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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
1 mg/kg bw/day
Effect on fertility: via inhalation route
Dose descriptor:
21.7 mg/m³
Additional information

Single exposure

In Cooper et al (1974), a single administration of 100 mg/kg orally to male wistar rats resulted in clear histological changes in epididymides and testis. All rats resulted sterile for 10 weeks, starting immediately after exposure.

Rats showed spermatocoeles in the ductuli efferentes and epididymis after single oral exposure to [alpha]-chlorohydrin (S) enantiomer or (RS) racemic mixture at concentration of 12.5, 25, 50, 100 mg/kg bw (Ford & Waites, 1982).

Repeated exposure

3-chloro-1,2-propanediol w

as administered orally by gavage to male rats at doses of 0, 1, 5 or 25 mg/kg bw/d for 14 days (Hoyt et al, 1994). Testicular and epididymal lesions occurred at 25 mg/kg bw/d. DNA ploidy distributions were predictive of testicular damage, with effects more pronounced on Test Day (TD) 29 than on TD 15. Sperm motion was altered at the 5 and 25 mg/kg dose levels on TD15. The percentage of motile sperm and the percentage of progressively motile sperm were markedly depressed at both the 5 and 25 mg/kg dose levels where antifertility effects occurred. Sperm velocities and amplitude of lateral head displacement were depressed at the 25 mg/kg dose level on both TD 15 and 29. Additionally, decreased epidymal sperm concentrations and increased breakage were recorded at this dose level. Waalkens-Berendsen DH and Arts JHE (1992) studied the effects after exposure via inhalation (2 weeks) in rats. Male fertility was examined by mating exposed males and controls with untreated young virgin pro-oestrus females two days after the exposure period. Mating was repeated 6-9 and 27-30 days after the last day of exposure for the recovery and control group. The NOAEC for effects on male fertility in rats was 4.8 ppm (corresponding to 21.7 mg/m3) based on the measured concentration. Reduced fertility was not accompanied by any histopathological changes in the testes and epididymides. Reduced fertility at 18 ppm was reversible within 9 days after the last exposure. Vickery et al. (1974) observed that the minimal effective daily antifertility dose in the Sprague-Dawley rat was found to be 2.5 mg/kg bw/d (oral administration). The number of days of treatment is related with the dose needed to demonstrate impaired fertility. This suggests a threshold effect and that the effect is exerted beyond the testis level (e.g. at level of the epididymis and/or secretions of the accessory glands). The number of spermatozoa and their motility is decreased, which might be the reason for observed infertility. Johnson & Pursel (1972) studied the effects of 3-chloro-1,2-propanediol in male swines fed 1, 5, 25 or 50 mg/kg bw/d for 25 days. The substance produced complete infertility in all exposed boars. Based on their observations, it is apparent that the substance acts rapidly and effectively to inhibit fertility in the boar. At the higher levels, there was a definite effect on the motility of boar spermatozoa, which returned to pretreatment levels after treatment. The substance also caused a reduction in sperm collected during treatment with subsequent recovery during post-treatment. Kirton et al. (1970) examined the effects of the substance in male rhesus monkeys (Macaca mulatta). The rhesus monkeys were exposed to 30 mg/kg bw/d in drinking water for a period of 6 weeks. Reduced fertility was observed at the dose level administered. Despite the toxic effects (bone marrow depression) noticed in three monkeys, it is the authors opinion that the antifertility efficacy was not the result of this toxicity. Reversibility was confirmed in three males by post-treatment conceptions (all of three matings fertile). Also Setty et al. (1970) examined the effects of 3-chloro-1,2-propanediol in rhesus monkeys, dosed 30 mg/kg bw/d orally for 15 days. A marked reduction in total lipid concentration was observed in the epididymis. The spermatozoa showed impaired motility. The results show that the substance had no effect on the gametogenic and endocrine functions of the rhesus monkey testis. The unimpaired pituitary gonadotrophic activity indicates the lack of any adverse effect on the hypothalamo-pituitary-gonadal axis and secondarily, the accessory genital organs. The observations strengthen the view that the substance exerts its antifertility effect by acting directly on extragonadal spermatozoa by damaging their membrane. In a study reported by Gunn et al. (1969), all rats were infertile after oral exposure for 10 -14 days with a dose of 6.5 mg/kg bw/d. Histological changes are observed in the epididymis of male rats after exposure with 9.5 mg/kg bw/d. Peritubular edema was observed in the initial segment of the caput after administration of 15 mg/kg bw/d (some rats after single administration, others after 4-14 days exposure).

Short description of key information:
3-chloro-1,2-propanediol is a known anti-fertility agent, which is confirmed by a long list of study reports.
The study of Johnson & Pursel (1972) is chosen as the key study for oral exposure since this is study observed effects at the lowest dose. Based on this study, a dose of 1 mg/kg bw/d produced complete infertility in all exposed swines.

Waalkens-Berendsen and Arts (1992) studied the effects after 2 weeks (6h/d, 5d/w) exposure via inhalation in rats. The NOAEC for effects on male fertility in rats was 4.8 ppm (21.7mg/m³).

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
25 mg/kg bw/day
Additional information

El Ramy et al. (2006) studied the effects of testicular organogenesis during gestation after in utero exposure in rats (oral gavage). Pregnant rats were given daily doses of 5, 10 or 25 mg/kg bw of 3-chloro-1,2-propanediol from days 11.5–18.5 postcoitum. The results show that fetal testes exposed at doses up to 25 mg/kg bw/day exhibited normal histology and produced testosterone at levels that were similar to controls. In addition, 3-chloro-1,2-propanediol did not alter gene expression in the fetal testes at doses up to 25 mg/kg bw/day. This lack of effect occurred under conditions where the substance and its main metabolite (beta-chlorolactic acid) were found to readily cross the placental barrier and diffuse throughout the fetal tissues.

Under the conditions of this study, 3-chloro-1,2-propanediol has minimal effect on rat testicular organogenesis. The NOAEL for teratogenicity and fetotoxicity was greater than 25 mg/kg bw/d.

Justification for classification or non-classification

According to CLP, 3-chloro-1,2 -propanediol is classified as a a presumed human reproductive toxicant: Category 1B. The classification is based on relevant data from animal studies, as discussed above.

Additional information

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