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Description of key information

Repeated dose toxicity:
The oral NOAEL was found to be 1000 mg/kg bw/day.

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
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Several study results on the test substance itself as well as read across data were considered reliable and suitable for assessment in a weight of evidence approach.

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

Oral route:

To evaluate the toxicity after repeated dosing, a study performed in large part equivalent to OECD guideline 408 can be used for assessment (Butterworth et al. 1978). 15 ASH/CSE rats per sex and dose received volumes of 5 mL/kg bw/day pentan-1-ol at doses of 50, 150, 1000 mg/kg bw/day in corn oil via gavage for 13 weeks. During the study, the animals were weighed initially, at days 1, 2 and 6 and then at intervals of not more than 1 week up to day 91 of the study. Also, food and water consumptions were measured over the 24-hr period preceding the day of weighing.

At the end of study, blood and urine were collected and haematological examination and serum analyses as well as urinalysis were performed. At autopsy all the tissues were examined for gross abnormalities and selected organs were examined by histopathology.

As result no abnormalities in appearance or behaviour were observed during the study and no significant differences between the treated and control rats in body weight or in food and water consumption were found. Although some isolated changes were observed in haematology pattern like a reduction in haemoglobin concentration in the male rats after 13 weeks, no consistent pattern with respect to dose-response, sex or time relationships was found. As this was also the case for isolated changes in organ weights, and no other effects on renal function, organ weights or histopathology could be detected, the highest dose of 1000 mg/kg bw can be seen as the NOAEL of pentan-1-ol.

 

In addition, there are data available from the structural analogue 3-methylbutan-1-ol (CAS No. 123-51-3) that was tested in a Combined repeated-dose / reproductive developmental toxicity study similar to OECD TG 422 and in compliance with GLP regulations (Kuraray Co. Ltd. 2008). The substance was administered to groups of 12 male and 12 female Sprague-Dawley strain SPF rats at dose levels of 0 (control group), 30, 100 or 300 mg/kg bw for a total of 42 days to males (for 14 days before mating throughout the mating period up to the day before necropsy) and for a total of 41 to 53 days to females (for 14 days before mating throughout the mating and gestation periods up to day 4 of lactation) to examine its repeated dose toxicity and reproductive and developmental toxicity. For 5 males and 5 females in the 0 and 300 mg/kg bw groups, a 14-day recovery period was provided after administration for 42 days to examine reversibility of the toxic changes. The females in the recovery group were treated additionally to the main groups and were not subjected to mating. No deaths occurred in any group, and there were no test article-related effects in clinical observation, detailed clinical observation, manipulative test, measurement of grip strength, measurement of motor activity, food consumption, urinalysis (including water intake), haematological examination, blood chemistry examination, organ weight, histopathological findings or gross pathological examination. In the measurement of body weight, a low value in body weight gain (from day 1 to day 42) during the administration period was observed in males of the 300 mg/kg bw group. During the 2-week recovery period, the body weight gain of males in the recovery group of the 300 mg/kg bw group was higher than that of the control group. Based on the results described above, it was judged that the no adverse effect levels for repeated dose toxicity of 3-methylbutan-1-ol were 100 mg/kg bw /day in males and 300 mg/kg bw /day in females. As the changes were slight, not accompanied by any further alterations, and these effects were not observed in two 90 day studies at higher doses, these values were not chosen as key parameter for the assessment of repeated dose toxicity.

 

Repeated dose toxicity of 3-methylbutan-1-ol was further investigated in a 90 day drinking water study performed according to OECD guideline 408 and in compliance with GLP regulations (BG-Chemie 1990). Ten Wistar rats per sex and dose received nominal concentrations of 1000, 4000 and 16000 ppm 3-methylbutan-1-ol corresponding to approx. 80, 340, 1250 mg/kg bw /day in the drinking water for 3 months. For comparison, one group of untreated animals (10 males, 10 females) was used as a control. Feed consumption, water consumption and body weight were determined once a week. The animals' state of health was checked each day, and once a week they were also subjected to an additional exact clinical examination. Prior to the beginning and towards the end of the study, ophthalmological examinations were carried out in the animals of the control and 16000 ppm group. One clinicochemical and one haematological examination were carried out toward the end of the study. At the end of the 3-month administration period all animals were sacrificed by decapitation and were assessed by gross pathology. Subsequently, a histopathological examination was carried out.

There were no clinical signs in the sense of a toxic effect notable during the study period. Although an increased water consumption of males and females in the 1000 and 4000 ppm groups was observed, it was assessed as being no toxic effect since there was no clear dose response relationship apparent and it varied at different times in degrees of intensity.

The administration of 3-methylbutan-1-ol caused an increase in the red blood cell count and a decrease in the mean corpuscular volume and the mean corpuscular haemoglobin content of the male rats at 16000 ppm (about 1250 mg/kg bw/d). There was also a slight increase in red blood cell number in the males after treatment with 4000 ppm. These effects were generally mild in extent and occurred in only one sex. They were all in the range of biological variation, e.g. the count of red blood cells between 7.76 and 8.94 E+12/L. Since the slightly increased erythrocyte count of the males in test group 2 (4000 ppm) was also in the range of historically observed biological variations, it is questionable if these effects were related to the test substance. Moreover, the deviations in haematology parameters from those of the controls did not correlate with other biochemical, haematological or histopathology results, and are thus not characteristic for a specific toxic effect. To conclude, it can be stated that from the clinical point of view a dose level which causes clear signs of toxicity in male and female rats is above 16000 ppm (= 1250 mg/kg bw/day). Under the experimental conditions of the present study, the NOAEL of 3-methylbutan-1-ol was thus found to be 16000 ppm (about 1250 mg/kg bw /d) for the male and female rats.

 

Additionally, a publication is available where a NOAEL was derived after repeated oral exposure for 119 days in rats (Carpanini et al.1973). Groups of 15 male and 15 female rats were given daily doses of 0(control), 150, 500 or 1000 mg 3-methylbutan-1-ol/kg body weight for 17 weeks. There were no effects associated with treatment in the results of the haematological examinations, serum analyses, urinary cell counts, renal concentration tests, or organ weights. A slightly reduced rate of body-weight gain at the highest dose level in males was shown to be due to a reduced food intake. Two rats given 1000 mg/kg/day died, but histopathological examination showed that these deaths were due to dosing into the lungs and not to any toxic effects of isoamyl alcohol. The no adverse effec level in this study was 1000 mg/kg/day.

 

As a conclusion, the oral NOAEL for repeated dose toxicity was determined to be 1000 mg/kg bw/day for all category members. A detailled read across justification is attached in IUCLID chapter 13. 

 

 

Inhalation:

There are no valid data available for pentan-1-ol concerning repeated dose toxicity by the inhalation route.

 

 

Dermal route:

There are no data available concerning repeated dose toxicity by the dermal route.

 

 

Other routes:

In a publication (Stoner 1973) it is described how the maximum tolerable dose (MTD) in 5 female mice was determined after 6 ip injections over a 2-week period. The post exposure period was 1-2 months. Doses of50 and 250 mg/kg/bw (nominal) were applied. As a result, the MTD was found to be 6000 mg/kg bw in the female mice.

 

 

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
reliable study, suitable for assessment

Justification for classification or non-classification

The available data are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008 (CLP).

As a result, the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation No (EC) 1297/2014.