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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction:
No reliable data were available for toxicity to reproduction for propylene carbonate. However, effects of the read-across substance propylene glycol, the main metabolite of propylene carbonate, have been analyzed in a continuous breeding study in mice, which is comparable to OECD guidelines for multigeneration studies (i.e. OECD 416) with respect to the assessment of fertility parameters (Morrissey, 1989; National Toxicology Program, 1985). No effects have been observed up to the highest dose tested, i.e. 10100 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 100 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction

Waiver screening study for reproductive/development toxicity:

According to the REACH Regulation, a screening study for reproductive/developmental toxicity according to OECD guideline 421 or 422 does not need to be conducted if a pre-natal developmental toxicity is available (Annex VIII, column 2 adaptation). A reliable pre-natal developmental toxicity study with propylene carbonate was performed in rats. As a consequence, no study needs to be performed to cover the effects on fertility. In addition, no apparent adverse effects on reproductive organs and performance were observed in rats in subchronic repeated dose toxicity and developmental studies with propylene carbonate.

Multi-generation study:

A continuous breeding study with the read-across substance propylene glycol in mice, performed within the frame of the National Toxicology Program, was available for assessment (Morrissey, 1989; National Toxicology Program, 1985), 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).

Available data on reproductive toxicity of the read-across substance monopropylene glycol have been assessed and evaluated by the expert panel of the NTP CERHR (National Toxicology Program, 2004a). 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 propylene 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.

A justification document for the read-across strategy is attached to section 13 of this substance dataset.


Effects on developmental toxicity

Description of key information
Developmental toxicity / teratogenicity:
In a developmental toxicity study in Sprague-Dawley rats, performed according to a method equivalent or similar to OECD Guideline 414, a NOAEL of > 5000 mg/kg bw/day (nominal) for developmental toxicity and a NOAEL of 1000 mg/kg bw/day (nominal) for maternal toxicity was observed after exposure to propylene carbonate from day 6 through day 15 of gestation (treatment was given once daily via gavage).
Even though a developmental study of propylene carbonate is not available in another species, a variety of studies exist for the read-across substance propylene glycol, the main metabolite of propylene glycol in several species, including mice, rats, rabbits and hamsters (NTP-CERHR, 2004). Since no adverse effects on development have been observed in any species up to the highest dose tested, it was concluded that propylene glycol is not a developmental toxicant in these species. This conclusion is further supported by a study of the Bushy Run Research Center from 1993, in which neither effects of treatment on gravid uterine weight, the number of ovarian corpora lutea, the number of total, viable or nonviable implantations/litter, on sex ratio, on fetal body weights/litter nor indicence of individual fetal external or visceral variations have been observed in mice up to the highest dose (10400 mg/kg/day, equivalent to OECD guideline 414).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

Pharmakon (1988) performed a dose-range-finding study in 6 female Sprague Dawley rats/dose at dose levels of 500, 1000, 2000, 3000 and 5000 mg/kg bw/day. Dams were dosed via oral gavage on Day 6 through Day 15 of gestation; cesarean section was performed on each dam post-copulation Day 20; dams and fetuses were observed. There were no statistically significant differences observed in the total number of implantation sites, corpora lutea, viable fetuses, non-viable fetuses, early or late resorptions, numbers of pre- and post-implantation losses or the percentage of these losses at any dose levels . The main developmental toxicity study performed by Pharmakon 1988 in 27 Sprague-Dawley rats at dose levels of 1000, 3000 and 5000 mg/kg bw/day reported that there were no gross fetal malformations observed in any dose group.The test substance was evaluated for the potential to induce developmental toxicity in orally exposed mated female Sprague Dawley rats. The test substance did not induce a developmental toxic effect at a dosage of 5000 mg/kg/day (high dose) or less. However, maternal toxicity was evidenced by dam mortality, reduced body weight gain and a reduction in the amount of feed consumed at and above 3000 mg/kg/day.

Because of high correlation, histopathology data and organ weights from repeated dose studies were used to assess male fertility (Mangelsdorf, 2003). These parameters, taken from 90 day studies, were in fact shown to be more sensitive than fertility parameters that were measured during multi-generation studies. It could also be shown that exposure for 4 weeks suffices for an assessment of male fertility, although 90 day studies have been regarded as superior in the past because they cover a complete cycle of spermatogenesis (Mangelsdorf, 2003). If such a 28 day study shows neither relevantly elevated testis or ovary weights nor histopathological alterations in those organs, the weight of the evidence is that effects on reproduction are also not expected (BAuA, 2003). A comparison of more than one hundred 90 day studies with two-generation studies that used the same test substance additionally showed that the NOAELs differed by less than the variation limit of studies, i.e. a factor of two (Janer, 2007). Based on the argumentation of Mangelsdorf (2003), the information gained from a two generation study can be regarded as minimal if a 90 day study has been performed. Thus, based on the data presented for propylene carbonate, information gained from a two-generation study are regarded as not necessary with regard to the fact that REACH allows the assessment of the reproductive toxicity of a given chemical with the help of findings from studies with repeated administration. This is in line with the idea that the information requirements under REACH are regarded as the evaluation of endpoints which does not necessarily require data from specific studies.

BAuA (2003). Extrapolation from results of animal studies to humans for the endpoint male fertility. Forschungsbericht Fb 984.

Janer G, Hakkert BC, Piersma AH, Vermeire T, Slob W (2007). A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicol 24: 103 -113

Mangelsdorf I, Buschmann J, Orthen B (2003). Some aspects relating to the evaluation of the effects of chemicals on male fertility. Reg Toxicol Pharmacol 37: 356 -369.

Pre-natal developmental toxicity in a second species

In the developmental toxicity study with mice (Bushy Run Research Center, 1993), the read-across substance 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. Available data on developmental toxicity of monopropylene glycol were also evaluated and assessed by the expert panel of NTP CERHR (National Toxicology Program, 2004a). Since 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), the panel concluded that monopropylene glycol was not a developmental toxicant in these species. This conclusion is further supported by a study of the Bushy Run Research Center from 1993, in which neither effects of treatment on gravid uterine weight, the number of ovarian corpora lutea, the number of total, viable or nonviable implantations/litter, on sex ratio, on fetal body weights/litter nor incidences of individual fetal external or visceral variations have been observed in mice up to the highest dose (10400 mg/kg/day, OECD 414). The amounts tested largely excel the limit doses that are proposed in the current OECD guidelines. However, even though high amounts have been used in these studies, an adverse effect of propylene glycol on development was not noticed in any of the species tested. Considering these data, it is unlikely that testing propylene carbonate in a second, non-rodent species gives any new information leading to a revised assessment of human hazard. Furthermore, it is inappropriate from the point of animal welfare to perform another animal study with only limited chance of gaining new information.

A justification document for the read-across strategy is attached to section 13 of this substance dataset.

Toxicity to reproduction: other studies

Description of key information

No other reproductive toxicity studies are available.

Justification for classification or non-classification

No developmental toxic effect was evoked after oral exposure of pregnant rats at dosage of 5000 mg/kg bw/d or less; maternal toxicity was observed at 1000 mg/kg bw/day: significant suppression of group mean body weight gain (high dose), reduced food consumption during day 6-13 gestational interval (mid + high dose) and day 13-20 interval (high dose).

Based on the absence of adverse effects on reproduction and development in available continuous breeding study and developmental toxicity study with the read-across substance propylene glycol in mice (NOAEL > 10000 mg/kg bw/day), and the data available on developmental toxicity of propylene carbonate, the latter substance does not have to be classified for reproductive and developmental toxicity in accordance with EU Directive67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.