A two-generation reproductive toxicity study of dicyclohexyl phthalate in rats.
The reproductive toxicity of dicyclohexyl phthalate (DCHP) was evaluated in a two generation test in which male and female Sprague-Dawley (SD) rats of parental (F0) and F1 generation were exposed to DCHP in the diet at concentrations of 0 (control), 240, 1200 or 6000 ppm. With regard to the effects on the F0 and F1 parental animals, changes included inhibition of body weight gain and food consumption, diffuse hypertrophy of hepatocytes, and hypertrophy of thyroidal follicular epithelial cells at the doses of 1200 ppm and 6000 ppm. The following changes were observed in the 6000 ppm group: increase weights of the liver and thyroid, increased hyaline droplets in the renal proximal tubular epithelium (F0 and F1 males), reduction of prostatic weight (F1 males), and diffuse and/or focal atrophy of testicular seminiferous tubules (F1 males). In addition, slight prolongation of the estrous cycle was noted in the F0 females of the 6000 ppm group, along with reduced spermatid head counts in the testes (homogenation-resistant spermatids) in F1 male receiving doses of 1200 ppm or 6000 ppm. It is thought that the prolonged estrous cycle was secondary to the suppression of body weight gain. There were no test substance related changes in clinical signs and reproductive capability (mating, fertility, gestation and birth index), or in data for the delivery and lactational periods, or serum hormone levels. With regard to effects on the offspring, inhibition of body weight gain was found in the F1 and F2 6000 ppm, and decrease of anogenital distance (AGD) and appearance of areola mammae were observed in the F1 male 6000 ppm and F2 male receiving doses of 1200 ppm or 6000 ppm. No effects of DCHP treatment on the offspring were observed on results of clinical signs, the number of the pups delivered, sex ratio, viability, physical development, reflex and response tests, external abnormalities, organ weights, or necropsy findings. From the present study of DCHP administered to rats over two-generations, the no observed effect level (NOEL) for effects on the parental animals including the endocrine system, is considered to be 240 ppm. With regard to the reproductive toxicological effects on the parental animals, the NOEL is 240 ppm for males and 1200 ppm for females. For offspring, the NOEL values are concluded to be 240 ppm for males and 1200 ppm for females.
Hoshino
Nobuhito
N
Toxicology Division I, kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd, 14 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan. n-hoshino@ankaken.co.jp
Iwai
Mayumi
M
Okazaki
Yoshimasa
Y
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D036401:Toxicity Tests, Chronic / Q000379:methods*
D052244:Endocrine Disruptors; D010795:Phthalic Acids; C036042:dicyclohexyl phthalate