; Cinkotai et al., 1978; Aune et al., 
1979; Shahin et al., 1980).  However, Mori et al. (1982) showed 
that 2,4-DAT was inactive for strains TA 98 and TA 100 at doses 
ranging from 5 to 1000 g/plate.  While 2,3-DAT is inactive in  S. 
 typhimurium (Florin et al., 1980), its homologue 3,4-DAT showed a 
marginal response in strains TA 98 and TA 1538 (Greene et al., 
1979). 

    2,4-DAT was shown to be a weak mutagen in  Drosophila 
 melanogaster, inducing sex-linked recessive lethals when fed to 
adult males at a concentration of 15.2 mmol (Blijleven, 1977; 
Venitt, 1978).  In a study reported by Fahmy & Fahmy (1977), 2,4-
DAT was injected around the testes of adult male  Drosophila at 
doses ranging from 5 to 20 mmol.  Mutagenicity was measured at the 
various stages of spermatogenesis, both on the X-chromosome and RNA 
genes.  The overall induced frequency of X-recessives was extremely 
low.  It was also observed that mutation yield was not dose-related 
and that it was maximal in the earliest progeny fraction, 
suggesting a greater toxicity for mature sperm. 

    2,4-DAT was mutagenic in L5178Y mouse lymphoma cells and CHO-
AT3-2 cells (Matheson & Creasy, 1976; Coppinger et al., 1984).  
Mutagenic activity was observed in L5178Y cells, only in the 
absence of exogenous metabolic activation, but was observed in CHO-
AT3-2 cells both with and without activation. 

    The  in vivo mutagenic activity of 2,4-DAT was studied in 
DBA/2J male mice by the dominant lethal assay, sperm abnormality 
assay, and the recessive spot test.  Mice were administered the 
compound by intraperitoneal injection and orally by gavage (2 daily 
doses of 40 mg/kg body weight), just before mating (Soares & Lock, 
1980).  No induction of dominant lethals was noted, nor was any 
increase in abnormal sperm or recessive spots reported. 

    No dominant lethals were induced in Charles River rats injected 
intraperitoneally, 3 times weekly for 8 weeks, with 20 mg 2,5-
DAT/kg body weight, before mating (Burnett et al., 1977). 

7.5.3.  Cell transformation

    Several studies have shown that the 2,4-, 2,5-, 2,6-, and 3,4-
isomers can induce morphological transformations in Syrian golden 
hamster embryo cells (Pienta et al., 1977a; Greene & Friedman, 
1980).  Each isomer chemically transformed secondary hamster embryo 
cells, but none were active in more than 50% of the 5 or 6 separate 
tests performed on each isomer (Greene & Freidman, 1980). 

7.5.4.  Chromosomal effects

    Cytogenetic preparations were made from the bone marrow of male 
mice, 30 and 48 h after intraperitoneal injection of 2 daily doses 
of 2,4-DAT at 40 mg/kg body weight.  The treatment did not induce 
any obvious chromosome breaks (Soares & Lock, 1980). 

    2,5-DAT did not induce micronucleated cells in bone marrow 
after oral administration of 120 mg/kg body weight to male and 
female rats, in 2 doses separated by an interval of 24 h (Hossack & 
Richardson, 1977). 

7.6.  Carcinogenicity

    Several long-term studies on the carcinogenic potential of the 
2,4-, 2,5-, and 2,6-DAT isomers have been published.  The 
experimental designs used in these studies are summarized in Table 
11.  The experimental designs used in 2 studies on the carcinogenic 
effects of hair dye formulations are also given in Table 11. 

    Although the early studies of Umeda (1955) and Ito et al. 
(1969) used protocols that generated data of minimal use for a 
hazard evaluation, they did produce qualitative information showing 
that 2,4-DAT was carcinogenic for rats.  These studies have been 
extended to the 2,5-, 2,6-, as well as 2,4-DATs using more animals 
per study and well-defined protocols (NCI, 1978, 1979, 1980; 
Weisburger et al., 1978). 

    Groups of 25 male Charles River/CD rats were administered 2,4-
DAT in the diet at time-weighted levels of 300 and 625 mg/kg for 18 
months.  Similarly, groups of 25 male and female CD-1 mice were 
given diets containing 500 and 1000 mg 2,4-DAT/kg for 18 months 
(Weisburger et al., 1978).  The rats and mice used in these studies 
had a high incidence of spontaneous tumours.  However, there was a 
statistically significant increase in subcutaneous fibromas in male 
rats and hepatocellular carcinomas and vascular tumours in male and 
female mice compared with controls. 

    Studies by the US National Cancer Institute on the 
carcinogenicity of 2,4-DAT in rats and mice (NCI, 1979) confirmed 
the report by Weisburger et al. (1978).  Administration of time-
weighted average doses of 79 and 176 mg 2,4-DAT/kg diet to groups 
of 50 male and 50 female Fisher 344 rats, for 103 weeks, led to a 
severe depression in body weight gain, high mortality, and a dose-
related development of hepatocellular carcinomas or neoplastic 
nodules in treated rats of both sexes.  In addition, NCI reported 
that carcinomas and adenomas of the mammary gland occurred in 
female rats at incidences that were dose related and significantly 
greater than those in the controls in both the high- and low-dose 
groups.  Groups of 50 male and 50 female B6C3F1 mice were similarly 
administered 2,4-DAT at 100 or 200 mg/kg diet, for 101 weeks.  In 
male mice, tumour incidence was not significantly increased 
compared with that in the control animals.  However, the incidence 
of hepatocellular carcinomas in female mice in both treated groups 
was dose related and significantly higher than that in the 
controls.  Numbers of lymphomas were also higher in low-dose female 
mice.  On the basis of these results, it was concluded that 2,4-DAT 
was carcinogenic for Fisher 344 rats of both sexes and for female 
B6C3F1 mice (NCI, 1979). 


Table 11.  Experimental designs of carcinogenicity studies on diaminotoluenes
---------------------------------------------------------------------------------------------------------
Isomer         Species (sex)              Initial size of   Route of administration/      Reference
                                          high-/low-dose    dose and duration
                                          groups (control)
---------------------------------------------------------------------------------------------------------
2,4-           rat (male and female)      20                subcutaneous; 2 mg in 0.5 ml  Umeda (1955)
                                                            propylene glycol weekly;
                                                            total of 28 injections; 452
                                                            days

2,4-           Wistar rat (male)          12/12 (6)         oral (diet); 0.6 and 1 g/kg;  Ito et al. 
                                                            36 weeks                      (1969)

2,4-           Charles River/CD rat       25/25 (25)        oral (diet); 500 and 1000     Weisburger et 
               (male)                                       mg/kg for 4 months and 250    al. (1978)
               Charles River mouse        25/25 (25)        and 500 mg/kg for 14 months;
               (male)                                       oral (diet); 500 and 1000
               Charles River mouse        25/25 (25)        mg/kg for 18 months
               (female)

2,5-           Fisher 344 rat (male)      50/50 (50/25)     oral (diet); 600 and 2000     NCI (1978)
               Fisher 344 rat (female)    50/50 (50/25)     mg/kg for 78 weeks + 31
                                                            weeks observation

               B6C3F1 mouse (male)        50/50 (50/50)     oral (diet); 600 and 2000
               B6C3F1 mouse (female)      50/50 (50/50)     mg/kg for 78 weeks + 19 
                                                            weeks observation

2,4-           Fisher 344 rat (male)      50/50 (20)        oral (diet); 125 and 250      NCI (1979)
               Fisher 344 rat (female)    50/50 (20)        mg/kg for 40 weeks reduced
                                                            to 50 and 100 mg/kg for 63
                                                            weeks (time-weighted-average
                                                            79 and 176 mg/kg); high-dose
                                                            males killed after 79 weeks
                                                            and high-dose females after
                                                            84 weeks

2,4            B6C3F1 mouse (male)        50/50 (20)        oral (diet); 100 and 200      NCI (1979)
               B6C3F1 mouse (female)      50/50 (20)        mg/kg for 101 weeks
---------------------------------------------------------------------------------------------------------

Table 11.  (contd.)
---------------------------------------------------------------------------------------------------------
Isomer         Species (sex)              Initial size of   Route of administration/      Reference
                                          high-/low-dose    dose and duration
                                          groups (control)
---------------------------------------------------------------------------------------------------------
2,6-           Fisher 344 rat (male)      50/50 (50)        oral (diet) 250 and 500       NCI (1980)
               Fisher 344 rat (female)    50/50 (50)        mg/kg for 103 weeks plus 1
                                                            week observation

               B6C3F1 mouse (male)        50/50 (50)        oral (diet); 250 and 500
               B6C3F1 mouse (female)      50/50 (50)        mg/kg for 103 weeks plus  1
                                                            week observation

2,5-           Sprague Dawley rat (male)  50 (50)           dermal application twice      Kinkel & 
(formulations  Sprague Dawley rat         50 (50)           weekly of 0.5 g of synthetic  Holzmann (1973)
with 6%        (female)                                     formulation containing 4%
hydrogen                                                    2,5-DAT mixed with equal
peroxide                                                    volume of 6% H202; treated 2
added)                                                      years

2,5-           Swiss Webster mouse        100 (250)         dermal application of 0.05    Burnett et al.
               (equal mixture male and                      ml weekly of formulation to   (1975)
               female)                                      which equal volume of 6%
                                                            H202 had been added;
                                                            treatment period, 18 months

2,5- + 2,4-    Swiss Webster mouse        100 (250)         dermal application of 0.05    Burnett et al. 
(formulations  (equal mixture male and                      ml weekly of formulation to   (1975)
with 6%        female)                                      which equal volume of 6%
hydrogen                                                    H202 had been added;
peroxide                                                    treatment period, 18 months
added)                                                      (same control group as
                                                            above study)
---------------------------------------------------------------------------------------------------------

                                                       
    The carcinogenic potential of 2,5-DAT and 2,6-DAT for rats and 
mice was determined by the US National Cancer Institute.  After 
administration of 2,5-DAT at 600 and 2000 mg/kg feed to groups of 
50 male and 50 female Fisher 344 rats and 50 male and 50 female 
B6C3F1 mice, for 78 weeks, there was not sufficient evidence to 
demonstrate the carcinogenicity of 2,5-DAT (NCI, 1978).  However, 
the study had been curtailed and this reduced the potential of the 
test for detecting carcinogenicity. 

    Using a similar protocol, 2,6-DAT was incorporated at levels of 
250 and 500 mg/kg into the diet of groups of 50 male and 50 female 
Fisher 344 rats, and B6C3F1 mice for 103 weeks (NCI, 1980).  There 
was some question of whether mice of either sex received a maximum 
tolerated dose, but the dose given to rats appeared to be at the 
maximum tolerated level.  As reported by NCI (1980), islet-cell 
adenomas of the pancreas and neoplastic nodules or carcinomas of 
the liver occurred in male rats in dose-related trends that were 
significant using the Cochran-Armitage test, but not using the 
Fisher exact test.  In the low-dose male mice, NCI reported that 
the incidence of lymphomas was greater than that in the controls. 
However, the incidence was not significant when the Bonferroni 
criterion of multiple comparison was used.  Similarly, the 
occurrence of hepatocellular carcinomas in female mice was dose 
related, but not significant by the Fisher exact test, when the 
incidence in the high-dose groups was compared with that in the 
controls.  Under the conditions of the bioassay, it was concluded 
that 2,6-DAT was not carcinogenic for male and female F344 rats or 
for male and female B6C3F1 mice (NCI, l980).  Summaries of the 3 
NCI bioassays have been published by Cardy (1979), Reuber (1979), 
and Sontag (1981). 

    Using the protocols outlined in Table 11, no evidence of 
carcinogenicity was obtained when hair-dye formulations containing 
2,5- and 2,5- plus 2,4-DAT were painted on the skin of rats and 
mice (Kinkel & Holzmann, 1973; Burnett et al., 1975).  Given the 
duration of exposure, the amounts of diaminotoluenes placed on the 
skin, and the use of hydrogen peroxide prior to administration, 
such negative results would be expected in studies on the formula 
containing 2,4-DAT (Burnett et al., 1975).  These studies have 
shown a low order of dermal toxicity for these hair dyes, even 
after long-term exposure.  However, no definitive statement can be 
made on the carcinogenic potential of 2,4- and 2,5-DAT after dermal 
administration. 

8.  EFFECTS ON MAN

8.1.  Single and Short-Term Exposures

    In human beings, as in animals, diaminotoluenes are considered 
to be irritants for the mucous membranes and skin, and to lead to 
conjunctivitis and corneal opacities.  When solutions come into 
contact with skin, they can cause irritation, severe dermatitis, 
and blistering (Von Oettingen, 1941).  In case of the inhalation of 
fumes, coughing, dyspnoea, and respiratory distress can result.  No 
data are available for evaluating the sensitizing potential of 
diaminotoluenes.  In the case of ingestion of massive amounts, 
nausea, vomiting, and diarrhoea would occur, with the possible 
production of methaemoglobinaemia.  No cases of human poisoning 
from short-term exposures to 2,4-DAT have been documented in the 
published literature. 

8.2. Long-Term Occupational Exposure - Epidemiological Studies

    Filatova et al. (1970) investigated the physiological and 
biochemical status of workers in a plant manufacturing 
diaminotoluenes.  Fifty-two of the 59 workers (58 males and 1 
female) had worked in the plant for > 2 1/2 years.  Seventeen 
workers were between 30 and 45 years of age and 42 workers were 
under 30 years old.  In general, all workers had equal exposure to 
the toxic chemicals used at the plant, namely, dinitrotoluene, 
diaminotoluenes, methanol, and  o-dichlorobenzene.  There were a 
few complaints of headache (2 cases), excess coughing (2 cases), 
stomach pains (2 cases), and chest pain (4 cases); however, the 
majority of the workers did not exhibit any exposure-related 
adverse effects.  Nevertheless, the investigators concluded that 
the 10 workers exhibiting the symptoms listed were indeed affected 
by their exposure to the complex of chemicals at this factory.  It 
is impossible to delineate the role played by the diaminotoluenes 
in the production of these adverse effects. 

    The US National Institute for Occupational Safety and Health 
(NIOSH) evaluated the reproductive health of workers in 3 plants 
manufacturing diaminotoluenes (NIOSH, 1980, 1981, 1982).  Exposure 
usually involved both DAT and dinitrotoluene (DNT).  All 3 surveys 
were conducted in response to requests from employees or their 
unions.  The reason for the first request was the workers' belief 
that their wives were suffering increased rates of spontaneous 
abortion.  The other 2 studies were prompted by the publicity given 
to the first study. 

    In 2 of the studies, environmental hygiene sampling took place 
(section 4.2) and workers were invited to volunteer for a medical 
examination, to complete a reproductive history questionnaire, and 
to provide semen and blood samples.  Semen samples were analysed 
for volume, sperm count, and sperm morphology.  Blood samples were 
analysed for various markers of renal and hepatic function, neither 
of which showed any significant inter-group differences in any of 
the studies. Wives of workers were given a more detailed 
reproductive history questionnaire. 

    In the first study (NIOSH, 1980), there were 44 volunteers, 30 
of whom provided usable semen specimens.  The total potential study 
population was not given.  Of the 30, 9 were exposed, 9 were 
controls, and 12 were in an intermediate category.  The rate of 
spontaneous abortions was higher among the wives of exposed workers 
(6/18 pregnancies while the husband was exposed) compared with the 
controls (4/23 pregnancies), with 6/28 for the intermediate group.  
The small number of congenital malformations was not exposure 
related.  The sperm count for the exposed (median = 49 million) was 
significantly ( P < 0.03) lower than that for the control group 
(median = 121 million); however, the latter figure was unusually 
high.  The exposed group showed a significant reduction in the 
proportion of the large morphological type.  The second study 
involved only a reproductive history questionnaire and the 
reporting of hygiene data by the company.  Thirty-five out of 41 
workers in DAT- and DNT-production areas were interviewed.  The 
rates of congenital abnormalities or spontaneous abortion did not 
significantly differ between exposure groups.  Where the husband 
was employed in DNT production, 1 out of 9 pregnancies ended in a 
spontaneous abortion; the equivalent data for DAT was 1 miscarriage 
out of 14 pregnancies. 

    In the third study, 50 volunteers were examined, 41 of whom 
provided semen specimens.  The total eligible population was not 
given, though it was reported that 25 workers were regularly 
exposed, 15 of whom participated in the study.  There were no 
significant differences in sperm count morphology between exposure 
groups, but the miscarriage rate was reported to be significantly 
( P < 0.05) higher for the wives of workers in the DAT-exposed area 
of the plant, where 6 out of 15 pregnancies ended in miscarriage 
compared with 1 out of 7 for the wives of DNT-exposed workers, and 
3 out of 38 for the wives of unexposed workers. 

    The ranges of levels of reported exposures overlapped between 
the 3 studies and were all within the OSHA recommended standard of 
1.5 mg/m3 for dinitrotoluenes (NIOSH, 1982).  The first study might 
have been expected to show an excess, because it was provoked by a 
cluster of miscarriages.  All the studies were of limited size and 
subject to some risk of selection bias, because the population was 
restricted to those who volunteered.  Also, in all 3 studies, crude 
figures, with no adjustment for age, were presented.  However, in 
the 2 follow-up studies, where apparently neither of the 
populations held a prior belief that there was an excess 
miscarriage rate, it is significant that an apparent excess of 
miscarriages was found in the wives of DAT-exposed workers. 

    An epidemiological assessment of the reproduction hazards for 
males after occupational exposure to diaminotoluenes and 
dinitrotoluenes was carried out by Hamill et al. (1982).  Reported 
occupational exposures were similar to those reported by NIOSH 
(1980, 1981, 1982) and were generally well within the OSHA 
recommended level of 1.5 mg/m3 for dinitrotoluenes.  Examination of 
84 workers and 119 unexposed subjects consisted of semen analysis, 
blood testing, medical examination, and an interview.  Seventy-two 
percent of non-vasectomized exposed workers provided semen samples.  

These groups of workers were defined by exposure intensity, 
frequency, and recency, and compared with controls.  Although no 
significant differences in miscarriage rates were reported between 
exposure categories, the categories were as defined at the time of 
the study, not at the time of pregnancy.  Fertility rates were 
reported to be unaffected by exposure, but no figures were given.  
There were no statistically significant differences in semen 
analysis, sperm count and morphology, and FSH levels, between the 3 
exposure groups and unexposed workers.  The authors concluded that 
the results of their study suggested that no detectable 
reproductive effects existed among male workers exposed to 
dinitrotoluenes and diaminotoluenes. 

    Levine et al. (1985) reported an analysis of the fertility of 
workers exposed to DNT and DAT.  The approach taken consisted of 
workers completing reproductive history questionnaires and of 
observed births being compared with expected births for the married 
workers.  Expected births were derived from US birth rates by age, 
calendar year, and parity, and the ratio of observed to expected 
was expressed as a standardized fertility ratio (SFR).  Populations 
of 137, 207, and 235 persons, respectively, were studied and were 
largely, but not exclusively, male.  It is not clear whether any of 
the plants were the same as those described above.  Comparisons of 
SFR between different exposure categories, both for the whole 
population and also among individuals who spent at least part of 
their reproductive life exposed, did not reveal any significant 
effects on SFR between exposure groups.  The authors estimated that 
the power of this study to detect a 50% reduction in fertility 
would have been 90%.  In the third NIOSH study, the miscarriage 
rate for wives of DAT-exposed workers was 6.8 times higher than 
that for wives of unexposed workers (rates given as miscarriages 
per 100 person-years), but the fertility rate was only 0.8 times 
lower (ratio of rates of live births per 100 person-years).  Thus, 
overall fertility may not be a sensitive index of adverse 
reproductive outcome. 

9.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

9.1.  Evaluation of Human Health Risks

9.1.1.  General considerations

    There are insufficient data on the effects of diaminotoluenes 
on human beings to carry out a detailed hazard assessment or risk 
evaluation.  However, absorption and metabolic studies in human 
beings have indicated that diaminotoluenes are rapidly absorbed, 
metabolized, and excreted in the urine in a manner similar to that 
found in experimental animals.  Therefore, the risk evaluation that 
follows is based largely on data from animals, supported by data 
from human studies, where available. 

9.1.2.  Assessment of exposure

    Diaminotoluenes can be absorbed through the skin and 
gastrointestinal tract, and by inhalation.  Given the properties of 
this class of chemicals, the major route of human exposure is 
dermal, in the work-place, with a possibility of the inhalation of 
fumes during heating.  Exposure through ingestion is minimal, 
except in case of accidents. 

    No data exist on general ambient levels of diaminotoluenes in 
air, water, and food.  Bioaccumulation of diaminotoluenes in the 
food-chain should not occur.  Levels in the work-place air of up to 
0.44 mg/m3, with occasional excursions up to 11 mg/m3, have been 
reported. 

9.1.3.  Single and short-term exposures

    Diaminotoluenes are classed as toxic, highly irritant 
chemicals.  The oral LD50 for animals is between 270 and 350 mg/kg 
body weight.  Dermal contact has been shown to cause irritation, 
severe dermatitis, blistering, and possible skin sensitization.  
Single oral doses of diaminotoluenes of 50 mg/kg body weight have 
led to methaemoglobinaemia in rats, rabbits, and guinea-pigs.  Eye 
contact with diaminotoluenes has led to conjunctivitis and corneal 
opacities.  In case of inhalation of fumes, coughing, dyspnoea, and 
respiratory distress can result. 

9.1.4.  Long-term exposure

9.1.4.1.  Carcinogenicity and mutagenicity

    No epidemiological data are available on the incidence of 
cancer in human beings after exposure to diaminotoluenes. 

    Several studies using 2,4-DAT have been carried out on 
experimental animals and, in each, the isomer was shown to be 
carcinogenic for rats and mice.  In the most recent study, doses 
of, or greater than, 79 mg/kg diet led to an increase in 
hepatocellular carcinomas or neoplastic nodules in rats; there was 
an increase in hepatocellular carcinomas and lymphomas in female 
mice at doses exceeding 100 mg/kg diet. 

    Using a similar protocol, the US NCI concluded that 2,6-DAT was 
not carcinogenic for rats and mice after administration of up to 
500 mg/kg diet for 103 weeks.  It should be noted that 
hepatocellular carcinomas, neoplastic nodules, and lymphomas were 
detected, as in the bioassay for 2,4-DAT, however, they were 
considered not significant after detailed statistical analyses. 

    There was no evidence of carcinogenicity in mice and rats after 
administration of 2,5-DAT at levels of up to 2000 mg/kg diet, for 
78 weeks.  However, the short duration of the study reduced the 
potential of the test for detecting carcinogenicity.  No evidence 
of carcinogenicity was noted after the dermal application of hair-
dye formulations containing 2,5-DAT (following application of 
hydrogen peroxide) or a mixture of 2,5-DAT and 2,4-DAT with 
hydrogen peroxide. 

    Positive mutagenic activity was noted in  S. typhimurium when 
2,4-, 2,5-, 2,6-, and 3,4-DAT were tested.  In addition, DAT 
isomers were mutagenic in mammalian cells  in vitro.  Significant 
DNA damage was produced by 2,4-DAT in human cultured fibroblasts, 
only after activation by prostoglandin synthase.  The isomer 2,4-
DAT was weakly mutagenic in  Drosophila melanogaster and induced 
unscheduled DNA synthesis in primary rat hepatocytes  in vitro. 

    The 2,4- and 2,5-isomers were inactive in  in vivo mammalian 
mutagenicity assays.  Micronuclei and dominant lethals were not 
produced by 2,5-DAT, and 2,4-DAT did not produce chromosomal 
breaks, dominant lethals, abnormal sperm morphology, or recessive 
spots. 

    It has been shown that 2,4-, 2,5-, and 2,6-DAT can inhibit DNA 
synthesis in the testes after ip injection of high doses.  On the 
basis of this study, 2,4-DAT may pose a genetic hazard in addition 
to its potential to cause adverse effects on reproduction. 

9.1.4.2.  Reproduction and teratogenicity

    The results of limited studies on the reproduction hazards for 
male workers exposed to diaminotoluenes are equivocal.  In surveys 
of reproductive outcome in 3 plants, an excess of spontaneous 
abortions among the wives of male workers exposed to DAT and 
dinitrotoluene was reported in 2 surveys, though these excesses 
were based on small numbers, and not all workers in the plants 
participated in the studies.  In 1 out of the 3 plants studied, 
some adverse effects on spermatogenesis were suggested.  Analysis 
of the overall fertility of workers in 3 other production plants 
did not reveal any adverse effects from exposure to DAT. 

    In a study on animals fed 2,4-DAT, there was a significant and 
persistent decrease in the sperm count. 

    Embryotoxicity was observed in animal studies after oral and 
dermal doses exceeding 30 mg/kg body weight for the 2,3-and 3,4-
isomers and 10 mg/kg body weight for 2,6-DAT. 

    Skeletal changes were noted after dermal application of a hair-
dye formula containing 3% 2,4-DAT at 2 ml/kg body weight. 

9.2.  Evaluation of Effects on the Environment

    Information is lacking concerning levels of diaminotoluenes in 
the environment, and their transport, bioconcentration, 
biotransformation, and biodegradation. 

    A few data indicate that diaminotoluenes may be hazardous for 
aquatic organisms.  No data on the effects of diaminotoluenes on 
other non-mammalian targets in the environment could be found. 

9.3.  Conclusions

    Diaminotoluenes are highly irritating to the skin and eyes and 
the fumes are irritating to the respiratory tract.  They are 
readily absorbed through the skin.  Methaemoglobinaemia may occur 
in exposed individuals.  Renal toxicity after oral administration 
of 2,4-DAT has been reported in experimental animals.  2,4-DAT has 
been shown to be carcinogenic for animals, but there is inadequate 
evidence to evaluate the carcinogenic potential of 2,5- and 2,6-
diaminotoluene.  All 3 of these isomers have been shown to be 
mutagenic.  Limited data are available concerning a reproductive 
hazard for male workers handling DATs.  DATs have been shown to 
impair spermatogenesis in experimental animals and to be both 
embryotoxic and teratogenic. 

10.  RECOMMENDATIONS

1.  Monitoring should be undertaken to determine the sources,
    levels, and fate of diaminotoluenes in the environment.
    Ecotoxicity data should be collected.

2.  For a better evaluation of occupational exposure and effects, 
    studies on the uptake, kinetics, and metabolism of DAT and the 
    relevant routes of exposure are important to provide a sound 
    basis for biological monitoring. 

3.  To assist in the development of appropriate health
    surveillance systems, a systematic evaluation of the toxicity 
    of diaminotoluenes should be carried out to compliment 
    available data on carcinogenicity and reproductive effects.

4.  Additional data should be obtained on human morbidity and
    mortality related to exposure to diaminotoluenes, with
    particular emphasis on carcinogenic, teratogenic, and
    reproductive end-points.

11.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    IARC (1978) evaluated the data on the carcinogenicity of 
diaminotoluenes and concluded that there was sufficient evidence of 
the carcinogenicity of 2,4-diaminotoluene in experimental animals.  
An evaluation of additional data by IARC (1986) further supported 
this conclusion. 

    In the absence of case reports or epidemiological studies, 
there was inadequate data to assess the carcinogenicity of 
diaminotoluenes for human beings (IARC, 1978). 

REFERENCES

AUNE, T., NELSON, S.D., & DYBING, E.  (1979)  Mutagenicity and 
irreversible binding of the hepatocarcinogen 2,4-diaminotoluene. 
 Chem.-biol. Interact., 25(1): 23-24. 

AUSTIN, G.T.  (1974)  Industrially significant organic chemicals. 
Part 9.  Chem. Eng., 11: 96-100.

BACKUS, J.K.  (1974)  Urethanes. In: Considine, D.M., ed. 
 Chemical and process technology encyclopedia, New York, McGraw 
Hill Book Co., pp. 1121-1125.

BECCI, P.J., REAGAN, E.L., KNICKERBOCKER, M.J., BARBEE, S.J., 
& WEDIG, J.H.  (1983)  Teratogenesis study of o-toluenediamine 
in rats and rabbits.  Toxicol. appl. Pharmacol., 71: 323-329.

BECHER, G.  (198l)  Glass capillary columns in the gas 
chromatographic separation of aromatic amines. 2. Application 
of samples from workplace atmospheres using nitrogen-selective 
detection.  J. Chromatogr., 211(1): 103-111.

BERMUDEZ, E. & BUTTERWORTH, B.E.  (1979)  Analysis of the 
activities of 2,4-diaminotoluene and 2,4- and 2,6-dinitrotoluene 
in the primary hepatocyte unscheduled DNA synthesis assay. 
 Environ. Mutagen., 1: 168-169.

BERMUDEZ, E., TILLERY, D., & BUTTERWORTH, B.E.  (1979)  Effect 
of 2,4-diaminotoluene and isomers of dinitrotoluene on 
unscheduled DNA synthesis in primary rat hepatocytes.  Environ. 
 Mutagen., 1: 39l-398.

BIERNACKA, T., SEKOWSKA, B., & MICHONSKA, J.  (1974) [Determination 
of 2,4- and 2,6-diaminotoluene in technical products by infra-red 
spectroscopy.]  Chem. Anal. (Warsaw), 19: 6l9-632 (in Polish).

BLIJLEVEN, W.G.H.   (1977)  Mutagenicity of four hair dyes in 
 Drosophila melanogaster. Mutat. Res., 48: 181-186.

BOUFFORD, C.E.  (l968)  Determination of isomeric diaminotoluenes 
by direct gas liquid chromatography.  J. Gas Chromatogr., 6: 
438-440.

BUIST, J.M.  (1970)  Isocyanates in industry.  Proc. R. Soc. Med., 
63: 365-366.

BURNETT, C., LANMAN, B., GIOVACCHINI, R., WOLCOTT, G., & SCALA, R.  
(1975)  Long-term toxicity studies on oxidation hair dyes. 
 Food Cosmet. Toxicol., 13(3): 353-357.

BURNETT, C., GOLDENTHAL, E.I., HARRIS, S.B., WAZETER, F.X., 
STRAUSBURG, J., KAPP, R., & VOELKER, R.  (1976)  Teratology 
and percutaneous toxicity studies on hair dyes.  J. Toxicol. 
 environ. Health, 1: 1027-1040.

BURNETT, C., LOEHR, R., & CORBETT, J.  (1977)  Dominant lethal 
mutagenicity study on hair dyes.  J. Toxicol. environ. Health, 
2: 657-662.

CARDY, R.H.  (1979)  Carcinogenicity and chronic toxicity of 
2,4-toluenediamine in F344 rats.  J. Natl Cancer Inst., 62: 
1107-1116.

CARPENTER, C.P., WEIL, C.S., & SMYTH, H.F., Jr  (1974)  
Range-finding toxicity data.  Toxicol. appl. Pharmacol., 28: 
313-319.

CHOUDHARY, G.  (1980)  Gas-liquid chromatographic determination 
of toxic diamines in permanent hair dyes.  J. Chromatogr., 193: 
277-284.

CIC JAPAN (1983)   Commercial industrial chemicals, Tokyo, 
Chemical Daily Co., Ltd.

CINKOTAI, K.I., JONES, C.C., TOPHAM, J.C., & WATKINS, P.A.  (1978)  
Experience with mutagenic tests as indicators of carcinogenic 
activity.  Mutat. Res., 53: 167-168.

COPPINGER, W.J., BRENNAN, S.A., CARVER, J.H., & THOMPSON, E.D.  
(1984)  Locus specificity of mutagenicity of 2,4-diaminotoluene in 
both L5l78Y mouse lymphoma and AT3-2 chinese hamster ovary cells. 
 Mutat. Res., 135: 115-123.

CRC  (1975)   CRC handbook of chemistry and physics, 56th ed., 
Cleveland, Ohio, CRC Press.

DENT, J.G. & GRAICHEN, M.E.  (1982)  Effect of hepatocarcinogens 
on epoxide hydrolase and other xenobiotic metabolizing enzymes. 
 Carcinogenesis, 3(7): 733-738.

DYBING, E. & THORGEIRSSON, S.S.  (1977)  Metabolic activation 
of 2,4-diaminoanisole, a hair dye component. 1. Role of 
cytochrome P-450 metabolism in mutagenicity  in vitro. Biochem. 
 Pharmacol., 26: 729-734.

DYBING, E., AUNE, T., & SODERLUND, E.J.  (1977)  Use of the 
 Salmonella mutagenicity test in drug metabolism studies.  Acta 
 pharmacol. toxicol., 41: 31.

DYBING, E., AUNE, T., & NELSON, S.  (1978)  Covalent binding 
of 2,4-diaminoanisole and 2,4-diaminotoluene  in vivo. Toxicol. 
 Aspects Food Saf. Arch. Toxicol., Suppl. 1: 213-217.

FAHMY, M.J. & FAHMY, O.G.  (1977)  Mutagenicity of hair dye 
components relative to the carcinogens benzidine in  Drosophila 
 melanogaster. Mutat. Res., 56: 31-38.

FILATOVA, V.S., TUBINA, A.Ya., SHARONOVA, Z.V., GOLOVA, I.A., 
FILINA, V.I., & DOROFEEVA, E.D.  (1970)  [Hygienic aspects of 
work and health of workers in the production of toluylene- 
diamine.]  Gig. i Sanit., 35(2): 16-30 (in Russian with English 
summary).

GAN, L.H., BLAIS, P., CARLSSON, D.J., SUPRUNCHUCK, T., & WILES, D.M.  
(1975)  Physicochemical characterization of some fully aromatic 
polyamides.  J. appl. polym. Sci., 19: 69-82.

GLINSUKON, T., BENJAMIN, T., GRANTHAM, P.H., WEISBURGER, E.K., & 
ROLLER, P.P.  (1975)  Enzymic  N-acetylation of 2,4-toluenediamine 
by liver cytosols from various species.  Xenobiotica, 5(8): 475-483.

GLINSUKON, T., BENJAMIN, T., GRANTHAM, P.H., LEWIS, N.L., & 
WEISBURGER, E.K.  (1976)   N-acetylation as a route of 2,4- 
toluenediamine metabolism by hamster liver cytosol.  Biochem. 
 Pharmacol., 25: 95-97.

GRANTHAM, P.H., MOHAN, L., BENJAMIN, T., ROLLER, P.P., MILLER, J.R., 
& WEISBURGER, E.K.  (1980)  Comparison of the metabolism of 2,4-
toluenediamine in rats and mice.  J. environ. Pathol. Toxicol., 
3(1-2): 149-l66.

GREENE, E.J. & FRIEDMAN, M.A.  (1980)   In vitro cell transformation 
screening of 4 toluene diamine isomers.  Mutat. Res., 79: 363-375.

GREENE, E.J., FRIEDMAN, M.A., & SHERROD, J.A.  (1979)   In vitro 
mutagenicity and cell transformation testing of four toluene 
diamine isomers.  Environ. Mutagen., 1: 194.

GREENE, E.J., SALERNO, A.J., & FRIEDMAN, M.A.  (1981)  Effect 
of 4 toluene diamine isomers on murine testicular DNA synthesis. 
 Mutat. Res., 91: 75-79.

GUTHRIE, J.L. & MCKINNEY, R.W.  (1977)  Determination of 2,4- 
and 2,6-diaminotoluene in flexible urethane foams.  Anal. 
 Chem., 49: 1676-1680.

HAMILL, V.V., STEINBERGER, E., LEVINE, R.J., RODRIGUEZ-RIGAU, 
L.J., LEMESHOW, S., & AVRUNIN, J.S.  (1982)  The epidemiologic 
assessment of male reproductive hazard from occupational 
exposure to TDA and DNT.  J. occup. Med., 24: 982-993.

HOSSACK, D.J.N. & RICHARDSON, J.C.  (1977)  Examination of the 
potential mutagenicity of hair dye constituents using the 
micronucleus test.  Experientia (Basel), 33: 377-378.

HRUBY, R.  (1977)  The absorption of  p-toluenediamine by the 
skin of rats and dogs.  Food Cosmet. Toxicol., 15: 595-599.

IARC  (1978)  2,4-Diaminotoluene. In:  Some aromatic amines and 
 related nitro compounds: hair dyes, colouring agents, and 
 miscellaneous industrial compounds, Lyons, International 
Agency for Research on Cancer, pp. 83-95 (Monographs on the 
Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 16).

IARC  (1986)   Some chemicals used in plastics and elastomers, 
Lyons, International Agency for Research on Cancer, p. 304 
(Monographs on the Evaluation of Carcinogenic Risk of 
Chemicals to Man, Vol. 39).

INOUYE, M. & MURAKAMI, U.  (1976)  Teratogenicity of 2,5- 
diaminotoluene, a hair dye component in mice.  Teratology, 14: 
241-242.

INOUYE, M. & MURAKAMI, U.  (1977)  Teratogenicity of 2,5- 
diaminotoluene, a hair dye constituent in mice.  Food Cosmet. 
 Toxicol., 15: 447-451.

ITO, N., HIASA, Y., KONISHI, Y., & MARUGAMI, M.  (1969)  The 
development of carcinoma in liver of rats treated with 
 m-toluylenediamine and the synergistic and antagonistic 
effects with other chemicals.  Cancer Res., 29: 1137-1145.

IZMEROV, N.F., SANOTSKY, I.V., & SIDOROV, K.K.  (1982)  
 Toxicometric paramaters of industrial toxic chemicals under 
 single exposure, Moscow, USSR/SCST/USSR Commission for UNEP, 
Centre of International Projects.

JOHANSSON, K., RAPPE, C., LINDBERG, W., & NYGREN, M.  (1981)  
Determination of aromatic diamines in hair dyes using liquid 
chromatography. In: Egan, H., Fishbein, L., O'Neil, I.K., 
Castegnaro, M., & Bartsch, H., ed.  Environmental carcinogens 
 selected methods of analysis. Volume 4: Some aromatic amines 
 and azo dyes in the general and industrial environment. Lyons, 
International Agency for Research on Cancer (IARC Publications 
No. 40).

KIESE, M. & RAUSCHER, E.  (1968)  The absorbtion of p-toluene- 
diamine through human skin in hair dyeing.  Toxicol. appl. 
 Pharmacol., 13: 325-331.

KIESE, M., RACHOR, M., & RAUSCHER, E.  (1968)  The absorption 
of some phenylenediamines through the skin of dogs.  Toxicol. 
 appl. Pharmacol., 12: 495-507.

KINKEL, H.J. & HOLZMANN, S.  (1973)  Study of long-term 
percutaneous toxicity and carcinogenicity of hair dyes 
(oxidizing dyes) in rats.  Food Cosmet. Toxicol., 11: 641-648.

KNICKERBOCKER, M., RE, T.A., PARENT, R.A., & WEDING, J.H.  
(1980)  Teratogenic evaluation of  ortho-toluenediamine 
(o-TDA) in Sprague Dawley rats and Dutch Belted rabbits. 
 Toxicologist, 19: A.89.

KORNBRUST, D.J. & BARFKNECHT, T.R.  (1984)  Comparison of 7 
azo dyes and their reduction products in the rat and hamster 
hepatocyte primary culture/DNA-repair assays.  Mutat. Res., 
136: 255-266.

KOTTEMANN, C.M.  (1966)  Two dimensional thin-layer 
chromatographic procedure for the identification of dye 
intermediates in arylamine oxidation hair dyes.  J. Assoc. Off. 
 Anal. Chem., 49(5): 954-959.

LEVINE, R.J., CORSO, D.D., & BLUNDEN, P.B.  (1985)  Fertility 
of workers exposed to dinitrotoluene and toluenediamine at 
three chemical plants. In: Rickert, D.E., ed.  Toxicity of 
 nitroaromatic compounds, Washington DC, Hemisphere.

LIEM, D.H. & ROOSELAAR, J.  (1981)  HPLC of oxidation hair 
colours.  Mitt. Geb. Lebensm. Hyg., 72: 164-176.

MCCANN, J., CHOI, E., YAMASAKI, E., & AMES, B.N.  (1975)  
Detection of carcinogens as mutagens in the  Salmonella microsome 
test: Assay of 300 chemicals.  Proc. Natl Acad. Sci. (USA), 72: 
5135-5139.

MACKE, G.F.  (1968)  Use of tetracyanoethylene as a thin-layer 
chromatographic spray reagent.  J. Chromatogr., 36: 537-539.

MARKS, T.A., GUPTA, B.N., LEDOUX, T.A., & STAPLES, R.E.  
(1981)  Teratogenic evaluation of 2-nitro-p-phenyl-enediamine, 
4-nitro-o-phenylendiamine, and 2,5-toluenediamine sulfate in 
the mouse.  Teratology, 24: 253-265.

MARZULLI, F.N., ANJO, D.M., & MAIBACH, H.I.  (1981)   In vivo 
skin penetration studies of 2,4-toluenediamine, 2,4-diamino- 
anisole, 2-nitro-p-phenylenediamine, p-dioxane and n-nitro- 
sodiethanolamine in cosmetics.  Food Cosmet. Toxicol., 19: 743.

MATHESON, D. & CREASY, B.  (1976)  Use of the L5178Y (TK+/-) 
mouse lymphoma cell line coupled with an  in vitro microsomal 
enzyme activation system to study chemical promutagens.  Mutat. 
 Res., 38: 400-401.

MATHIAS, A.  (1966)  Analysis of diaminotoluene isomer 
mixtures by nuclear magnetic resonance spectrometry.  Anal. 
 Chem., 38: 1931-1932.

MATSUI, S., MURAKAMI, T., SASAKI, T., HIROSE, Y., & IGUMA, Y.  
(1975)  Activated sludge degradability of organic substances 
in the wastewater of the Kashima petroleum and petrochemical 
industrial complex in Japan.  Prog. Water Technol., 7:645-659. 

MILLIGAN, B. & GILBERT, K.E.  (1978)  Diaminotoluenes. In: 
 Kirk-Othmer encyclopaedia of chemical technology, 3rd ed., 
New York, John Wiley and Sons, Vol. 1, pp. 321-329.

MIRSALIS, J.C. & BUTTERWORTH, B.E.  (1982)  Induction of 
unscheduled DNA synthesis in rat hepatocytes following  in vivo 
treatment with dinitrotoluene.  Carcinogenesis, 3: 241-245.

MIRSALIS, J.C., TYSON, C.M., & BUTTERWORTH, B.E.  (1982)  
Detection of genotoxic carcinogens in the  in vivo/in vitro 
hepatocyte DNA repair assay.  Environ. Mutagen., 4: 553-562.

MORI, M.A., MIYAHARA, T., TANIGUCHI, K., HASEGAWA, K., KOZUKA, 
H., MIYAGOSHI, M., & NAGAYAMA, T.  (1982)  Mutagenicity of 
2,4-dinitrotoluene and its metabolites in  Salmonella typhimurium. 
 Toxicol. Lett., 13: 1-5.

NCI  (1978)   Bioassay of 2,5-toluenediamine sulfate for 
 possible carcinogenicity, Bethesda, Maryland, National Cancer 
Institute (NCI Carcinogenesis Technical Report Series No. 126; 
DHEW Publication No. (NIH) 78-1381).

NCI  (1979)   Bioassay of 2,4-diaminotoluene for Possible 
 Carcinogenicity, Bethesda, Maryland, National Cancer Institute 
(NCI Carcinogenesis Technical Report Series No. 162).

NCI  (1980)   Bioassay of 2,6-toluenediamine dihydrochloride 
 for possible carcinogenicity, Bethesda, Maryland, National 
Cancer Institute (NCI Carcinogenesis Technical Report Series 
No. 200; NTP No. 80-20; NIH Publication No. 80-1756).

NIEMINEN, E.H., SAARINAN, L.H., & LAAKSO, J.T.  (1983) 
Simultaneous determination of aromatic isocyanates and some 
carcinogenic amines in the work atmosphere by reversed-phase 
high-performance liquid chromatography.  J. liq. Chromatogr., 
6: 453-469.

NIOSH  (1978)   NIOSH manual of analytical methods, 2nd ed., 
Cincinnati, Ohio, US National Institute for Occupational 
Safety and Health, US Department of Health, Education and 
Welfare, Public Health Service, Center for Disease Control, 
Vol. 4 (Publication No. 78-175).

NIOSH  (1980)   Health hazard evaluation determination report 
 HE 79-113-728, Brandenburg, Kentucky, Olin Chemical Company, 
and Cincinnati, Ohio, National Institute for Occupational 
Safety and Health, US Department of Health and Human Services, 
Center for Disease Control.

NIOSH  (1981)   Interim Report No. 1. HETA 81-118, 
New Martinsville, West Virginia, Mobay Chemical Corporation, 
and Cincinatti, Ohio, US National Institute for Occupational 
Safety and Health, US Department of Health and Human Services, 
Center for Disease Control.

NIOSH  (1982)   Interim report No. 1. HETA 81-295-1155, 
Moundsville, West Virginia, Allied Chemical Company, and 
Cincinnati, Ohio, US National Institute for Occupational 
Safety and Health, US Department of Health and Human Services, 
Center for Disease Control.

NORDENSKJOLD, M., ANDERSSON, B., RAHIMTULA, A., & MOLDEUS, P.  
(1984)  Prostaglandin synthesis-catalyzed metabolic activation 
of some aromatic amines to genotoxic products.  Mutat. Res., 
127: 107-112.

OLUFSEN, B.   (1979)  Glass capillary columns in the gas 
chromatographic separation of aromatic amines.  I. J.  Chromatogr., 
179: 97-103.

OSHA  (1983)   Code of federal regulations, Washington DC, US 
Occupational Safety and Health Administration, pp. 660-664 
(29CFR, 19101000, Table Z-1).

PERKINS, W.E. & GREEN, T.J.  (1975)  Effect of 3,4-toluenediamine 
on output from  in situ rat brunner's glands pouches (38941). 
 Proc. Soc. Exp. Biol. Med., 149: 991-994.

PIENTA, R.J., POILEY, J.A., & LEBHERZ, W.B., III  (1977a)  
Morphological transformation of early passage golden Syrian 
hamster embryo cells derived from cryopreserved primary 
cultures as a reliable  in vitro bioassay for identifying 
diverse carcinogens.  Int. J. Cancer, 19: 642-655.

PIENTA, R.J., SHAH, M.J., LEBHERZ, W.B., & ANDREWS, A.W.  
(1977b)  Correlation of bacterial mutagenicity and hamster 
cell transformation with mutagenicity induced by 2,4- 
toluenediamine.  Cancer Lett., 3: 45-52.

PURNELL, C.J. & WARWICK, C.J.  (1981)  Application of electro- 
chemical detection in high-performance liquid chromatography 
to the measurement of toxic substances in air.  Anal. Proc., 
18: 151-154.

PURNELL, C.J., BAGON, D.A., & WARWICK, C.J.  (1982)  The 
determination of organic contaminant concentrations in 
workplace atmospheres by high-performance liquid chromatography. 
 Pergamon Ser. environ. Sci., 7: 203-219.

RAHIMTULA, A., MOLDEUS, P., ANDERSSON, B., & NORDENSKJOLD, M.  
(1982)  Prostaglandin synthetase catalyzed DNA strand breaks 
by aromatic amines. In:  Prostaglandins and related lipids,  
New York, Alan R. Liss, Vol. 2, pp. 159-162.

REUBER, M.D.  (1979)  Carcinomas of the liver in female mice 
fed toluene-2,4-diamine.  Gann, 70: 453-457.

RIGGIN, R.M. & HOWARD, C.C.  (1983)  High performance liquid 
chromatographic determination of phenylenediamines in aqueous 
environmental samples.  J. liq. Chromatogr., 6: 1897-1905.

SCHAFER, U. METZ, J., PEVNY, I., & ROCKL, H.  (1978)  
[Attempts of sensitizing guinea pigs with five different 
derivates of para-substituted benzene.]  Arch dermatol. Res., 
216: 153-161 (in German).

SELYE, H.  (1973)  Production of perforating duodenal ulcers 
by 3,4-toluenediamine in the rat.  Proc. Soc. Exp. Biol. Med., 
142: 1192-1194.

SHAHIN, M.M., BUGAUT, A., & KALOPISSIS, G.  (1980)  Structure- 
activity relationship within a series of m-diaminobenzene 
derivatives.  Mutat. Res., 78: 25-31.

SHOOTER, K.V. & VENITT, S.  (1979)  Phosphotriesters in DNA: 
non-repairable lesions as markers for the early detection of 
chemical carcinogens in intact animals.  Mutat. Res., 64: 106.

SKARPING, G., RENMAN, L., & SMITH, B.E.F.  (1983a)  Trace 
analysis of amines and isocyanates using glass capillary gas 
chromatography and selective detection. I.  Determination of 
aromatic amines as perfluoro-fatty acid amines using electron- 
capture detection.  J. Chromatogr., 267: 315-327.

SKARPING, G., RENMAN, L., & DALENE, M.  (1983b)  Trace 
analysis of amines and isocyanates using glass capillary gas 
chromatography and selective detection. II Determination of 
aromatic amines as perfluoro-fatty acid amines using nitrogen- 
selective detection.  J. Chromatogr., 270: 207-218.

SMIRNOVA, A.N., TOROPOVA, L.A., & DOBROVOL'SKAYA, V.V.  
(1967)  [Effect of toluylenediamine and ortho-toluidine on 
aquatic organisms.]  Vodosnarzh Kanaltz Giurotekh, 5: 17-23 (in 
Russian) (EPA translation).

SNYDER, R.C. & BREDER, C.V.  (1982)  High performance liquid 
chromatographic determination of 2,4- and 2,6-toluenediamine 
in aqueous extracts.  J. Chromatogr., 236: 429-440.

SNYDER, R.C., BRUMLEY, W.C., BREDER, C.V., & FAZIO, T.  
(1982)  Gas chromatographic and gas chromatographic-mass 
spectrometric confirmation of 2,4- and 2,6-toluenediamine 
determined by liquid chromatography in aqueous extracts.  J. 
 Assoc. Off. Anal. Chem., 65(6): 1388-1394.

SOARES, E.R. & LOCK, L.F.  (1980)  Lack of an indication of 
mutagenic effects of dinitrotoluenes and diaminotoluenes in 
mice.  Environ. Mutagen., 2: 111-124.

SONTAG, J.M.  (1981)  Carcinogenicity of substituted-benzene- 
diamines (phenylenediamines) in rats and mice.  J. Natl Cancer 
 Inst., 66: 591-602.

SPENGLER, J., OSTERBURG, I., & KORTE, R.  (1986)  Abstract: 
Teratogenic evaluation of p-toluenediamine sulphate. 
Resorcinal and p-aminophenol in rats and rabbits.  Teratology, 
33(2): 31.

THYSEN, B., BLOCH, E., & VARMA, S.K. (1985a) Reproductive 
toxicity of 2,4-toluenediamine in the rat. 2. Spermatogenic 
and hormonal effects.  J. Toxicol. environ. Health, 16: 763-769.

THYSEN, B., VARMA, S.K., & BLOCH, E (1985b) Reproductive 
toxicity of 2,4-toluenediamine in the rat.  1. Effect on male 
fertility.  J. Toxicol. environ. Health, 16: 753-761.

UMEDA, M.  (1955)  Production of rat sarcoma by injections of 
propylene glycol solution of m-toluylenediamine.  Gann, 46: 
597-606.

UNGER, P.D. & FRIEDMAN, M.A.  (1979)  High-performance liquid 
chromatography of 2,6- and 2,4-diaminotoluene, and its 
application to the determination of 2,4-diaminotoluene in 
urine and plasma.  J. Chromatogr., 174: 379-384.

UNGER, P.D., SALERNO, A.J., NESS, W.C., & FRIEDMAN, M.A.  
(1980)  Tissue distribution and excretion of 
2,4[143]-toluenediamine in the mouse.  J. Toxicol. environ. 
 Health, 6: 107-114.

US EPA  (1980)   Materials balance for 2,4-diaminotoluene. 
 Level 1. Preliminary, Washington DC, US Environmental 
Protection Agency, Office of Toxic Substances (EPA-560/13: 
79-016).

US ITC  (1977)   Synthetic organic chemicals: US production and 
 sales, 1975, Washington DC, US International Trade Commission, 
pp. 22, 36, 42, 49, 60, 62, 65, 74 (US ITC Publication 804).

US ITC  (1982)   Preliminary report on US production of 
 selected synthetic organic chemicals. Preliminary totals 1981, 
Washington DC, US International Trade Commission (SOC Series 
C/P-82-1).

US ITC  (1985)   Preliminary report on US production of 
 selected synthetic organic chemicals. November, December, and 
 cummulative totals, 1984, Washington DC, US International 
Trade Commission (SOC Series C/P-85.1).

VENITT, S.  (1978)  Mutagenicity of hair dyes: some more 
evidence and the problems of its interpretation.  Mutat. Res., 
53: 278-279.

VON OETTINGEN, W.F.  (1941)   The aromatic amino and nitro 
 compounds: their toxicity and potential dangers. A review of 
 the literature, Washington DC, Division of Industrial Hygiene, 
National Institute of Health, pp. 55-63.

WAGNER, J.C.  (1975)  Linear compartment models. In: 
 Fundamentals of clinical pharmacokinetics, Hamilton, Illinois, 
Drug Intelligence Publications, pp. 57-63.

WARING, R.H. & PHEASANT, A.E.  (1976)  Some phenolic metabolites 
of 2,4-diaminotoluene in the rabbit, rat and guinea-pig. 
 Xenobiotica, 6: 257-262.

WEISBROD, D. & STEPHAN, U.  (1983)  [Studies of the toxic, 
methaemoglobin-producing and erythrocyte-damaging effects of 
diaminotoluene after a single administration.]  Z. gesamte 
 Hyg., 29: 395-397 (in German).

WEISBURGER, E.K., RUSSFIELD, A.B., HOMBURGER, F., WEISBURGER, 
J.H., BOGER, E., VAN DONGEN, C.G., & CHU, K.C.  (1978)  
Testing of twenty-one environmental aromatic amines or 
derivatives for long-term toxicity or carcinogenicity. 
 J. environ. Pathol. Toxicol., 2(2): 325-356.

WILLEBOORDSE, F., QUICK, Q., & BISHOP, E.  (1968)  Direct gas 
chromatographic analysis of isomeric diaminotoluenes.  Anal. 
 Chem., 40: 1455-1458.

WILLIAM, R.T.  (1971)  The metabolism of certain drugs and 
food chemicals in man.   Ann. N.Y. Acad. Sci., 179: 141-154.

WILLIAMS, G.M.  (1977)  Detection of chemical carcinogens by 
unscheduled DNA synthesis in rat liver primary cell cultures. 
 Cancer Res., 37: 1845-1851.

WILLIAMS, G.M.  (1978)  Further improvements in the hepatocyte 
primary culture DNA repair test for carcinogens: detection of 
carcinogenic biphenyl derivatives.  Cancer Lett., 4: 69-75.

WILLIAMS, G.M. & LASPIA, M.F.  (1979)  The detection of 
various nitrosamines in the hepatocyte primary culture/DNA 
repair test.  Cancer Lett., 66: 199-206.



    See Also:
       Toxicological Abbreviations