Propane-1,2-diyl diacetate

Endpoint summary

Description of key information

A 28-day dermal GLP study according to or equivalent to OECD guideline 410 has been conducted with 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, available repeated dose toxicity studies of propylene glycol is included in this summary. The repeated dose toxicity of monopropylene glycol by oral and inhalatory exposure routes is low. The lowest NOAEL of 1700 mg/kg bw/day was obtained in a chronic study with rats receiving monopropylene glycol in diet. In the subchronic inhalation study with rats, exposed to aerosol of monopropylene glycol at concentration levels of 160-2200 mg/m3, reported nasal haemorraghic discharge and ocular discharge occurred in all dose groups; this was accompanied by microscopically observed prominent goblet cell and/or mucus production in mid- and high-concentration groups. Based on these findings, the lowest dose level of 160 mg/m3 is considered a LOAEL for local effects. For systemic effects, a NOAEL of 1000 mg/m3 was established, based on the reduced body weight and decreased food consumption in high-dose females.

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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1 700 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

1 310 mg/m³

Study duration:

subacute

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Oral route of exposure - propylene glycol

A chronic study with rats administered monopropylene glycol in diet was available for assessment. Gaunt et al., 1972, administered diets containing 0, 6250, 12500, 25000 and 50000 ppm monopropylene glycol to groups 30 male and 30 female weanling rats for 2 years. Next to histopathological examinations and gross necropsy haematological examination and urinalysis were performed. No adverse effects were noted at the highest tested dose, resulting in NOAELs of 1700 mg/kg bw/day and 2100 mg/kg bw/day for male and female rats, respectively, based on the determined daily average food intake.

Cats appear to be more sensitive to monopropylene glycol. The study of Toxicology Research Laboratory (1979) reported a species-specific increase in Heinz bodies after dietary administration of monopropylene glycol at actual ingested doses of 0, 443 or 4239 mg/kg bw/day for 94 days, or 0, 80, 675 and 1763 mg/kg bw/day for 69 days to male cats. Increased hemosiderin deposits were also noted in liver and spleen, but appeared secondary to Heinz body formation. The formation of Heinz bodies and increased hemosiderin occured in a dose-related manner at doses of 675 mg/kg bw/day and higher. Although a daily dose level of 443 mg/kg bw/day appeared to cause a slight increase in Heinz body formation (without detectable increased hemosiderin present in the liver or spleen), the levels of Heinz body formation in this group of cats was comparable to levels observed in one of the four control cats; therefore a NOAEL of 443 mg/kg bw/day was set in the study.

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.

Dermal: in a GLP study in rats according to OECD guideline 410 (28 days) no test substance related mortality occurred and moreover no evident signs of systemic toxicity were observed in any of the treatment groups up to the limit dose of 1000 mg/kg bw/day. No test substance related effects on body weight gain and food consumption were found. Temporary local eschar formation on the treated skin side of several animals among all groups was induced ,by shaving in combination with the way of bandaging and not by the test substance. Organ weights, organ/body weight ratios, haematology and clinical chemistry data, and gross and microscopic pathology revealed no test substance related changes. Based on these findings it was concluded that repeated dermal dosing of PGDA for 28 days up to a level of 1000 mg/kg body weight caused no adverse health problems. The no observed effect level is > 1000 mg/kg bw/day.

 

Inhalation: in a GLP study in rats equivalent to OECD guideline 412 (14 days) no treatment related effects were observed at the highest exposure concentration which was near the maximum practically attainable concentration for PGDA. The NOEC was greater than 200 ppm (1310 mg/m3). Considering the low vapor pressure of PGDA it is unlikely that PGDA would pose a human vapor inhalation hazard at room temperature and normal atmospheric pressure.

Inhalation route of exposure - propylene glycol

A subchronic inhalation toxicity study with rats exposed to propylene glycol aerosol at dose levels of 0.0, 0.16, 1.0 and 2.2 mg/L air for 6 hr/day, 5 days/week for 90 days was reported by Suber et al., 1989. A treatment-related effect was reported nasal haemorrhaging which began during the second week of exposure and persisted throughout the study; recovery from these clinical signs occurred during the non-exposure weekend periods. The frequency of this reported nasal haemorrhaging remained constant throughout the study and was highest (65-75%) in the medium-and high-concentration groups. Similar trends were observed for ocular discharge, with incidences of 16% in low-exposure males, 40% in medium and high exposure males and 5% in controls. There was generally less ocular discharge in females, who had incidences of 8% in controls, 14% in the low-exposure group, 28% in the medium-exposure group and 35% in the high-exposure group. Minute volume, tidal volume and respiratory rates were not significantly altered at any dose levels.

A reduction in mean body weight by 5-7% was observed in the high-exposure female rats. This reduction correlated with the observed reduction in feed consumption. There was no trend towards reduced feed consumption among male rats, but reduced consumption on selected days for the high-exposure male rats was seen. Inconsistent but statistically significant changes were observed with absolute organ weights, but these changes were not considered to be biologically significant by the authors when the weights for all of the treatment groups were compared and when the gross histological findings were taken into account. No adverse changes in gross pathological and histopathological variables were noted, except of an increase in the number of goblet cells or an increase in the mucin content of the goblet cells present, observed in the nasal turbinates of both male and female rats. In addition, white blood cell counts revealed a concentration-related decrease in total white blood cells in mid- and high-concentration females, a decrease in banded neutrophils in mid-concentration females and high-concentration males and females, and finally a decrease in lymphocytes in mid- and high-concentration females.

Based on the reported nasal hemorrhaging and ocular discharge at all dose levels, accompanied by the lowest dose level of 160 mg/m³is considered to be a LOAEL for local effects and shall be used for the risk assessment. However, it should be noted that the reported nasal “hemorrhage” observed in the study was not supported by microscopic evidence of tissue damage and hemorrhage. An alternative explanation is that the reported “hemorrhage” was pigment/porphyrin staining following an increase in lacrimal secretion caused by the mildly irritating or drying effect of propylene glycol aerosols on mucous membranes. The increased number of goblet cells and/or increased mucin content in the mid- and high dose groups appears to be an adaptive response.

For systemic effects, the NOAEL of 1000 mg/m³was established, based on the reduced body weight and decreased food consumption in high-dose females.

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

The no observed adverse effect levels for PGDA and propylene glycol exceed the values triggering classification. Therefore, no classification for prolonged exposure is required.