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Toxicological information

Carcinogenicity

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Description of key information

No data on carcinogenicity of tripropylene glycol were available. However, no histopathological changes, including hyperplasia, were observed in the available combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, and the substance is not genotoxic. Furthermore, available long-term studies on two structural homologues and metabolites of tripropylene glycol, mono- and dipropylene glycol, showed the absence of (pre-)neoplastic lesions. Based on this evidence, tripropylene glycol is considered to be non-carcinogenic. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 800 mg/kg bw/day
Study duration:
chronic
Species:
mouse

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data on carcinogenicity of tripropylene glycol were 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.

An NTP 2-year drinking water study with rats and mice on a metabolite and structural homologue of tripropylene glycol, dipropylene glycol, was available for assessment (National Toxicology Program, 2004). In the rat study,the exposure concentrations for the 2-year drinking water study were 0, 2,500, 10,000, and 40,000 ppm, corresponding to actual average ingested doses of 115 , 470 and 3040 mg/kg bw/day in males and 140, 530 and 2330 mg/kg bw/day in females. In the study with mice, the used exposure levels were 0, 10000, 20000 and 40000 ppm, corresponding to average ingested doses of 735, 1220 and 2390 mg/kg bw/day (males) and 575, 1040 and 1950 mg/kg bw/day (females). In the rat study, dipropylene glycol-related non-neoplastic lesions were found in the kidney, liver, and nose (see Section on repeated dose toxicity for more details). In the mice study, no compound-related neoplasms or non-neoplastic lesions were observed; only the reduced body weights (see Section on repeated dose toxicity for further details). In conclusion, no evidence of carcinogenic activity of dipropylene glycol was observed in either rats or mice in the 2 -year drinking water study.

Also two long-term studies with rats, using 2 years and 140 days exposure duration, and a 104 -week study with dogs with another metabolite and structural homologue of tripropylene glycol, monopropylene glycol, were 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. No adverse effects and no histopathological changes, including (pre-) neoplastic lesions, 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.

In the old study of Seidenfeld et al., 1932, with only limited parameters examined, groups of 5 rats were administered propylene glycol in drinking water as 0, 1, 2, 5, 10, 25 and 50% solutions for 140 days, corresponding to average daily doses of 1600, 3680, 7700, 13200, 21000 and 37000 mg/kg bw/day, respectively. Histopathological examination was performed on kidneys, hearts, spleens and livers. All animals given 25% or 50% propylene glycol in water died within the first 9 days of treatment. No adverse effects were noted in other dose groups, resulting in NOAEL of 13200 mg/kg bw/day.

In the 104-week study with dogs reported by Weil et al., 1971, groups of 5 male and 5 female beagle dogs were fed diets containing monopropylene glycol at dosage levels of 5000 and 2000 mg/kg bw for 2 years. A second series of animals was given an isocaloric amount of dextrose mixed with food (2540 and 6350 mg/kg bw/day) and served as another set of controls. Micropathology was performed at the end of the study period. Apart from a slight increase in bone marrow activity in female dogs from the high dose group, histopathological lesions occurred with comparable severity and incidence in the treated, control and equicaloric control groups. The change in bone marrow activity was considered a physiological, rather than a toxicological, response. Overall, there were no adverse, treatment-related histopathological changes linked to chronic ingestion of propylene glycol.

Using the lowest NOAEL of 1700 mg/kg bw/day, observed in the 2-year dietary study with rats on monopropylene glycol as a point of departure, and applying a correction for a greater molecular weight of tripropylene glycol (192.3 g/mol vs. 72.1 g/mol for dipropylene glycol), a NOAEL of 4300 mg/kg bw/day is derived. However, using the figure of 1950mg/kg as the NOAEL from the DPG drinking water study in mice, leads to a NOAEL of 2800mg/kg bw/day (with a molecular weight correction based on 192.3g/mol for TPG and 134.2g/mol for DPG). Since the latter is more conservative, this is used as the key value for this end point.

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 classification or non-classification

Based on the lack of genotoxicity for tripropylene glycol and the absence of preneoplastic lesions in the available repeated dose toxicity study, as well as the evidence from the available studies on structural homologues and metabolites of tripropylene glycol, mono- and dipropylene glycol, classification of tripropylene glycol for carcinogenicity is not warranted in accordance with Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.