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toluidine. Followup of this subcohort from 1940 to 1975 indicated that a nonsignificant excess of total
cancer deaths occurred (12 observed, 8 expected) and no bladder cancer was observed.
Two studies were conducted on a cohort of 355 male workers in p-chloro-o-toluidine manufacturing
plants in the Federal Republic of Germany (FRG) who had been followed up for mortality from 1929 to
1982. No deaths due to bladder cancer were found in the first study (Stasik et al., 1985). The second
study examined a subcohort of 116 workers exposed prior to 1970 (the implementation date of
improved exposure controls) with presumed high p-chloro-o-toluidine exposure levels. Excluding 2
cases of urinary bladder carcinomas in the current work force, 6 cases of bladder carcinoma were
found between January 1983 and June 1986 in hospital and other institution records. No cancer
registry data was available for the area of the FRG where the plant was located; cancer registration
rates for a different area of the FRG was therefore used as a basis of comparison. The expected
number of tumors was 0.11 based on sex- and age-specific cancer rates. Two patients had
hemorrhagic cystitis thought to be due to massive exposure to p-chloro-o-toluidine. Cigarette smoking
was discounted as a confounding variable after reviewing patient smoking histories (3 patients were
nonsmokers). Quantitative exposure data was unavailable, but the predominant chemical exposure was
to p-chloro-o-toluidine; however, exposure to other amines could have occurred.
Animal Studies
Male and female random-bred CD-1 albino mice (derived from HaM/ICR mice) and male Charles
River CD Sprague-Dawley-derived rats (25/sex/group) were fed diets containing p-chloro-o-toluidine
hydrochloride (97-99% pure) as part of a larger carcinogenicity study of several compounds
(Weisburger et al., 1978). Mouse exposure levels were 0, 750 or 1500 mg/kg diet and 0, 2000 or
4000 mg/kg diet for males and females, respectively; the mice were fed treated diet for 18 months,
followed by an additional 3 month observation period. Rats were fed diet containing 2000 or 4000
mg/kg diet p-chloro-o-toluidine for 3 months; the doses were then reduced to 500 and 1000 mg/kg diet
for 15 months. An untreated control group (25 males) was included. All rats were killed after 24
months. Tumor incidence differences between control and exposed rat groups were not statistically
significant. Hemangiomas and hemangiosarcomas were observed in male and female mice; tumor
incidence data is listed in Table 1. These tumor types were found in 5/99 male and 9/102 female
pooled controls from the larger carcinogenicity study, but were not present in the simultaneous controls.
Diets containing p-chloro-o-toluidine hydrochloride (99% pure) were fed to groups of male and female
B6C3F 1 mice and Fischer 344 (F344) rats (50 animals/sex/species/treatment group) (NCI, 1979).
Exposure levels for mice were 3750 or 15000 and 1250 or 5000 mg/kg diet for males and females,
respectively. Exposure levels for rats were 1250 or 5000 mg/kg diet. Untreated control groups (20
animals/sex/species) were included. Exposed animals were fed treated diet for the duration of the
study. All surviving mice were killed at 99 weeks; however, all high-dose females had died by 92
weeks. All surviving rats were killed at 107 weeks.
Exposure to p-chloro-o-toluidine did not affect mortality of either male or female rats; a dose-related
increase in mortality was noted for both male and female mice (NCI, 1979). However, sufficient
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