Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Quality of whole database:
Conclusion based on the results from a screening study with the test substance and a full study with read across substances in multiple species.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, conducted in accordance with OECD guideline 422 and with GLP, was conducted by the Ministry of Health and Welfare of Japan (MHW, 1993). Although the original study has been requested, only its abstract in English could be recovered. Nevertheless, as the study was conducted within the HPV/SIDS framework and considered to be reliable by OECD SIDS (1994), it was considered to be acceptable for assessment. Groups of 12 male and female Crj: CD(SD) rats were orally administered (gavage) tripropylene glycol at doses of 0, 8, 40, 200 and 1,000 mg/kg/day. In male rats, the administration period was two weeks prior to mating, the 2 weeks of mating and the 2 weeks after the completion of mating period. Female rats were administered tripropylene glycol from 14 days before mating to Day 3 of lactation. Males were autopsied on day 50 of the experiment and females on day 4 of lactation. There were no effects on mating, fertility, and the oestrus cycle of dams during the pregnancy and lactation period. The NOEL values for both parental and F1 offspring in reproductive toxicity were therefore considered to be 1,000 mg/kg/day. The NOAEL for general toxicity was 200 mg/kg bw/day, based on kidney and liver effects observed at the highest dose.

In addition, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. A continuous breeding study with mice with the structurally related substance monopropylene glycol was available for assessment (Morrissey, 1989), comparable to OECD guidelines for multi-generation studies (i.e. OECD 416) with respect to the assessment of fertility parameters. Mice were exposed to the test substance for 7-day premating period, and were then randomly grouped as mating pairs and cohabited and treated continuously for 98 days. Data were collected on all newborns during this period within 12 hours of birth, after which each litter was discarded. After the 98-day cohabitation, the pairs were separated but continued on treatments. During the next 21 days, any final litters were delivered and kept for at least 21 days (weaning). The mother was dosed through weaning and F1 mice were dosed until mated at 74 ± 10 days of age. For this, male offspring were mated to female off-spring from the same treatment group (n = 20/group/sex) and the F2 litters were examined for litter size, sex and pup weight.

No data on maternal toxicity were reported. No effects on fertility were observed in P animals.

No effects on fertility index or mating index were observed in F1 animals.

No differences were found between control and test P animals in the mean No. litters per pair, mean No. live pups per pair, mean No. live male pups per litter, mean No. live female pups per litter; proportion of pups born alive; sex of pups born alive; mean live pup weight per litter; mean live male pup weight per litter; mean live female pup weight per litter; adjusted mean live pup weight per litter; adjusted mean live male pup weight per litter; adjusted mean live female pup weight per litter.

No differences were found between control and F1 animals in mean No. live pups per litter; mean No. liver male pups per litter; mean No. live female pups per litter; proportion of pups born alive and sex of pups born alive.

The NOAEL for effects on fertility was established to be 10100 mg/kg bw/day (the highest dose tested).

In conclusion, the available evidence from the studies on tripropylene glycol and its structural homologue monopropylene glycol suggests that tripropylene glycol does not exhibit adverse effects on fertility. The NOAEL was considered to correspond to 1000 mg/kg bw/day, which is the lowest NOAEL out of two available studies. A full justification for read across within the propylene glycol series is contained in a separate document attached to chapter 13 of the lead registrants IUCLID dossier.


Short description of key information:
A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with tripropylene glycol, performed in accordance with OECD guideline 422 and GLP, indicated no adverse effects on fertility up to the highest tested dose of 1000 mg/kg bw/day. In addition, no adverse effects on fertility were observed in the continuous breeding study with mice on structural homologue monopropylene glycol up to the dose level of 10100 mg/kg bw/day, supporting the conclusion that tripropylene glycol does not exhibit reproductive toxicity.

Effects on developmental toxicity

Description of key information
A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with tripropylene glycol, performed in accordance with OECD guideline 422 and GLP, indicated no adverse effects on development up to the highest tested dose of 1000 mg/kg bw/day. In addition, no adverse effects on development were observed in the developmental toxicity studies with rats and rabbits and developmental toxicity study with mice on structural homologues di- and monopropylene glycol, respectively, supporting the conclusion that tripropylene glycol is not a developmental toxicant. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Quality of whole database:
Conclusion based on the results from a screening study with the test substance and a full studies with two read across substances.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, conducted in accordance with OECD guideline 422 and with GLP, was conducted by the Ministry of Health and Welfare of Japan (MHW, 1993). Although the original study has been requested, only its abstract in English could be recovered. Nevertheless, as the study was conducted within the HPV/SIDS framework and considered to be reliable by OECD SIDS (1994), it was considered to be acceptable for assessment. Groups of 12 male and female Crj: CD(SD) rats were orally administered (gavage) tripropylene glycol at doses of 0, 8, 40, 200 and 1,000 mg/kg/day. In male rats, the administration period was two weeks prior to mating, 2 weeks of mating and 2 weeks after the completion of mating period. Female rats were administered tripropylene glycol from 14 days before mating to Day 3 of lactation. Males were autopsied on day 50 of the experiment and females on day 4 of lactation. Parameters to evaluate developmental toxicity were limited to only body weights at day 0 and day 4 after birth, and autopsy findings at day 4.

In parental animals, increased salivation was observed in 1000 mg/kg bw/day males. The 1000 mg/kg males showed significantly higher values for absolute and relative liver weights and relative kidney weight, and the 1000 mg/kg bw/day females showed higher values for relative liver weight. No further adverse effects were noted. External examination of pups revealed no increase in appearance of abnormal pups. Body weight gain of pups was normal. Pups killed at postnatal day 4 showed no abnormal gross findings. Based on these results, the NOAEL for developmental toxicity was established to correspond to 1000 mg/kg bw/day.

In addition, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. Two developmental toxicity studies with rats and rabbits, performed in accordance with methods similar to OECD guideline 414, on the structural homologue dipropylene glycol, and one developmental toxicity study with mice on monopropylene glycol were available for assessment. Dipropylene glycol was administered by gavage at nominal concentrations 0, 800, 2000 and 5000 mg/kg bw/day to pregnant female rats at gestation days 6 -15 (NTP TER-91-013, 1992) and to pregnant female rabbits at nominal concentrations 0, 200, 400, 800 and 1200 mg/kg bw/day at gestation days 6 -19 (NTP TER-91-014, 1992). Clinical signs of toxicity were observed in the rat study at dose levels 2000 and 5000 mg/kg bw/day, including ataxia, weight loss, lethargy, unstable gait, piloerection, morbidity and/or mortality. Relative liver weights were significantly increased compared to controls in maternal animals of 2000 and 5000 mg/kg bw/day groups. There were no significant differences between the exposed groups and the control in the average number of corpora lutea, implants, live fetuses, early deaths (resorptions), late deaths, or non-live implants per litter. The percent pre- and post-implantation losses per litter were not significantly different from control values. A significant decreasing linear trend from the control to high dose group was observed for mean fetal weight, but mean male and female body weights in the dipropylene glycol exposed groups were not significantly different from control. There were no other treatment-related effects. The NOAEL for maternal toxicity was established to correspond to 800 mg/kg bw/day, the NOAEL for developmental toxicity was 5000 mg/kg bw/day (the highest dose tested).

In the rabbit study with dipropylene glycol, no maternal lethality or dose-related clinical signs of toxicity were observed. Examination of the ovaries from pregnant animals revealed a significant decrease in the number of corpora lutea in the high dose group compared to control. This observation was not treatment related since exposure of the maternal animals did not begin until ca. 6 days after ovulation. The mean number of implantation sites in the dipropylene glycol exposed groups was equivalent to controls. No significant differences between the dipropylene glycol exposed groups and the control in the average number of implants, live fetuses, early deaths (resorptions), late deaths, or non-live (early deaths + late deaths) implants per litter were observed. The percent postimplantation losses per litter were not significantly different from control values. No significant effects were observed on average fetal weight or on the percent of male fetuses per litter. Statistical examination of the prevalence of morphological abnormalities from the fetuses showed no significant effects of dipropylene glycol exposure. The only significant linear trend was associated with the number of litters with visceral malformations; however, it was within historical control ranges. No significant effects were noted in the prevalence of variations in the fetuses. The NOAEL for both maternal and developmental toxicity of dipropylene glycol was 1200 mg/kg bw/day (no effects at the highest dose tested).

In the developmental toxicity study with mice (Bushy Run Research Center, 1993), monopropylene glycol was administered to pregnant mice at dose levels of 0, 0.5, 5.0 and 10.0 ml/kg bw/day (0, 52, 520 and 10400 mg/kg bw/day) on gestation days 6 through 15. Mice were sacrificed on gestation day 18 and evaluation of fetuses, uterine weight, number of corpora lutea and implantation sites was performed. Increased water consumption was observed in the 10.0 ml/kg bw/day group and, although not statistically significant, in the middle dose group. No further treatment-related clinical signs, effects on maternal body weights and body weight gains, food consumption were observed at any dose level and no treatment-related necropsy findings of the dams at the scheduled sacrifice on gestation day 18 were found. Therefore, the increase in water consumption is likely to be a normal physiological reaction to the administration of a high quantity of substance by gavage, which may cause a surge in the osmolarity of body fluids. Consequently, this effect is not considered to be of toxicological significance.

There were no effects of treatment on gravid uterine weight, the number of ovarian corpora lutea, the number of total, viable or nonviable implantations/litter or on sex ratio. Also no effects on fetal body weights/litter were observed which were attributed to treatment. There were no treatment related increases in the incidences of individual fetal external or visceral variations. Based on the results of the study, the NOAEL for developmental toxicity was established to correspond to 10400 mg/kg bw/day.

In conclusion, the available evidence from the studies with tripropylene glycol and its structural analogues mono- and dipropylene glycol suggests that tripropylene glycol is not a developmental toxicant. The NOAEL for developmental toxicity is considered to correspond to 1000 mg/kg bw/day, which is the lowest value out of the three available studies. A full justification for read across within the propylene glycol series is contained in a separate document attached to chapter 13 of the lead registrants IUCLID dossier.

Justification for classification or non-classification

Based on the absence of adverse effects on fertility and development in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with tripropylene glycol and in the available studies with structural analogues mono- and dipropylene glycol, classification of tripropylene glycol for reproductive and/or developmental toxicity is not warranted in accordance with Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.