Propane-1,2-diol, propoxylated

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Additional information

No data on reproductive toxicity of ‘propane-1,2-diol, propoxylated’ were available for assessment. However, 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 monomer of ‘propane-1,2-diol, propoxylated’, 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. Monopropylene glycol is also one of the constituents of ‘propane-1,2-diol, propoxylated’, usually present in the commercial product at concentration levels of 0 -2%. In this study, 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).

Available data on reproductive toxicity of monopropylene glycol have also been assessed and evaluated by the expert panel of the NTP CERHR (National Toxicology Program, 2004b). No human data were identified. Based on the data reported in the continuous breeding study by Morrissey (Morrissey, 1989; NTP, 1985) the Panel concluded that monopropylene glycol is not a reproductive toxicant in males or females or in their progeny under the conditions of this study. These data were assumed by the Panel to be relevant for assessing human hazard. Based on these findings, the Panel concluded that current estimated exposures to monopropylene glycol are of negligible concern for reproductive toxicity in humans.

In addition, 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, 1993b) on another constituent and structural homologue of ‘propane-1,2-diol, propoxylated’, tripropylene glycol. Tripropylene glycol is usually present in commercial ‘propane-1,2-diol, propoxylated’at concentration levels of 20 -75%. 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 and1,000 mg/kg/day. In male rats, the administration period was two weeks prior to mating, the2 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 conclusion, the available evidence from the studies on mono- and tripropylene glycol suggests that both substances do not exhibit adverse effects on fertility. Based on these results, ‘propane-1,2-diol, propoxylated’ is also considered to be not toxic to reproduction. The NOAEL was considered to correspond to 1000 mg/kg bw/day, which is the lowest NOAEL out of two available studies.

Short description of key information:
No data on reproductive toxicity of ‘propane-1,2-diol, propoxylated’ are available for assessment. A full OECD416 two generation reprotoxicity study is available for monopropylene glycol. This study did not show any reprotoxic effects up to the maximum tested dose of 10g/kg. There is also a screening OECD 422 study available for tripropylene glycol which found no effects up to the maximum tested dose of 1000mg/kg. There is no evidence of any reprotoxic effects from the data available on the propylene glycol series from other repeat dose studies. On the basis of the similar physicochemical characteristics of monopropylene glycol and tripropylene glycol to the other members of the propylene glycol series, the results from these substances can be extrapolated to conclude that the higher members of the series (tetra and pentapropylene glycol) will also not exhibit reprotoxic characteristics. Based on these results, ‘propane-1,2-diol, propoxylated’ is concluded to be not toxic to reproduction.

Effects on developmental toxicity

Description of key information

No data on developmental toxicity of ‘propane-1,2-diol, propoxylated’ are available for assessment. There is developmental toxicity data available on the following:
•	Rat: dipropylene glycol, tripropylene glycol (latter screening study only.
•	Mouse: monopropylene glycol.
•	Rabbit: dipropylene glycol.
There was no evidence of developmental effects up to the maximum tested dose in any species for any of the substances tested (rat 5g/kg – dipropylene glycol, mouse 10g/kg – monopropylene glycol, rabbit 1.2g/kg – dipropylene glycol and monopropylene glycol).  It can be concluded with certainty that neither monopropylene glycol, dipropylene glycol nor tripropylene glycol exhibit developmental toxicity. On the basis of the similar physicochemical characteristics of the propylene glycol series, it is reasonable to extrapolate these negative findings to the adjacent higher members of the propylene glycol series: Tetrapropylene glycol and pentapropylene glycol. Based on these results, ‘propane-1,2-diol, propoxylated’ is concluded to be not toxic to development.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Additional information

No data on developmental toxicity of ‘propane-1,2-diol, propoxylated’was available for assessment. However, 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 asin vitrotests, QSARs, grouping and read-across. Reliable developmental toxicity studies, performed according to methods comparable with modern guidelines, were available for assessment on structural analogues and constituents of ‘propane-1,2-diol, propoxylated’, mono- and diprorpylene glycol. In addition, 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, 1993b) on another constituent and lower homologue of ‘propane-1,2-diol, propoxylated’, tripropylene glycol. Three substances are usually present in the commercial product at concentration levels of 0-2%, 5-75% and 20-75%, respectively.

In the developmental toxicity study with mice (Bushy Run Research Center, 1993) on monopropylene glycol, the test substance 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.

Available data on developmental toxicity of monopropylene glycol were also evaluated and assessed by the expert panel of NTP CERHR (National Toxicology Program, 2004b). In addition to the study of Bushy Run Research Center(1993), they have also evaluated the study of the Food and Drug Research Laboratories (FDRL. Teratologic evaluation of FDA 71-56 (monopropylene glycol) in mice, rats, hamsters and rabbits. Waverely (NY): Food and Drug Research Laboratories, Inc., 1973) with rats, mice, hamsters and rabbits, and a screening study with mice (Kavlock et al., Teratog. Carcinog. Mutagen. 1987, 7, 7-16). Despite the limitations of each study, no adverse developmental or maternal effects were noted in any species at the highest tested dose (10000 mg/kg bw/day in mice in the screening study; 1600 mg/kg bw/day in rats, 1550 mg/kg bw/day in hamsters and 1230 mg/kg bw/day in rabbits), leading the Panel to the conclusion that monopropylene glycol was not a developmental toxicant in these species. These data were judged to be adequate for human risk assessment.

Based on these findings, the Panel concluded that current estimated exposures to monopropylene glycol are of negligible concern for developmental toxicity in humans.

Two developmental toxicity studies with rats and rabbits, performed in accordance with methods similar to OECD guideline 414, on the structural homologue dipropylene glycol were also 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).

Furthermore, a combined repeating dose toxicity with reproductive/developmental screening test was conducted on tripropylene glycol by Ministry of Health and Welfare of Japan (MHW, 1993b). 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 summary, the available studies on structural homologues and constituents of ‘propane-1,2-diol, propoxylated’, mono-, di- and tripropylene glycol, indicated no concern for possible developmental effects. Based on these results, ‘propane-1,2-diol, propoxylated’ is considered to be not a developmental toxicant.

Justification for classification or non-classification

There is no evidence for any reproductive effects of any of the components of ‘propane-1,2-diol, propoxylated’ and therefore it is reasonable to conclude that classification for this endpoint is not required for the multi-constituent substance itself in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.