Registration Dossier

Diss Factsheets

Administrative data

Description of key information

No toxicity after repeated exposure was observed with the main constituents of Fusel oil, being ethanol (CAS No. 64-17-5), 3-methylbutan-1-ol (CAS No. 123-51-3), 2-methylbutan-1-ol (CAS No. 137-32-6), and 2-methylpropan-1-ol (CAS No. 78-83-1). For all 4 substances the NOAELs were ≥ 1000 mg/kg bw/day after oral exposure. The minor constituents of Fusel oil have no influence on the toxicity after repeated exposure based on the absence of a hazard and their low concentration. The available data from the main constituents of Fusel oil indicate that Fusel oil is not toxic after repeated exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 068 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Fusel oil is a UVCB substance comprising a complex mixture of alcohols, aldehydes, esters and other substances. The constituents and their concentration ranges are known. Fusel oil contains 4 main constituents being above ≥ 10%. In total, the 4 main constituents account for ≥ 80% of all constituents. In order to fulfil the standard information requirements set out in Annex IX in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from surrogate substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from surrogate substances (grouping or read-across).

The physicochemical, toxicological and ecotoxicological properties of the main constituents of Fusel oil determine, to a great extent, the physicochemical, toxicological and ecotoxicological properties of Fusel oil itself. Therefore, having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, 1.5, of Regulation (EC) No 1907/2006, a read-across is appropriate as their physicochemical, toxicological and ecotoxicological properties are likely to be similar. A detailed justification for use of read-across is given in chapter 13 of the technical dossier.

In conclusion, hazard assessment was based on the main constituents, when no experimental data was available with Fusel oil itself. The main constituents are ethanol (CAS No. 64-17-5), 3-methylbutan-1-ol (CA 123-51-3), 2-methylbutan-1-ol (CAS No. 137-32-6), and 2-methylpropan-1-ol (CAS No. 78-83-1).

Repeated exposure, oral route

A study, which was performed according to OECD 408 and in compliance with GLP, is available for 2-methylpropan-1-ol (CAS No. 78-83-1) (Schilling et al., 1997). Ten Wistar rats per sex and dose were treated by gavage with 75, 300, 1251 mg/kg bw (males) and 91, 385, 1657 mg/kgbw (females). The animals were treated oncedaily, 7 days per week for 90 days. No clinical signs attributable to the administration of 2-methylpropan-1-ol were observed throughout the study period. One animal of the control group was found dead after 42 days of the study. No effects on body weight and body weight gain were observed. Marginal increase of food consumption was observed in the low dose males and sporadically in the low dose females. On account of the isolated occurrences and the lack of a corresponding dose-response relationship, the observed slight increases in food consumption were assessed to be incidental in nature. No effects on haematology and clinical chemistry parameters were observed. No differences in organ weights between control and treated groups were observed. The macroscopical examination for gross lesions at necropsy did not reveal any substance-induced changes due to the administration of 2-methylpropan-1-ol. Histopathological changes of the testes (tubular degeneration and diffuse hyperplasia of Leydig’s cells), the spleen (minimal increase in extramedullary hematopoiesis) or the kidneys (dilation of the renal pelvis) occurred sporadically in control or test substance treated groups. In conclusion, as no adverse effects were observed after treatment of rats, NOAELs of≥ 1251and ≥ 1657 mg/kg bw/day was deduced for male and female animals. Data from a further subchronic study in rats also reported a NOAEL of ≥ 1000 mg/kg bw/day (TRL, 1985).

A study performed according to OECD 408 and in compliance with GLP is available for 3-methylbutan-1-ol (CAS No. 123-51-3) in rats (Schilling et al., 1997). Ten Wistar rats per sex and dose were treated by gavage with 73, 295, 1068 mg/kg bw (males) and 90, 385, 1431 mg/kg bw (females) once daily, 7 days per week for 90 days. No clinical signs and no mortality attributable to the administration of the test substance were observed throughout the study period. No effects on body weight, body weight gain, and food consumption were observed. No treatment-related effects were observed after the ophthalmoscopic examination. In the high dose group males an increase in the erythrocyte (RBC) values, a reduction in the mean corpuscular volume (MCV), and a decrease in the mean corpuscular hemoglobin (MCH) was observed. In addition, the erythrocyte count was slightly elevated in the males of the 295 mg/kg bw dose group. Statistically significant deviations from the control group figures were found in the leukocyte count (WBC) in the males of the low dose group and in the prothrombin time in the females of the 385 and 1431 mg/kg bw groups. In both cases the observed effects do not appear to be relevant to the treatments, since the determined values fell within the range of biological variation. Additionally, with regard to leukocytes counts, no relationship to the administered substance concentration was observed; the change in prothrombin time was only registered in females. No differences in organ weights between control and treated groups were observed. The macroscopic examination for gross lesions at necropsy did not reveal any substance-induced changes due to test substance administration. In the histological examination, ectopia of thymus tissue in the region of the thyroid glands was found in one male and two female animals of the control group as well as in five males of the high dose group. In conclusion, as no adverse effects were observed after treatment of rats, a NOAEL of ≥ 1068 and ≥ 1431 mg/kg bw/day was deduced for male and female rats, respectively. Data from a further subchronic study in rats also reported a NOAEL of ≥ 1000 mg/kg bw/day (Carpanini, 1973).

A study performed similar to OECD 408 and in compliance with GLP is available for ethanol (CAS No. 64-17-5) (Procter and Gamble, 1982). 21 Sprague-Dawley rats per sex and dose were treated daily by gavage with5, 10, 20 mL/kg of a test mixture containing 16.25% ethanol, water and another substance regarded as inert or with 4 mL of pure ethanol for 14 weeks. Interim kills were performed after 7 weeks. The daily dose was administered in two treatments per day resulting in a total daily dose volume of 20 mL/kg. One rat in the water control and 5 rats in the ethanol treated group died spontaneously or were sacrificed in a moribund condition during the study. Clinical observations and necropsy lesions supported aspiration of gavage fluid or gavage related trauma as being the cause of all these deaths except one (a rat in the ethanol group). Generally, rats in the ethanol group were noted to struggle during gavage, which increased the likelihood of gavage accidents. Occasionally, animals became dyspneic or developed a bloody nasal discharge following gavage but recovered later. These symptoms, which were attributed to aspiration of gavage fluid, occurred more frequently in the ethanol group. No comparison between pure ethanol treated animals and the water control was reported regarding body weight, body weight gain, and food efficiency. In the groups treated with 16.25% ethanol no differences were observed in weekly body weights and total body weight gains as well as for food efficiency. No statistically significant differences between treatment and control groups were observed. No ocular changes were seen during the study. No effects on haematology or clinical chemistry parameters as well as urinalysis were reported. Adrenal weights of female rats were increased by exposure to the ethanol (100%) group. All abnormalities after gross pathology occurred at very low frequency and were interpreted to be due directly or indirectly to the method of treatment rather than the test substance. Minimal focal to multifocal renal tubular epithelial hyperplasia occured at higher frequencies in rats given 20 mL/kg mixture containing ethanol (16.25%) and the 4 mL/kg (100%) ethanol by gavage versus rats given 20 mL/kg water by gavage. It was noted that renal tubular epithelial hyperplasia is a common incidental finding in laboratory rats and it is uncertain whether the higher incidence of this lesion in the ethanol dosed rats compared with water controls is due to a random variation or to ethanol. In conclusion, based on the renal effects observed in the 20 mL/kg mixture containing ethanol and 4 mL ethanol (100%) dose group, a NOAEL of 10 mL/kg mixture containing 16.25% ethanol equivalent to 1730 mg/kg bw was deduced for rats. The LOAEL was 3160 mg/kg bw.

Further subchronic data from rats reported NOAELs of 3250 and 3900 mg/kg bw/day in a drinking water and feeding study (NTP, 1996; Holmberg, 1986). In the NTP (1996) study a LOAEL for the females of < 4400 mg/kg bw/day was deduced based on small but clear and significant histopathological changes in the liver (diaphragmatic nodules), accompanied by a non-statistically significant liver weight increase, and an increase in nephropathy (although male rats showed 100% evidence of this in every dose group including controls). In the second study a LOAEL of 5850 mg/kg bw/day was deduced based on effects on the liver (Holmberg, 1986). In a subchronic drinking water study mice were dosed with ethanol at a level of 5%. A NOAEL of > 5% (> 9400 mg/kg bw/day) was selected for females and a LOAEL of 9700 mg/kg bw/day for males.

The effect of chronic ethanol feeding was determined on parameters of hepatic collagen metabolism in monkeys (Mezey, 1983). The animals were fed a nutritionally adequate diet with 50% of the calories provided as ethanol (equivalent to 6200 mg/kg bw/day) with controls consuming ethanol isocalorifically substituted by carbohydrate. Feeding was carried out for 48 months, with intermediate liver biopsies taken at 3, 12 and 24 months. Blood and urine were monitored to determine ethanol concentrations. The ethanol fed animals developed various degrees of liver fatty infiltration but no necrosis, inflammation or fibrosis. There was no effect on the amount or distribution of collagen types, liver free proline or protein bound hydroxyproline levels or in collagen prolyl hydroxylase activity. A no effect level was not established due to the fatty infiltration. The NOAEL was established at 6200 mg/kg bw/day, based on the fact that no cirrhosis and fibrosis was observed, which are the typical adverse effects of ethanol exposure.

Repeated exposure, inhalation route

In the subacute studies a NOAEC of > 20 mg/mL and > 6130 ppm was reported for ethanol (CAS No. 64-17-5) (Di Luzio and Stege, 1979; Chu et al., 2005).

Conclusion

In conclusion no toxicity after repeated exposure was observed with the main constituents of Fusel oil, being ethanol (CAS No. 64-17-5), 3-methylbutan-1-ol (CAS No. 123-51-3), and 2-methylpropan-1-ol (CAS No. 78-83-1). For these substances the NOAELs were ≥ 1000 mg/kg bw/day after oral exposure. Based on the similar structure and toxicokinetics read-across from 3 -methylbutan-1-ol to 2-methylbutan-1-ol can be performed (see read-across justification document in chapter 13 of the technical dossier). Therefore no hazard is expected for 2-methylbutan-1-ol (CAS No. 137-32-6) regarding repeated dose toxicity.

The minor constituents of Fusel oil have no influence on the toxicity after repeated exposure based on the absence of a hazard and their low concentration. The available data from the main constituents of Fusel oil indicate that Fusel oil is not toxic after repeated exposure.

 

 

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Most reliable data of the main constituents of Fusel oil were used for hazard assessment.

Justification for classification or non-classification

Based on available data of the main constituents of Fusel oil on repeated dose toxicity, Fusel oil does not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.