Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-

Endpoint summary

Description of key information

A GLP-study according to OECD guideline 422 is available for TPnB-highers. In addition a 90-day drinking water study in rats - conducted according to GLP and OECD guideline 408 - is available for the structural analogue TPnB.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Additional information

An OECD guideline 422 is available for TPnB-highers. In addition, a 90-day drinking water study in rats is available for the structural analogue tripropylene glycol n-butyl ether (TPnB).

TPnB and TPnB-highers are closely related in molecular structure and physicochemical properties and thus, the potential for toxicological effects. They are liquids with similar physical chemical properties. Increasing boiling point and vapor pressure are consistent with increasing molecular weight. No major differences in the toxicological profile have been observed between other members of the propylene glycol n-butyl ether family (e.g. propylene glycol n-butyl ether, dipropylene glycol n-butyl ether and tripropylene glycol n-butyl ether). The effects observed consistently with propylene glycol ethers in repeated dose studies are increased liver and kidney weights at high dose levels. For propylene glycol methyl ether and other glycol ethers for which liver effects have been observed these have been interpreted to be adaptive changes associated with increased metabolism. The kidney effects as observed with propylene glycol methyl ether were apparent in male rats only and were identified to be related to alpha 2µ-globulin nephrophathy. Moreover, no effects on the kidney were observed in the repeated dose study with TPnB-highers.

In an OECD 422 study in rats via oral gavage administration of TPnB-highers, treatment-related effects in males and females were observed in the 500 mg/kg/day dose group including transient clinical observations, higher liver weights, and liver and thyroid gland hypertrophy. Clinical observations included perioral soiling (all animals, most test days) and occurrences of: muscle twitches (both sexes, lower incidence and frequency in males), incoordinated gait (females only) and decreased activity (females only). All clinical observations had an onset between 5-30 minutes post-dosing, but had completely resolved within one hour after dosing, consistent with a bolus dosing effect of a solvent compound. At necropsy, absolute and relative liver weights were higher in males and females (16-26%) compared to controls and corresponded to very slight centrilobular/midzonal hypertrophy of hepatocytes in the majority of males (9/12) and females (11/12) at this dose level (versus 1/12 male and 3/12 female controls). Additionally, there was an increased incidence of slight, diffuse thyroid gland follicular cell hypertrophy in males and females in the 500 mg/kg/day group relative to controls. There was no treatment-related toxicity in the 100 and 20 mg/kg/day dose groups and no indication of neurological toxicity at any dose level. Based upon these results, the no-observed-effect level (NOEL) for general toxicity was 100 mg/kg/day.

In a 90-day drinking water study with tripropylene glycol butyl ether (TPnB), treatment-related effects occurred in the liver and kidneys of male rats given 1000 mg/kg/day and only in liver of females given 1000 mg/kg/day. Liver effects consisted of an increase in size of hepatocytes in centribular region of hepatic lobule and were accompanied by altered staining of the cytoplasm. These effects were accompanied by an increase in liver weight of male and female rats. This alteration was not accompanied by evidence of hepatocellular degeneration and was interpreted to be an adaptive change, possibly associated with the metabolism of TPnB. Treatment related histologic liver effects were not observed in rats given 100 or 350 mg/kg/day. A slight increase in the severity of renal tubular degeneration occurred in the kidneys of three of ten males’ rats given 1000 mg/kg/day, as compared to the control male rats. This degree of change represents a minimal difference in severity over that seen in the control male rats. Alterations were not observed in sections of bone marrow or spleen that correlated with the hematologic differences statistically identified in male and female rats given 1000 mg/kg/day. Liver alterations previously identified in male and female rats given 1000 mg/kg/day for 13 weeks were not present in male and female rats given 1000 mg/kg/day followed by a 4 week period recovery. These data indicate that the liver alteration induced by 1000 mg/kg/day TPnB was reversible. One male given 1000 mg/kg/day dose followed by 4 week recovery period had a greater degree of renal tubular degeneration than occurred in concurrent controls. The incidence was lower than seen in the 13 week study also indicating that the renal lesion was reversible. Based on results of this study the NOAEL for male and female rats was 1000 mg/kg/day.

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

Justification for classification or non-classification

The no observed adverse effect level for TPnB-highers exceed the values triggering classification. Therefor,e no classification for prolonged exposure is required.