2-hydroxy-2-methylpropionitrile

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

There are two reliable fertility studies available, one covering female fertility and one covering male fertility. Both studies have been quoted as well in an assessment report of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC report, JACC No. 53, Volume I, 2007; in the following cited as ECETOC) as in a report on AEGLs (Acute Exposure Guideline Levels) established by AEGL-Committee (US-NAC, Acetone Cyanohydrin, Interim Acute Exposure Guideline Levels (AEGLs), Interim final draft, 2005; in the following cited as AEGL). In these reports 2-hydroxy-2-methylproanenitril is designated as acetone cyanohydrin (ACH).

“In a male fertility study, Sprague-Dawley rats (15 males/group) were exposed (6 h/d; 5 d/wk) on 48 exposure days, i.e. for 69 days in total, to concentrations of 0, 10.0, 28.5 or 57.2 ppm ACH (equivalent to 0, 3.1, 8.7 or 17.5 ppm CN¯; 0, 10.8, 30.8, 61.9 mg CN¯/m3). After the treatment period, each male was mated consecutively with 3 untreated females. There were no effects of treatment on males as indicated by mortality, clinical observations and necropsy observations (males were killed about 3 weeks after the end of the exposure period). Only at 57.2 ppm did the rats show lower mean body weights but the difference was not statistically significant from controls. The number of live implants and pre- and post-implantation losses were comparable for females mated with untreated or treated males. The authors concluded that exposure to 57.2 ppm ACH (equivalent to 8.4 mg CN¯/kg bw/d a) did not exhibit reproductive toxicity in male rats (Monsanto, 1985a). The highest exposure studied can be assumed as the NOEL for male reproductive effects, although no effect level (LOEL) was identified in this study.” (quotation from ECETOC)

“In a female fertility study, Sprague-Dawley rats (24 females/group) were exposed (6 h/d, 7 d/wk) by inhalation for 21 days to 0, 10.7, 30.4 or 58.6 ppm ACH (equivalent to 0, 3.3, 9.3 or 17.9 ppm CN¯; 0, 11.6, 32.9, 63.4 mg CN¯/m3). There was no indication of treatment-related effects on body weight during exposure or during gestation. After the exposure period, the females were mated with untreated males. At examination on gestational day 13 to 15, the fertility of mated females was comparable between treated groups and the control group for mating efficiency, pregnancy rates, number of live implants and pre- and post-implantation losses. The authors concluded that exposure to 58.6 ppm ACH (equivalent to 8.6 mg CN¯/kgbw/d a) did not have any effects on fertility of female rats (Monsanto, 1985b). The highest exposure studied can be assumed as the NOEL for female reproductive effects, although no effect level (LOEL) was identified in this study.” (quotation from ECETOC)

“In male and female fertility studies in rats, inhaled ACH showed no reproductive effects up to concentrations that were limited by the threshold to acute toxicity (local irritative effects and systemic lethality) as indicated in repeated-dose inhalation studies.” (quotation from ECETOC)

In conclusion, there are no indications of any adverse effects of 2-hydroxy-2-methylpropionitril on fertility, neither in males nor in females.

Short description of key information:
There are 2 fertility studies with 2-hydroxy-2-methylpropionitrile available, one for male and one for female fertility.
There were no effects on fertility observed when 2-hydroxy-2-methylpropionitrile was exposed by inhalation up to concentrations, limited by the threshold of acute lethality, to male or female rats.

Effects on developmental toxicity

Description of key information

For developmental toxicity including teratology one reliable study is available.
In this study, no effects on developmental toxicity including teratogenicity were observed in the rat when 2-hydroxy-2-methylpropionitril was administrated orally by gavage up to and including maternal toxic doses.

Additional information

For developmental toxicity including teratogenicity one study is available. This studies has been quoted as well in an assessment report of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC report, JACC No. 53, Volume I, 2007; in the following cited as ECETOC) as in the report on AEGLs (Acute Exposure Guideline Levels) established by AEGL-Committee (US-NAC, Acetone Cyanohydrin, Interim Acute Exposure Guideline Levels (AEGLs), Interim final draft, 2005; in the following cited as AEGL). In these reports 2-hydroxy-2-methylproanenitril is designated as acetone cyanohydrin (ACH).

“In a teratogenicity study, pregnant Sprague-Dawley rats (25/group) were dosed on days 6 to 15 of gestation with 0, 1, 3 or 10 mg ACH/kg bw (corresponding to 0, 0.31, 0.92 and 3.06 mg CN¯/kg bw). Dose selection was made on the basis of marked maternal toxicity observed at higher doses observed in a range-finding study (Monsanto, 1983a). No deaths were observed during the exposure period. Maternal toxicity was evident by slight reductions in body-weight gain in mid and high exposure groups. Statistically significant differences between the high-dose group and controls were observed for the number (per dam) of corpora lutea and number of implantations. Numbers (per dam) of viable foetuses, post-implantation losses, mean foetal body weight and foetal sex distribution at all doses were comparable to controls. The incidence of foetal malformations and developmental variations for all foetuses of treated rats were also comparable to controls (Monsanto, 1983c,d). It may be concluded that 3.07 mg CN¯/kg bw was not teratogenic in the rat in the presence of maternal toxicity.” (quotation from ECETOC)

“ACH showed no evidence for teratogenic effects following gavage dosing in rats up to and including doses that produced maternal toxicity. In male and female fertility studies in rats, inhaled ACH showed no reproductive effects up to concentrations that were limited by the threshold to acute toxicity (local irritative effects and systemic lethality) as indicated in repeated-dose inhalation studies.” (quotation from ECETOC)

In conclusion, there are no indications on developmental or teratogenic effects of  2-hydroxy-2-methylpropionitril in the rat from a reliable gavage study up to and including maternal toxic doses.

Justification for classification or non-classification

In a reliable study, 2-hydroxy-2-methylpropionitrile showed no evidence for developmental or teratogenic effects in rats, when administrated by gavage up to and including maternal toxic doses. In male and female fertility studies in rats, inhaled 2-hydroxy-2-methylpropionitrile showed no reproductive effects up to concentrations limited by the threshold to acute toxicity (local irritative effects and systemic lethality) as indicated in repeated-dose inhalation studies.

In conclusion, no toxicity to reproduction was observed in the studies with 2-hydroxy-2-methylpropionitril.

Thus 2-hydroxy-2-methylpropionitrile does not comply with the classification requirements regarding reproductive toxicity outlined in regulation (EC) 1272/2008 or the former directive on classification and labelling 67/548/EWG.