Propane-1,2-diyl diacetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

no other studies available

Effect on fertility: via oral route

Dose descriptor:

NOAEL

10 100 mg/kg bw/day

Additional information

Oral - propylene glycol

A continuous breeding study with 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 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.

The justification for using data on the PGDA metabolite propylene glycol is provided in the read across document attached to Section 13 of the IUCLID dossier.
Short description of key information:
There is no data for PGDA. A TK/metabolism study comparing molar equivalent amounts of radiolabeled PGDA and propylene glycol showed similar absorption and elimination parameters and indicated rapid metabolism of PGDA to propylene glycol (PG) and presumable acetic acid (not the labeled portion of PGDA). Therefore, the use of propylene glycol as a surrogate is justified. A continuous breeding study with mice was conducted using propylene glycol. No adverse effects on fertility were found in a continuous breeding study with mice, administered monopropylene glycol at levels up to 10100 mg/kg bw/day for 7 days pre-mating period, followed by cohabitation and continuous treatment for 98 days. The NOAEL for reproductive toxicity was established to exceed 10100 mg/kg bw/day.

The other metabolite of PGDA is acetic acid (AA) which does not have standard/guideline study databut due to its use in the food industry (GRAS classification) and presence in vinegar, it has been determined to have low toxicological concern. See read across document for summaries of non-standard studies using acetic acid/vinegar.

The PGDA/PG TK study dosed animals with 500 mg/kg bw PGDA which is less than the limit dose of 1000 mg/kg. However, the acute toxicity data on PGDA shows that by all major dose routes there are no deaths at 2000 mg/kg bw or greater and up to the highest attainable vapor concentration. PGDA has also been dosed in a 28-day study and developmental toxicity study at the limit dose of 1000 mg/kg bw/day with no adverse findings which shows the same lack of adverse toxicity as propylene glycol and acetic acid. Therefore, this weight of evidence (very low acute toxicity, lack of systemic toxicity at 1000 mg/kg PGDA and rapid metabolism to propylene glycol and acetic acid) supports the use of the highest dose levels from the read across material propylene glycol.

The justification for using data on the PGDA metabolite propylene glycol is provided in the read across document attached to Section 13 of the IUCLID dossier.

Effects on developmental toxicity

Description of key information

A GLP study in rabbits according to OECD guideline 414 has been conducted with PGDA. In addition, a TK/metabolism study comparing molar equivalent amounts of radiolabeled PGDA and propylene glycol showed similar absorption and elimination parameters and indicated rapid metabolism of PGDA to propylene glycol (PG) and presumable acetic acid (not the labeled portion of PGDA). use of propylene glycol as a surrogate is justified. A developmental toxicity study of propylene glycol in mice is available. No adverse effects on development were noted in the developmental toxicity study with mice, administered monopropylene glycol at dose levels up to 10400 mg/kg bw/day on gestation days 6 to 15. Based on these data, monopropylene glycol is considered to be not a developmental toxicant.

The other metabolite of PGDA is acetic acid (AA) which does not have standard/guideline study data but due to its use in the food industry (GRAS classification) and presence in vinegar, it has been determined to have low toxicological concern. See read across document for summary of studies using acetic acid/vinegar.

The PGDA/PG TK study dosed animals with 500 mg/kg bw PGDA which is less than the limit dose of 1000 mg/kg. However, the acute toxicity data on PGDA shows that by all major dose routes there are no deaths at 2000 mg/kg bw or greater and up to the highest attainable vapor concentration. PGDA has also been dosed in a 28-day study and developmental toxicity study at the limit dose of 1000 mg/kg bw/day with no adverse findings which shows the same lack of adverse toxicity as propylene glycol and acetic acid. Therefore, this weight of evidence (very low acute toxicity, lack of systemic toxicity at 1000 mg/kg PGDA and rapid metabolism to propylene glycol and acetic acid) supports the use of the highest dose levels from the read across material propylene glycol.

The justification for using data on the PGDA metabolite propylene glycol is provided in the read across document attached to Section 13 of the IUCLID dossier.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

10 400 mg/kg bw/day

Effect on developmental toxicity: via dermal route

Dose descriptor:

NOAEL

1 058 mg/kg bw/day

Additional information

In a dermal teratology probe study in rabbits 0.1, 0.3 and 1.0 ml PGDA/kg bw/day were administered daily from gestational day 6-18. During the study, no abnormalities in condition or behaviour were observed that could be related to the treatment with PGDA. No mortality occurred. During the course of the study several rabbits of various groups showed inflammatory skin reactions in the neck region. However, since this part of the skin was not dermally treated with PGDA or water and, moreover the effects were observed in all groups, including controls, these effects were considered to be due to chafing by the rims of the neck collars, rather than the result of PGDA treatment. It was concluded that, under the conditions of the study PGDA is well-tolerated by pregnant female rabbits when it is applied dermally at levels up to 1.0 ml/kg body weight/day (equivalent to 1058 mg/kg bw/day). The results of this study further indicated that PGDA when administered dermally at levels up to 1.0 ml/kg body weight/day is not embryo- or foetotoxic to New Zealand White rabbits.

 

In the definitive study, conducted according to OECD guideline 414 and GLP, PGDA was examined for its potential embryotoxic and teratogenic properties in New Zealand white rabbits. Groups of at least 24 rabbits were dermally treated during days 6 through 18 with 0, 0.3 and 1.0 ml PGDA per kg bw (equal to 0, 0.317 or 1.058 g/kg bw). 1 g/kg bw is a limit quantity for substances with low toxicity, as specified by OECD. No mortality or abnormality in condition or behavior were observed in any of the groups that could be related to the treatment. Fertility and gestation were comparable in all groups and well above the average of the historical controls. Body weights, food intake, autopsy findings and litter data did not reveal any treatment related effect. No compound related visceral or skeletal malformations, anomalies or variants were observed in the foetuses. PGDA, applied dermally to rabbits in the sensitive period of pregnancy with a limit quantity of 1 ml/kg bw per day was not embryo/foetotoxic or teratogenic.

 

The NOEL for maternal toxicity and for developmental toxicity is 1058 mg/kg bw/day.

Oral - propylene glycol

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. Available data on developmental toxicity of monopropylene glycol were also evaluated and assessed by the expert panel of NTP CERHR (National Toxicology Program, 2004a). 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 (propylene 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.

The justification for using data on the PGDA metabolite propylene glycol is provided in the read across document attached to Section 13 of the IUCLID dossier.

Justification for classification or non-classification

Fertility studies are not available for PGDA. Since PGDA has undergone repeated dose toxicity testing at substantial doses with extensive histopathology, definitive conclusions can be drawn regarding damage to reproductive organs. Results from these repeated dose tests indicate that PGDA did not cause toxicity to the testes. Specifically, no reduction in testicular weight, no damage to the sperm or sperm-producing cells, and no damage to the epididymis or seminiferous tubules were reported. Likewise, no damage to female reproductive organs was found.

A TK/metabolism study comparing molar equivalent amounts of radiolabeled PGDA and propylene glycol showed similar absorption and elimination parameters and indicated rapid metabolism of PGDA to propylene glycol (PG) and presumable acetic acid (not the labeled portion of PGDA). Therefore, use of propylene glycol as a surrogate is justified. In a fertility study with propylene glycol, no treatment-related fertility effects were observed with propylene glycol.

The other metabolite of PGDA is acetic acid (AA) which does not have standard/guideline study databut due to its use in the food industry (GRAS classification) and presence in vinegar, it has been determined to have low toxicological concern. See read across document for summaries of non-standard studies using acetic acid/vinegar.

The PGDA/PG TK study dosed animals with 500 mg/kg bw PGDA which is less than the limit dose of 1000 mg/kg. However, the acute toxicity data on PGDA shows that by all major dose routes there are no deaths at 2000 mg/kg bw or greater and up to the highest attainable vapor concentration. PGDA has also been dosed in a 28-day study and developmental toxicity study at the limit dose of 1000 mg/kg bw/day with no adverse findings which shows the same lack of adverse toxicity as propylene glycol and acetic acid. Therefore, this weight of evidence (very low acute toxicity, lack of systemic toxicity at 1000 mg/kg PGDA and rapid metabolism to propylene glycol and acetic acid) supports the use of the highest dose levels from the read across material propylene glycol.

The justification for using data on the PGDA metabolite propylene glycol is provided in the read across document attached to Section 13 of the IUCLID dossier.

 

In a teratology study in rabbits no treatment related developmental effects have been observed with PGDA.

 

Hence, no classification for reproductive toxicity is required for PGDA.