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Administrative data

Description of key information

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with rats exposed to tripropylene glycol by gavage resulted in NOAEL of 200 mg/kg bw/day, based on increased relative liver weights in male and female rats and increased relative kidney weights in male rats. Based on read-across from a structural analogue of tripropylene glycol, dipropylene glycol, a long-term NOAEL of 673 mg/kg bw'day has been derived and shall be used for the risk assessment. No studies using inhalation or dermal routes of exposure were recovered, therefore route-to-route extrapolation shall be used to derive DNELs for these endpoints.  

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
673 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data available from the substance in a screening study and sub-chronic studies for two read across substances.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No studies using inhalation or dermal routes of exposure to tripropylene glycol were available for assessment.

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, 1993). 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 (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.

In addition, 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. An NTP drinking water study in rats on a structural analogue and metabolite of tripropylene glycol, dipropylene glycol, using 90-day and 2-year exposure duration was available for assessment (National Toxicology Program, 2004). 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 inluding 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.

 

The applicability of data on dipropylene glycol for risk assessment of tripropylene glycol

The available toxicokinetic study with tripropylene glycol demonstrated tripropylene glycol to be rapidly metabolized to dipropylene glycol and monopropylene glycol, which is then further oxidized to CO2(Dow Chemical Company, 1995). As can be seen from the reported above data on dipropylene glycol, its administration to F344 rats by drinking water for 13 weeks produced significant increases in absolute and relative liver weights of males and females at 10,000 ppm (890 mg/kg bwt/day for males; 920 mg/kg bwt/day for females) and greater concentrations, resulting in a NOAEL of 425 and 460 mg/kg bw/day for male and female rats, respectively. These increases in liver weight were not accompanied by histopathological changes, which were present only at dose levels of 20000 ppm (1690 mg/kg bw/day for males; 1840 mg/kg bw/day for females) and above.Exposure to 20000 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.The same type of effects (increases in liver and kidney weight in the absence of histopathological changes) were observed in the in the available combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with tripropylene glycol at approximately the same dose levels (1000 mg/kg bw/day). As tripropylene glycol is rapidly metabolized to dipropylene glycol, 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. In summary, as tripropylene glycol is metabolized to dipropylene glycol and similar liver and kidney responses are observed for both substances in subchronic studies at similar dose levels, the liver histopathology change (bile duct hyperplasia) observed in the chronic study for dipropylene glycol would be reasonably expected to be observed for comparable chronic exposures for tripropylene glycol. 

Hence it is considered to be acceptable to use the NOAEL of 470 mg/kg bw/day and 530 mg/kg bw/day for male and female rats, observed in the 2-year drinking water study for dipropylene glycol, as a point of departure for risk assessment and DNEL derivation in case of tripropylene glycol. Applying a correction for a greater molecular weight of tripropylene glycol (192.3 g/mol vs. 134.2 g/mol for dipropylene glycol), a NOAEL of 673 mg/kg bw/day has been derived and shall be used for risk assessment.

A full justification for read across within the propylene glycol series is contained in a separate document attached to chapter 13 of the lead registrants IUCLID dossier.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Multiple key studies.

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

Justification for classification or non-classification

Based on the results of the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with rats (observed NOAEL = 200 mg/kg bw/d, which is above the cut-off value of 50 mg/kg bw/day established for a 90-day study) and the available results of a 2 -year drinking water study with a structural analogue and metabolite of tripropylene glycol, dipropylene glycol (NOAEL = 470 mg/kg bw/day), classification is not warranted according to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.