Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats.
2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.
Saitoh
M
M
Division of Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
Umemura
T
T
Kawasaki
Y
Y
Momma
J
J
Matsushima
Y
Y
Sakemi
K
K
Isama
K
K
Kitajima
S
S
Ogawa
Y
Y
Hasegawa
R
R
Suzuki
T
T
Hayashi
M
M
Inoue
T
T
Ohno
Y
Y
Sofuni
T
T
Kurokawa
Y
Y
Tsuda
M
M
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000633:toxicity*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000648:ultrastructure; D004032:Diet; D004435:Eating / Q000187:drug effects; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012408:Rubber / Q000008:administration & dosage / Q000633:toxicity*
D000975:Antioxidants; D001562:Benzimidazoles; D009153:Mutagens; C049825:bemethyl; D012408:Rubber