Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
The NOAEL for maternal effects was 150 mg/kg/day while the NOAEL for developmental and fetal effects was 300 mg/kg/day.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day

Toxicity to reproduction: other studies

Additional information

The potential for 2,2,4,4-tetramethyl-1,3-cyclobutanediol to cause developmental toxicity is well understood and is based on the results of a study that followed OECD Guideline 414 and was conducted under GLP assurances. The test article was administered orally by gavage to 3 groups of 25 bred rats twice daily from gestation days 0 through 19. Total daily dosage levels initially were 150, 300 and 600 mg/kg/day. Due to the excessive toxicity (mortality, body weight loss, reduced food consumption and adverse clinical signs) in the 600 mg/kg/day group, this dosage level was reduced to 500 mg/kg/day. On gestation day 20, a laparohysterectomy was performed on each surviving female. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. Six and 13 females in the 300 and 600/500 mg/kg/day groups, respectively, were found dead or euthanized in extremis between gestation days 1 and 19. No internal findings were noted. Predominant clinical findings for all animals that survived to the scheduled necropsy consisted of clonic convulsions and various other neurobehavioral changes.Lower mean food consumption was noted in the 150, 300 and 600/500 mg/kg/day groups during gestation days 0-3 and/or 3-6. Corresponding mean maternal body weight losses were noted at 300 and 600/500 mg/kg/day during gestation days 0-3 and at 150 mg/kg/day during gestation day 0-1. Mean food consumption and body weight gains in these groups were generally similar to or slightly higher than the control group values for the remainder of the treatment period and only the effects observed in the 300 and 600/500 mg/kg/day groups were considered to be adverse due to the magnitude and persistency of the effects and on mean body weight changes in these groups. Mean body weights and net body weights in the 150 mg/kg/day group were similar to the control group values. Evidence of developmental toxicity was noted at 600/500 mg/kg/day. The mean litter proportion of postimplantation loss (primarily early resorptions) in the 9 surviving pregnant females in the 600/500 mg/kg/day group was higher than the control group value and resulted in a decrease in the mean litter proportion of viable fetuses. However, live litter size in the 600/500 mg/kg/day group was unaffected by test article administration. There were no test article-related effects on intrauterine growth and survival or fetal morphology at 150 and 300 mg/kg/day.

Justification for classification or non-classification

No evidence of developmental toxicity was observed at dose levels that exceeded maternal toxicity.