Propane-1,2-diol, propoxylated

Endpoint summary

Description of key information

No data on the repeated dose toxicity of ‘propane-1,2-diol, propoxylated’ are available. However, sufficient data are available on its lower homologues and constituents mono-, di- and tripropylene glycol. As di- and tripropylene glycol are major constituents of ‘propane-1,2-diol, propoxylated’ and it is feasible to assume based on the toxicokinetic data that metabolism of higher oligopropylene glycol homologues will proceed via the formation of their lower structural analogues, it is considered acceptable to use the NOAEL of 470 mg/kg bw/day, established in the 2-year drinking water study with dipropylene glycol, for DNEL derivation of ‘propane-1,2-diol, propoxylated’. Route-to-route extrapolation shall be used to derive DNELs for dermal and inhalation route of exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

470 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

No data on repeated dose toxicity of ‘propane-1,2-diol, propoxylated’ are available. 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.

Sufficient data on repeated dose toxicity are available on structural analogues of ‘propane-1,2-diol, propoxylated’, mono-, di- and tripropylene glycol. All three substances are also the constituents of ‘propane-1,2-diol, propoxylated’ (a multi-constituent substance), usually present in the commercial product at following concentrations: 0 -2% monopropylene glycol, 0 -50% dipropylene glycol and 10 -80% tripropylene glycol. Therefore it is considered acceptable to derive the data on repeated dose toxicity of ‘propane-1,2-diol, propoxylated’by read-across from its constituents (see separate read across justification document appended to chapter 13 of the IUCLID dossier).

 

Oral route of exposure

For monopropylene glycol, several long-term studies on different species (rats, dogs and cats) were available for assessment. The most recent 2 -year diet study with rats was chosen as a key study and shall be briefly summarized here. 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. Histopathological examinations, 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.

Cats appear to be more sensitive to monopropylene glycol. The study of Dow Chemical Company (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.

For dipropylene glycol, an NTP drinking water study in rats using 90-day and 2-year exposure duration was available for assessment (National Toxicology Program, 2004a). In the 90-day study with rats, animals were exposed to 0, 5000, 10000, 20000, 40000 or 80000 ppm in drinking water, resulting in actual ingested doses of 425, 890, 1840, 3890 and 12800 mg/kg bw/day (males) and 460, 920, 1690, 3340 and 8950 mg/kg bw/day (females). It should be noted that these doses vastly exceeded the limit dose values currently established by OECD and EPA guidelines. Two test groups were used, a core group and a clinical pathology group, each including 10 animals/sex/dose. In addition to gross necropsy, histopathological and clinical chemistry examinations conducted, at the end of the studies, sperm motility and estrous cycle evaluations were conducted on the animals in the 0, 5,000, 20,000, and 80,000 ppm groups.

The main effects were observed in liver and kidneys. Exposure to 10,000 ppm or greater caused significant increases in absolute and relative liver weights of males and females compared to those of the controls. Exposure to 20000 ppm or greater in males and 40000 ppm or greater in females caused significant increases in relative kidney weights. In male rats exposed to 80,000 ppm, the incidence of foci of hepatocellular alteration, classified histologically as atypical hepatocellular foci, was significantly increased. The left testis, cauda epididymis, and epididymis weights; motility of epididymal spermatozoa; epididymal sperm counts per cauda; and spermatid heads per gram testis of 80,000 ppm males were significantly decreased. No significant differences were noted in estrous cycle parameters between exposed and control females. The toxicological relevance of these findings is however questionable, as it is obvious that the doses ingested by the study animals were excessively high, surpassing the currently by OECD and EPA established limit doses (see section toxicity to reproduction for further discussion). The established NOAELs were 425 mg/kg bw/day for male and 460 mg/kg bw/day for female rats.

In the 2-year drinking water study with rats, exposure concentrations were 0, 2500, 10000 and 40000 ppm, corresponding to actual ingested doses of 115, 470 and 3040 mg/kg bw/day in male and 140, 530 and 2330 mg/kg bw/day in female rats. Again, the dose levels exceeded the currently established limit dose of 1000 mg/kg bw/day according to OECD and EPA guidelines. Survival of 40,000 ppm males was significantly less than that of the control group. Reduced survival was largely due to a high rate of moribund sacrifices that occurred between days 431 and 690; moribundity being probably caused by chronic progressive nephropathy (CPN) and subsequent renal insufficiency. Although chronic nephropathy occurred in most male rats, including the controls, the incidences and severities in 10,000 and 40,000 ppm males were increased. Nephropathy is a common spontaneous age-related lesion in F344/N rats, particularly males, and occurs in virtually all male rats in NTP 2-year studies. Exacerbation of nephropathy is frequently observed as a treatment-related effect and is manifested as an increase in severity. According to the expert review of Hard et al., 2009, rodent CPN has no strict counterpart in humans, and therefore these changes should be regarded as having no significance for human risk assessment.

The incidences of parathyroid gland hyperplasia and heart mineralization were significantly increased in 40,000 ppm males. These lesions are considered to be secondary to chronic nephropathy.

The incidences of minimal to mild focal granulomatous inflammation of the liver were significantly increased in 10,000 and 40,000 ppm males and slightly increased in 10000 ppm females. This inflammation was morphologically consistent with the spontaneous microgranulomatous lesions that are commonly observed in aged rats and considered to result from bacterial showering from the intestinal tract. The incidences of bile duct hyperplasia in 40,000 ppm males and females were significantly greater than those in the controls. In addition, the incidences of minimal to moderate olfactory epithelial atrophy in 40,000 ppm male rats and of minimal to moderate olfactory degeneration in 40,000 ppm male and female rats were significantly greater than those in the controls. The incidence of mild to marked thrombosis in males exposed to 40,000 ppm was significantly increased. The biological significance of these nasal lesions is not certain but could be related to metabolism of dipropylene glycol in the olfactory epithelium. Overall, the NOAELs of 470 mg/kg bw/day and 530 mg/kg bw/day were established for male and female rats, respectively, based on the effects in the liver and the increase of nasal lesions.

For tripropylene glycol, 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). 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 (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 (total exposure approximately 50 days). Animals were observed for clinical signs, body weight changes and food consumption. Males were autopsied on day 50 of the experiment and females on day 4 of lactation and gross necropsy, histopathological, haematological and clinical chemistry examinations were performed.

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. Body weight gains in all dosed groups in both sexes were almost the same as those of the controls.

Tripropylene glycol did not cause any changes in food consumption, hematology, and blood chemistry or necropsy findings. In histopathological examinations, no changes which may have been caused by the test substance were observed in the heart, kidneys, liver, thymus, testes, ovaries, epididymides, adrenal, brain or spleen in both sexes. Based on the results of the study, the NOAEL for repeated dose toxicity was considered to be 200 mg/kg bw/day, based on the increased relative liver weights in males and females and increased relative kidney weight in males.

Inhalation route of exposure

Only one study on monopropylene glycol using inhalation route of exposure was available for assessment. Rats were 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 (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 onthe reported nasal hemorrhaging and ocular discharge at all dose levels, accompanied by the lowest dose level of 160 mg/m³is considered to be a LOEC 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.

Dermal route of exposure

Only one limited study using dermal route of exposure, with monopropylene glycol, was available for assessment (Stenbäck et al. (1974)). Groups of 50 female Swiss mice were treated twice a week with 0.02 ml of either neat monopropylene glycol or its 50% or 10% solution in acetone, by dropping the liquid on the dorsal skin between the flanks on a 1-inch square area which was shaved regularly. Mice were allowed to die spontaneously or killed when moribound. Complete autopsies were performed on all animals and the skin and all grossly observed tumors and other lesions were examined histopathologically. The authors concluded that no substance-caused increase in tumor evidence was evidenced in any group; however, no further data on toxicity are presented.

Applicability of the obtained results of ‘propane-1,2-diol, propoxylated’

As can be seen from the available results, the systemic toxicity of the lowest homologue of ‘propane-1,2-diol, propoxylated’ and its monomer, monopropylene glycol, by repeated exposure is very low. No adverse effects were noted at the highest tested dose in the chronic toxicity study with rats, resulting in NOAELs of 1700 mg/kg bw/day and 2100 mg/kg bw/day for male and female rats, respectively. In the available 90 -day inhalation toxicity study, effects at the highest dose level of 2200 mg/m3 were limited to the reduced body weight and decreased food consumption in high-dose females. Cats appear to be more sensitive to monopropylene glycol demonstrating blood effects, however, similar effects have not been observed in humans despite wide-spread use of this substance.

In the available studies with di- and tripropylene glycol, effects were mainly observed in the liver and kidneys. In the 90 -day drinking water study with rats, dipropylene glycol caused significant increases in absolute and relative liver weights of males and females at dose levels of 10,000 ppm (males 890 mg/kg bw/day and females 920 mg/kg bw/day). These increases in liver weight were not accompanied by histopathological changes, which were present only at dose levels of 20,000 ppm (1690 mg/kg bw/day for males and 1840 mg/kg bw/day for females) and above. Exposure to 20,000 ppm or greater (1840 mg/kg bw/day) in males and 40000 ppm or greater (8950 mg/kg bw/day) in females caused also significant increases in relative kidney weights. In the two-year drinking water study with rats, the incidences of bile duct hyperplasia at 40,000 ppm (3040 mg/kg bw/day for males and 2330 mg/kg bw/day for females) were significantly greater than those in the controls. In addition, the incidences of minimal to moderate olfactory epithelial atrophy in 40,000 ppm male rats and of minimal to moderate olfactory degeneration in 40,000 ppm male and female rats were significantly greater than those in the controls. Overall, the NOAELs of 470 mg/kg bw/day and 530 mg/kg bw/day were established for male and female rats, respectively, based on the effects in the liver and the increase of nasal lesions.

In the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with tripropylene glycol the effects in relative liver and kidney weight were observed at 1000 mg/kg bw/day, i. e. at approximately the same dose level as in the 90 -day rat study with dipropylene glycol. Similarly to dipropylene glycol, these increases were not accompanied by histopathological changes. Available toxicological data on tripropylene glycoldemonstrated tripropylene glycol to be rapidly metabolized to dipropylene glycol and monopropylene glycol, which is then further oxidized to CO₂(Dow Chemical Company, 1995). Taking this into account, it is very likely that the observed effects can be explained by dipropylene glycol formed by metabolism of tripropylene glycol. In the 2-year drinking water study with dipropylene glycol histopathological changes in liver, namely bile duct hyperplasia, were observed only at 40000 ppm (3040 mg/kg bw/day and 2330 mg/kg bw/day for male and female rats, respectively). This indicates that only a very high sustained dose of dipropylene glycol is required to produce potentially damaging changes to the liver and this dose is significantly higher than the dose that produced liver weight changes in the 13 week study. The organ weight changes observed in the 13 week study with dipropylene glycol at dose levels of 890-920 mg/kg bw/day do not translate to adverse structural changes to organs at this dose level, and much higher doses are needed to produce structural changes to the liver (and kidney), as the results of the 2-year drinking water study with dipropylene glycol indicate. 

Based on the available data, it is feasible to assume that higher homologues of ‘propane-1,2-diol, propoxylated’, i. e. tetra- and pentapropylene glycol, shall be metabolized in the same way, i. e. via the formation of lower homologues, and thus their toxicological behavior shall be governed by dipropylene glycol formed by metabolism. Di- and tripropylene glycol are also the main constituents of ‘propane-1,2-diol, propoxylated’, which can be present at concentrations up to 75%. Taking this into account and using a precautionary principle, it is considered to be acceptable to use the (lower) NOAEL of 470 mg/kg bw/day, established in the 2 -year drinking water study with dipropylene glycol, without applying the correction for molecular weight, for DNEL derivation for polypropylene glycol. For other routes of exposure, route-to-route extrapolation shall be used to derive DNELs for systemic toxicity.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

The classification endpoint that is relevant for repeat dose toxicity is STOT-RE (Specific Target Organ Toxicity – Repeated Exposure.) According to the CLP regulation 1272/2008, classification for this endpoint needs to be considered when significant toxic effects are observed in a 90 day study in experimental animals at doses at or below 100 mg/kg bw/day in an oral study. An OECD 422 study is available for tripropylene glycol (which in terms of exposure duration is comparable to a sub-acute toxicity study.) For dipropylene glycol and monopropylene glycol, there are chronic and sub-chronic studies in the rat. For dipropylene glycol there is also chronic and sub-chronic data in the mouse and for monopropylene glycol further data on the cat. There is the suggestion of a slight increase in toxicity as molecular weight increases, however any differences should consider the wide gaps between doses used and hence between the NOAELs and LOAELS. Cats are known to be uniquely sensitive to monopropylene glycol (Bauer 1992, Christopher 1989). Excluding this species, the NOAEL for monopropylene glycol in the rat is likely in excess of 2000 mg/kg bw/day and for dipropylene glycol in the range 500-3000 mg/kg bw/day (and for mouse in the range 1000 mg/kg bw/day). For tripropylene glycol the screening study does suggest higher toxicity, with a NOAEL of 200 mg/kg bw/day and a LOAEL of 1000 mg/kg bw/day, although this still overlaps with where the possible true NOAEL could lie for dipropylene glycol. Coupled with the fact that the data for dipropylene glycol indicates no progression in severity of findings (at least in terms of the NOAEL in moving from sub-chronic to chronic exposure), it can be concluded from the available data and taking the ‘worse case’ result that a sub-chronic study on the target substance tripropylene glycol would not cause adverse specific organ toxicity at doses at the STOT RE 2 guidance value of 100 mg/kg bw/day or less. The third and fourth components of this multi-constituent substance are tetrapropylene glycol and pentapropylene glycol. From the considerations of similarity and predictability of change across the propylene glycol homologous series, it can be concluded that the repeat dose toxicity of these components will be similar to tripropylene glycol. None of the components of ‘propane-1,2-diol, propoxylated’ meet the criteria for STOT(RE) classification. Data on the components can be considered representative of the substance itself, which would lead to the conclusion that the multi-constituent substance of ‘propane-1,2-diol, propoxylated’does not need to be classified for STOT(RE) in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.