3-chloropropene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

Two studies on the effect of 3-chloropropene on spermatogenesis and sperm motility in albino rats (Guseinov 1981 and 1982) after single and repeated inhalative exposure reported adverse effects: decreased sperm motility after single exposure of 24 h to 18.2 ppm and higher; in addition a decreased spermatogenic index, decreased average number of normal spermatogonia and the number of tubules with desquamated spermatogenic epithelium and adverse effects on testicular weight in repeated dose experiments of 2.5 and 4 mo (4h/d, 5 d/wk) at 0.3 ppm and higher. At these levels also general toxicity is reported which is in contradiction to findings in guideline compliant studies on repeated dose toxicity which report NOAEC of 10 ppm and higher. The studies are only available as summaries from the SIDS report and based on the assessment of a comparable repeated dose study by Guseinov these studies are regarded as unreliable.

In the only other available study giving information on fertility (McGregor 1981) B6C3F1 mice were treated 7 h on 5 consecutive days via inhalation with 1 and 25 ppm and were sacrificed 5 weeks later. Morphological analysis of sperm cells revealed no adverse effects on the morphology but the concentrations used are rather low.

The SIDS report on 3-chloroprope states in its summary (p. 3):

“Reproduction studies have not been carried out with allylchloride. However, effects on the male reproductive system were investigated in vitro as well as in vivo. Testosterone production was not affected in rat foetal testes in vitro. Effects on the male gonads of rats and rabbits were observed in vivo. In mice, which survived a single s.c. dose = 496 mg/kg b.w. allylchloride, various degrees of damage in the testes was observed. However, no histopathological effects were found in the testes of rats after subchronic inhalatory exposure to concentrations = 782.5 mg/m3. “

But from the assessment of the study summaries in the SIDS report it remains unclear where these conclusions are derived from.

Based on this limited data available, a final assessment on fertility is not possible.

Short description of key information:
The database is not sufficient for the derivation of a threshold value and a classification concerning adverse effects of 3-chloropropene on fertility.

Effects on developmental toxicity

Description of key information

- Developmental toxicity/teratogenicity: relevant fetotoxicity is dose dependent but only seen at doses of moderate to severe maternal toxicity.
Therefore a classification of 3 -chloropropene for developmental toxicity is deemed not necessary.

Effect on developmental toxicity: via inhalation route

Dose descriptor:

NOAEC

93 mg/m³

Additional information

Four studies are available for this endpoint. Alizade 1982 describe a non-significant reduction of live embryos/litter and a significant increase in resorption sites, reduced foetal weight and increase in total embryo mortality due to increased post-implantation loss but there was also a significant increase in pre-implantational loss at the highest dose level (inhalation, 4h, 0, 0.29, 3.1 mg/m3 (0, 0.1, 1 ppm), throughout gestation). There was evidence of maternal toxicity at this dose level. The study is only available as a summary from the SIDS report and based on the assessment of a comparable repeated dose study by Guseinov this study is regarded as unreliable.

In the study by Deacon 1980 pregnant Spague Dawley rats and New Zealand White rabbits were exposed to 0, 30 and 300 ppm 3-chloropropene for 7 h of gestation day 6 – 15 (rats) and 6 – 18 (rabbits) in compliance with OECD TG 414 and GLP. Assuming a breathing rate of 0.8 l/min/Kg for the rat and an absorption of 100 % of the inhaled test item the daily intake in the rat could be calculated as ca. 0, 10 and 100 mg/Kg.

In both species at the high dose an initial slight body weight decrease was seen within the first 3 days of treatment that was compensated by subsequently higher body weight gains. In addition raised statistically significant absolute liver weights were seen in both species in both treatment groups while the relative liver weights were only significantly different in high dose rabbits. A trend for elevated absolute kidney weights was also observed in both species but was only significant in high dose rats. In rats at this high dose exposure related effects on the foetus with delayed ossification of vertebral centra and sternebrae was reported. In rabbits signs of fetal toxicity or teratogenicity were not found in any of the treatment groups. Therefore based on the results in rats a NOAEC of 30 ppm (=93 mg/m³) can be derived for maternal and fetotoxicity (in accordance with the SIDS record on 3-chloropropene).

In the study reported by Hardin 1981 pregnant Sprague Dawley rats were treated with previously determined MTD of 80 mg/Kg bw 3-chloropropene from gestation day 1 to 15 via i.p. injection. Maternal toxicity was revealed by increased heart, liver and kidney weights, without histopathological correlation. A statistically significant rise in resorption was determined as well as a statistically significant rise in incidences of fetuses with edema and short snout with produding tongue. No visceral or skeletal malformations were found. The results are available only as part of a review article on 19 different substances lacking individual animal data and only one dose was tested. In addition the test item purity is unclear and the effect of the uncommon route of exposure on the results is unclear. Therefore the relevance and reliability of these findings are questionable.

In Hardin 1987 prednant CD-1 mice were treated via gavage with 3-chloropropene in corn oil at 500 mg/Kg bw from gestation day 6 to 13. The dose was determined as LD10 in a pretest with non-pregnant female mice. Dams were allowed to deliver and litters were analyzed for no of live and dead pups, litter weight and survival and weight development until post natal day 3. Of the 50 mice tested in the main test 28 were pregnant and 22 non- pregnant. Of the 28 pregnant dams 21 died prior to gestation day 21 while only 4 of the 22 non-pregnant mice died. Due to the low number of derived litters no significant effects could be derived but a trend for lowered percentage of survival until day and lowered birth weight of the offspring was noted. The results are available only as part of a review article on 60 different substances lacking individual animal data and only one dose was tested. In addition the test item purity is unclear and the effect of the uncommon route of exposure on the results is unclear. Therefore the relevance and reliability of these findings are questionable. Nevertheless the raised susceptibility of dams to 3-chloropropene toxicity as compared to non-pregnant females is noticeable.

The SIDS-report on 3-chloropropene summarizes on developmental toxicity: “In developmental studies with rats and rabbits by the inhalation route a slight delay in skeletal development in rats was observed at maternal toxic doses. In adequately performed studies the NOAEL for foetal/embryo and maternal toxicity was 93 mg/m3 (duration adjusted: 27.3 mg/m3).” This refers to the study of Deacon 1980.

Justification for classification or non-classification

Adverse effects have been stated for male reproductive organs in absence of systemic toxicity but the source of information is not reliable and was not considered in the recent derivation of a classification for reproductive toxicity in the SIDS-report on 3 -chloropropene. Studies giving positive results are only available as summaries, are regarded as unreliable and are not sufficient for a descision on classification. For developmental toxicity slight effects on ossification is reported at doses where slight maternal toxicity was observed (30 and 300 ppm inhalation = approximately 10 and 100 mg/Kg bw, Deacon 1980 rats and mice). At higher doses (80 mg/Kg bw, ip) teratogenic alterations are reported by Hardin 1981 in rats and increased maternal mortality (at 500 mg/Kg bw, gavage in corn oil) in mice by Hardin 1987. So relevant fetotoxicity is dose dependent but only seen at doses of moderate to severe maternal toxicity.

Therefore a classification of 3 -chloropropene for reproductive toxicity is deemed not necessary.