Screening of toxicological properties of 4-methylbenzoic acid by oral administration to rats.
Oral toxicity of 4-methylbenzoic acid in male and female Sprague-Dawley rats was profiled through a twenty-eight-day repeated dose toxicity study (the 28-day study) and a screening test for reproductive/developmental toxicities (the reproduction/developmental study) conducted under Organisation for Economic Co-operation and Development (OECD) test guidelines. Daily administration of 4-methylbenzoic acid, at a dose level of 0, 100, 300 or 1,000 mg/kg, did not show any adverse effect on reproductive organs of animals in the 28-day study. In the reproductive/developmental study, however, 1,000 mg/kg/day of the compound reduced epididymal weights and increased incidence of cauda epididymal oligo/azoospermia. While the compound did not affect estrous cycle or mating performances, 1,000 mg/kg of the compound reduced fertility. Furthermore, 300 mg/kg or more of the compound increased pre-implantation loss, which resulted in a decrease in the number of offspring, and reduced body weight gain of the dams during the latter period of gestation. From these results, the no-observed-effect-level (NOEL) for reproductive/developmental toxicities is considered to be 100 mg/kg, whereas 1,000 mg/kg did not show any effect on neonates. In the 28-day study, NOEL is considered to be 300 mg/kg for male and female rats, since 1,000 mg/kg of the compound caused, in both sexes, a few minor changes, such as temporal salivation, a slight increase in food consumption and a moderate increase in blood aspartate aminotransferase (AST) activity. Thus, 4-methylbenzoic acid has the potential for reproductive toxicity, with diverse adverse effects on the epididymis, after repeated administration, observed in the two studies.
Shirota
Mariko
M
Hatano Research Institute, Food and Drug Safety Center, Hadano, Kanagawa, Japan. shirota.m@fdsc.or.jp
Seki
Takayuki
T
Tago
Kazumi
K
Katoh
Hiroyasu
H
Marumo
Hideki
H
Furuya
Mami
M
Shindo
Tomoko
T
Ono
Hiroshi
H
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D001565:Benzoates / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004822:Epididymis / Q000187:drug effects*; D005260:Female; D005298:Fertility / Q000187:drug effects; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D036401:Toxicity Tests, Chronic
D001565:Benzoates; C009504:4-toluic acid