(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

6.2.5.2 Chronic Toxicity
Repeat-dose chronic toxicity studies have been conducted by the oral route in both rats and
mice.
Rat: Two chronic rat studies have been conducted by gavage (Maltoni et al., 1985; NTP, 1986;
Huff et al., 1989). The Maltoni study did not provide detailed toxicological information, and
statistical evaluations were not included. The more thorough NTP study was conducted
according to good laboratory practices (GLP). In this latter study, rats of both sexes were
treated by gavage with benzene at 0, 36, 71, and 143 mg/kg/day (actual analyzed
concentrations); females received 0, 18, 36, and 71 mg/kg/day (actual analyzed concentrations)
for up to 24 months. Dose-related changes in weight gain were pronounced in the males and
lower than controls by week 22, thereafter reaching a reduction of 23% by week 103 in the
143-mg/kg group. At 71mg/kg, weight-gain reduction was similar in both males and females by
study termination. No notable clinical signs were observed. There was a dose-related decline
in survival for both males and females. Dose-related leukocytopenia was seen in females at
18 mg/kg and higher from 3 to 12 months but was similar after 15 months. In males,
leukocytopenia was significant at 36 mg/kg and above. Dose-related lymphoid depletion was
seen in the thymus of male rats at all treatment levels. In the spleen, lymphoid depletion was
significantly increased at all treatment levels in males.
LOAEL (females) = 18 mg/kg/day (leukopenia/lymphocytopenia) – lowest dose tested
(males) = 36 mg/kg/day (leukopenia/lymphocytopenia) – lowest dose tested
NOEL (females)