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Description of key information

Repeated dose toxicity:
- oral (OECD 408, GLP, rat): NOAEL = 150 mg/kg bw/d (BASF 1996; 51C0279/94026; read across: 2-propyl-1-heptanol, CAS 10042-59-8 )

Key value for chemical safety assessment

Additional information

No key study for tetrahydrogeraniol is available. However, a study with the structural analogue 2-propyl-1-heptanol (CAS 10042-59-8), a C7-alcohol including a propyl-group, was taken into account for assessment. This analogue shares the same functional groups, and belongs to the group of the saturated branched chain alcohols with a similar chain length.

A subchronic oral repeated dose toxicity study was performed with 2-propyl-1-heptanol under GLP in compliance with OECD guideline 408 (BASF 1996; 51C0279/94026). Male and female Fischer 344 rats were dosed daily via gavage with 0, 30, 150 and 600 mg/kg bw/day 2-propyl-1-heptanol in Cremophor EL in distilled water for 90 days.

No substance-related deaths occurred at 600 mg/kg bw/d. During the study period, all animals of the high dose group showed salivation at one hour after administration and urine-smeared fur in the anogenital region was recorded for 4 males and 6 females for 3 – 4 hours after administration. This was seen as being the consequence of local effects of the test substance on the upper digestive tract, rather than being a systemic effect on the autonomic nervous system. Reduced food consumption in animals receiving 600 mg/kg bw/d was noted, with a statistically significant reduction up to 18% for males and up to 10% for females compared to controls. Also, an impairment of body weight change and the final body weight of the males were observed in the highest dose group.

Treatment of rats with the test substance resulted in increased mean absolute and relative liver weights in high dose male and in female rats. In mid dose females, the mean relative liver weight was also significantly increased. In high dose male and female animals, diffuse hypertrophy and loss of fatty infiltration (males only) of the liver cells was observed. The diffuse hypertrophy of the liver cells was seen in one female animal of the mid dose only. Liver findings were most likely due to peroxisome proliferation. This corresponds to the increase in cyanide-insensitive palmitoyl-CoA-oxidation in the serum of high dose animals, which is probably caused by hepatic peroxisome proliferation accompanied by induction of peroxisomal enzymes involved in oxidation of fatty acids.

In males of the high dose group, the thyroid follicular epithelium was found to be hypertrophic (in 7/10 animals) and in three of these males, the thyrotrophic basophilic cells of the anterior (glandular) part of the pituitary gland were vacuolated. This effect is considered to be a rat specific adaption of the hypothalamic-pituitary axis as a consequence of a higher rate or an accelerated metabolic degradation of T3 and/or T4 in the liver.

Decreases in platelet counts were seen in the high dose animals of either sex and were regarded to be treatment-related, although the underlying mechanism of this isolated finding remains unclear. Additionally, increases in albumin and the decreases in globulins in the high dose animals indicative for a disturbance in protein metabolism were considered to be test substance-related.

Decrease in urinary specific gravity in females, an increase in urinary volume and transitional epithelial cells (females) and an increase in squamous epithelial cells in the urine in both sexes was observed. Together, the changes seen in urinalyses of the high dose males and females are indicative signs of a mild nephrotoxic potential of the test compound at a dose level of 600 mg/kg.

 

Overall, the data show that substance-related effects were seen at 600 mg/kg in both sexes and at 150 mg/kg in females only. Thus, the NOAEL was set at 150 mg/kg bw/day for males and 30 mg/kg bw/day for females based on liver effects indicative for peroxisomal proliferation. Considering the rodent specific effects observed in the mid dose, i.e. peroxisomal proliferation, the NOAEL relevant for human hazard is set at 150 mg/kg bw.

A subchronic repeated dose toxicity study in rats with tetrahydrogeraniol is proposed in order to substantiate the data used via read across.

Justification for classification or non-classification

The present data on repeated dose toxicity do not fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008, and therefore, a non-classification is warranted.