Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 000 mg/m³
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The effects of dibasic esters, a read-across substance containing mostly dimethyl glutarate, on fertility was assessed by the inhalation route in a one-generation study (equivalent to an OECD 415 study) in rats, exposed to the test concentrations of 0, 160, 400 or 1000 mg/m3 for 14 weeks pre-breeding, and for 8 weeks through breeding, gestation and lactation (Kelly, 1988). No relevant effects occurred in mating performance, fertility, gestation duration, litter size, development or viability, and lactation performance up to the highest concentration tested. The NOAEC for reproductive toxicity was therefore 1000 mg/m3.

Furthermore, changes in sex hormones were observed in one of three repeat-dose inhalation toxicity study in rats exposed to each component of the dibasic ester blend for 90 days (for details, see "Repeated dose toxicity: inhalation" section). Increased epididymal sperm counts were noted in male rats exposed to 400 mg/m3 dimethyl adipate, 400 mg/m3 dimethyl succinate, and 50 or 400 mg/m3 dimethyl glutarate. A statistically significant decrease in serum estradiol concentrations was noted in female rats exposed to 400 mg/m3 dimethyl succinate. A statistically significant decrease in serum testosterone concentrations was noted in male rats exposed to 50 or 400 mg/m3 dimethyl glutarate. Serum luteinizing hormone (LH) concentrations were also statistically significantly decreased at 400 mg/m3 in rats exposed to dimethyl glutarate. The toxicological significance of these statistically significant changes was unclear, as a decrease in male sex hormones should have resulted in areductionof epididymal sperm counts, and yet the opposite was observed. In addition, none of these effects were observed in the dedicated fertility study using the dibasic ester blend, nor were any histopathological findings noted in the reproductive organs and tissues in 2 additional 90-day studies using the dibasic ester blend. These hormonal variations can therefore be considered of no toxicological significance. See further discussion in IUCLID Section 7.12 - Additional Toxicological Information.

 


Short description of key information:
No effects on mating performance, fertility, gestation duration, litter size, development or viability, and lactation performance in rats by inhalation.

Effects on developmental toxicity

Description of key information
No effects on number of resorptions or fetal weight and no increase in external, visceral or skeletal abnormalities in offspring from parent rats exposed by inhalation.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 000 mg/m³
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a developmental toxicity study equivalent to OECD 414 (Munley, 2003), dimethyl glutarate was administered by inhalation to groups of 22 time-mated rabbits at 0, 30, 100, 300, or 1000 mg/m3. At 1000 mg/m3, there was compound-related mortality; one animal was found dead on gestation day 13 and one animal was sacrificed in extremis on gestation day 22. Among survivors, there were compound-related reductions in maternal body weight gains and food consumption and there were compound-related clinical observations (ocular discharge and wet fur). At 300 mg/m3, evidence of compound-related maternal toxicity was limited to reduced maternal body weight gains and increased clinical observations (ocular discharge). Under the conditions of the current study, there was no evidence of compound-related maternal toxicity at 30 or 100 mg/m3 and there was no evidence of developmental toxicity at any level tested. Thus, the no observed adverse effect concentration (NOAEC) for maternal toxicity was considered 100 mg/m3 and the NOAEC for developmental toxicity was considered 1000 mg/m3.

Justification for classification or non-classification

Based on the absence of any relevant sign of reproductive or developmental toxicity in rats up to the concentration of 1000 mg/m3 by inhalation exposure, taking account of the classification criteria of Annex VI Directive 67/548/EEC or EU Regulation 1272/2008 (CLP), no classification is warranted for reproductive and developmental toxicity.