o-TOLUIDINE CAS N°: 95-53-4 - UNEP Chemicals

OECD SIDS o-TOLUIDINE
examination yielded mainly (low, high dose versus control) hepatocellular carcinomas (m: 16/50,
11/50 versus 4/19; f: 2/49, 7/50 versus 0/20) and adenomas (m: 3/50, 3/50 versus 1/19; f: 2/49, 6/50
versus 0/20) but also vascular tumors were reported without specification of the localization
(hemangiosarcoma, m: 1/50, 10/50 versus 1/20, f: 1/50, 2/50 versus 1/20; hemangioma, m: 1/50,
2/50 versus 1/20). The tumors were regarded to be treatment related, even if there were no clear
dose-dependency at all tumor sites (NCI, 1979).
In another study over a period of 21 months (18 months feeding and 3 months post exposure
observation) 25 male and female mice were initially fed with 16000 and 32000 ppm (approximately
2400 and 4800 mg/kg bw/day) o-toluidine hydrochloride, dosages which had to be reduced after 3
months due to significantly decreased body weights (> 10 %) and increased mortality rate when
compared to the concurrent controls. The male and female mice received then 8000 and 16 000 ppm
(approximately 1200 and 2400 mg/kg bw/day) for further 15 months. At the end of the observation
period necropsy was performed and mice with tumors recorded: Significant increased number of
vascular tumors were identified when compared to the concurrent and the pooled controls (m: 5/14
and 9/11 in low and high dosed mice versus 0/14 and 5/99 in concurrent and pooled controls; f:
5/18, 9/21 versus 0/15 and 9/102) (Weisburger et al., 1978).
Study in Humans
In connection with the production of o-toluidine there are several publications, which report the
occurrence of bladder cancer in workers who were exposed for years (e.g.: Gropp, 1958; Oettel,
Thies and Uhl, 1968; Acquavella et al., 1991; Ward and Dankovic 1991; Ward et al., 1991 and
1996; Rubino et al., 1982; Ruder et al., 1992; Teass et al., 1993; Freudenthal and Anderson, 1995;
Freudenthal, Stephens and Anderson, 1999; Ouellet-Hellstrom and Rench, 1996; Khlebnikova et al.
1970). However, this finding cannot definitely be attributed to o-toluidine because of the coexposure
to other arylamines including p-toluidine, aniline, o-nitrotoluene, rosaniline, safranine T,
4,4'-methylene-bis-(2-methylaniline) or 2-naphthylamine as well as toluene.
Following a re-evaluation of o-toluidine IARC working group evaluated o-toluidine of limited
evidence of carcinogenicity in humans due to this increased number of observations in workers with
urinary bladder cancer. However, the working group noted as well that in none of these cases could
confounding by concomitant exposure to various other potential bladder carcinogens be ruled out
with confidence. Taking into account the sufficient evidence for the carcinogenicity of o-toluidine
in experimental animals the overall evaluation of the working group is: o-toluidine is probably
carcinogenic to humans (Group 2A; IARC, 2000).
Conclusion
After oral administration to mice o-toluidine induced and increased incidence of hemangiomas and
hemangiocarcinomas and hepatocellular carcinomas or adenomas. In rats, oral administration
increased the incidence of tumors in multiple organs including fibromas, sarcomas, mesotheliomas,
mammary fibroadenomas and transitional cell carcinomas of the urinary bladder. In the open
literature, o-toluidine is suspected to cause urinary bladder tumors in workers. However, this
finding cannot definitely be attributed to o-toluidine because of the co-exposure to other arylamines.
IARC classified o-toluidine in group 2A (probably carcinogenic to humans).
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