Maternal exposure to procymidone has no effects on fetal external genitalia development in male rabbit fetuses in a modified developmental toxicity study

Abstract

INTRODUCTIONProcymidone, N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximide (hereafter PCM), is a fungicide used to control plant diseases such as sclerotinia rot and gray mold on a range of vegetables, fruits, soya bean, sunflowers, tobacco, and oil seed rape, as well as on ornamental plants and flower bulbs. The mechanism of pesticidal action involves the inhibition of triglyceride synthesis in fungi.The toxicities of PCM were evaluated by the Joint FAO/WHO Meeting on Pesticide Residues (FAO and WHO, 2007). The Meeting established an acceptable daily intake (ADI) of 0-0.1 mg/kg body weight (bw) based on a no-observed-adverse-effect-level (NOAEL) of 12.5 mg/kg bw per day in a two-generation study of reproductive toxicity and a study of developmental toxicity in rats, on the basis of hypospadias and alterations in testes, prostate, and epididymis weights, and safety factor of 100. PCM is an active anti-androgen (Hosokawa et al., 1993) and the androgen receptor antagonism is the likely to be the mechanism of those toxicities described above.Although PCM alters sexual differentiation of male offspring in rats, no alterations in rabbit male fetuses were observed in a conventional teratology study in rabbits receiving up to 1,000 mg/kg bw (FAO and WHO, 2007). These results suggest that species difference of developmental effects of PCM on sexual differentiation exists. However, in the conventional teratology study in rabbits (FAO and WHO, 2007), some concerns were raised regarding a shorter treatment period (gestation day (GD) 7 to 19) and an observation method of external genitalia development. In rats, Ostby et al. (1999) reported that PCM alters sexual differentiation of male offspring in rats receiving 25 mg/kg bw and above from GD 14 to postnatal day (PND) 4. It seems that the critical period of sexual differentiation such as external genitalia development is late in gestation, and the treatment period in the rabbit study described above might not have included the critical period of external genitalia development in rabMaternal exposure to procymidone has no effects on fetal external genitalia development in male rabbit fetuses in a modified developmental toxicity study Kunifumi Inawaka, Noriyuki Kishimoto, Hashihiro Higuchi and Satoshi KawamuraEnvironmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan (Received December 25, 2009; Accepted January 12, 2010) ABSTRACT -This study was conducted to evaluate the effects of procymidone (PCM) on development of male rabbit fetal external genitalia. PCM was administered once daily by gavage at dose levels of 0 (control) and 125 mg/kg/day to pregnant rabbits from gestation day 6 through 28 and fetal external genitalia was observed in detail. This treatment period covered the critical stage of sexual differentiation of fetal external genitalia in rabbits. In the maternal animals, food consumption was reduced in the PCM group. There were no effects of PCM on maternal caesarean section...

Species differences in the developmental toxicity of procymidone—Placental transfer of procymidone in pregnant rats, rabbits, and monkeys—

“…However, developmental toxicity studies failed to detect such abnormalities in rabbits or monkeys. [4][5][6] Previous in vivo metabolism studies of procymidone in rats and mice have extensively investigated the metabolic fate of procymidone. [7][8][9] The major biotransformation reactions are known to be the oxidation of the hydroxymethyl group to alcohol and carboxylic acid, and the glucuronidation of derived hydroxylated metabolites (Fig.…”

Identification of Metabolism and Excretion Differences of Procymidone between Rats and Humans Using Chimeric Mice: Implications for Differential Developmental Toxicity

“…Since procymidone is used worldwide, many toxicity studies have been conducted to evaluate its safety. External genital abnor mality has been observed as a major toxicity of procymidone in male rats but not in rabbits and monkeys. − To explain the species differences in procymidone developmental toxicity, a series of mechanism studies were conducted. ,− In vitro receptor binding assay demonstrated that procymidone has antiandrogenic activity while PCM-CH 2 OH also has weak inhibitory activity. , In an in vivo experiment, metabolism of procymidone in rats, rabbits, and monkeys was examined in detail. In the research, it was identified in rabbits and monkeys that hydroxylated-PCM is conjugated in liver, transferred to blood, and then rapidly excreted in urine, leaving the presence of only a low residual concentration of hydroxylated-PCM (Figure A).…”

Development of the External Genitalia and Their Sexual Dimorphic Regulation in Mice

“…There are variations on how to measure the AGD. One method is to measure the distance between the lower end of the urethra and the upper end of the anus [Inawaka et al, 2010]. The AGD is correlated with the perineum which is anatomically defined as the surface region between the coccyx and the pubic symphysis [Gray, 1918].…”