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Administrative data

Description of key information

13-week drinking water toxicity study in Fischer 344 rats, Reproduction/Developmental Toxicity Screening Test in CRL:CD(SD) Rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

In a 13 week drinking water toxicity study (as per OECD TG 408 and in accordance with the principles of GLP) conducted in Fischer 344 rats, four groups of 10 male and 10 female were given drinking water solutions at levels of 50, 150 and 500 mg Dipropylene glycol n-propyl ether (DPnP)/kilogram body weight/day (mg/kg/day) for 13 weeks to evaluate the potential for systemic toxicity. Standard toxicologic parameters were evaluated. Treatment-related effects consisted of an increased absolute and relative liver weight for males given 500 mg/kg/day, decreased water consumption for females given 500 mg/kg/day, decreased urine volume in males and females given 500 mg/kg/day, increased urine specific gravity for females given 500 mg/kg/day and an increase in cholesterol of males given 500 mg/kg/day.

The differences in liver weight and cholesterol were likely due to the induction of organelles required for the metabolism of DPnP and altered lipid metabolism, respectively, and were not toxicologically significant.Alterations in urinary parameters for females were directly attributed to decreased water consumption.

The no-observed-adverse-effect level (NOAEL) for male Fischer 344 rats was the targeted concentration of 500 mg/kg/day. The no-observed-effect level (NOEL) for males and females was 150 mg/kg/day.

In a Reproduction/Developmental Toxicity Screening Test in CRL:CD(SD) Rats (as per OECD TG 421 and in accordance with the principles of GLP), groups of 12 male and 12 female CRL:CD(SD) rats were administered Dipropylene Glycol n-Propyl Ether (DPnP) daily, by gavage at dose levels of 0 (control), 100, 300, or 1000 mg/kg/day. Females were dosed once daily for two weeks prior to breeding, through breeding (two weeks), gestation (three weeks), and lactation up to postpartum day 4. Females were necropsied on postpartum day 5. Males were dosed two weeks prior to breeding and continuing through breeding (two weeks) until necropsy (test day 29). Effects on reproductive function as well as general toxicity were evaluated. In addition, postmortem examinations included a gross necropsy of the adults with collection of organ weights and histopathologic examination of tissues. Litter size, pup survival, sex, body weight, and the presence of gross external abnormalities were also assessed.

Administration of 1000 mg/kg/day of DPnP resulted in treatment-related parental toxicity in males and females consisting of increases in the incidence of hepatocellular hypertrophy and corresponding increases in absolute and relative liver weights. In addition, absolute and relative kidney weights were increased in males and females at this dose level. Microscopic examination of the kidneys revealed hyaline droplet formation in the proximal renal tubules of males given 1000 mg/kg/day, but there were no treatment-related histopathologic findings in the kidneys of high-dose females. Transient, excess salivation was noted in the majority of high-dose males and females immediately after dosing, but was considered to be a local response and of no toxicological significance. Accompanying the parental toxicity at 1000 mg/kg/day was a slight, treatment-related increase in post implantation loss, along with a corresponding slight increase in gestation survival and very slight decrease in litter size. One high-dose female also had a difficult birth and retained placentae, although the relationship of this finding to treatment is equivocal. There was no parental or reproductive toxicity at 300 or 100 mg/kg/day.

Based on these results, the no-observed-effect level (NOEL) for parental and reproductive toxicity and was 300 mg/kg/day.

Justification for classification or non-classification

Based on the results of the study and Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging of substances and mixtures, dipropylene glycol n-propyl ether will not be classified for repeated dose toxicity, i.e. STOT (RE).