Alcohols, C13-15-branched and linear

Endpoint summary

Description of key information

The NOAEL for oral repeated dose toxicity was 150 mg/kg bw after oral administration (gavage) in an OECD 406 study, based on the structural analogue CAS 10042-59-8.

In support, the NOAEL in an OECD 422 (BASF, 2022) with C13-C15 alcohol was 1000 mg/kg bw for systemic toxicicty and reproductive performance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See justification attached to IUCLID chapter 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

food efficiency

other: based on human relevant hazards (effects due to peroxisomal proliferation: increased mean absolute and relative liver weights, diffuse hypertrophy of the liver cells, thyroid gland and pituitary gland were excluded)

Remarks on result:

other: as determined from read-across CAS 10042-59-8

Critical effects observed:

yes

Lowest effective dose / conc.:

150 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

600 mg/kg bw/day (nominal)

System:

other: reduced body weight

Organ:

other: general toxicity

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subchronic

Species:

rat

System:

other: general toxicity: reduced b.w. and food consumption

Additional information

A repeated dose toxicity test was performed with the structural analogue CAS 10042-59-8. The study was conducted according to OECD guideline 408 and fulfilled GLP criteria. Groups of 10 male and 10 female Fischer 344 rats received dose levels of 30, 150 or 600 mg/kg bw test substance per gavage for three months. Animals were observed for clinical signs at least daily. Gross and microscopic examinations were performed on all animals from all dosage groups. Also, clinical chemistry, hematology, urinalysis or ophthalmoscopic examinations were conducted and organ weights were taken. Substance-related effects were seen at 600 mg/kg in both sexes and at 150 mg/kg in females, only. No substance-related deaths occurred at 600 mg/kg bw. All males and females showed salivation one hour after administration and urine-smeared fur in the anogenital region was recorded for males and females for 3 to 4 hours after administration. At 600 mg/kg bw/day, reduced food consumption was recorded in animals of both sexes as well as impaired body weight gain including reduced body weights at the end of administration in males. Ophthalmoscopy revealed no treatment-related changes.

At 600 mg/kg bw/day, hematology showed a decrease in platelets. The toxicological relevance of this singular finding is unclear. Globulins and cholesterol were decreased in both sexes and triglycerides only in males, while albumin was increased. These changes might be indicative of increased liver metabolism. There was also an increase in cyanide- insensitive palmitoyl-CoA-oxidation in both sexes, which is typical for peroxisome proliferation. Correspondlingly, pathology showed an increased absolute and relative liver weight in both sexes, which was associated with diffuse hepatic hypertrophy. There was also a loss of fatty infiltration of liver cells in males only. Diffuse follicular hypertrophy in the thyroid gland in males and vacuolation of basophilic (thyrotrophic) cells in the glandular part of the pituitary gland in males are also secondary to peroxisome proliferation and parallelly induced xenobiotic metabolism, which results in an increased elimination of T3/T4 from rat serum by increased glucuronidation. At 150 mg/kg bw/day, one female showed diffuse hepatic hypertrophy, resulting in an increase in relative liver weight in one female only. Thus, the NOAEL was 150 mg/kg bw/day in males and 30 mg/kg bw/day in females mainly based on liver effects indicative for peroxisomal proliferation. Peroxisomal proliferation is a rodent-specific effect and not relevant for human hazard. Therefore the NOAEL relevant for human hazard is 150 mg/kg bw based on body weight effects.

 

In an OECD 422 study, the test substance C13-C15-Alcohol was administered daily to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d, test groups 1-3, respectively) to screen for potential systemic, reproductive and developmental toxicity. Control animals (10 male and 10 female Wistar rats) were dosed daily with the vehicle only (0.5% Sodium carboxymethyl cellulose suspension (CMC) in deionized water with 10 mg/ 100 mL Tween 80). The duration of treatment covered a 37 days in-life period in males (including premating, mating [mating pairs were from the same test group] and postmating period) and a 2-weeks premating and mating period, the entire gestation and approximately 3 weeks of lactation period in females. Parental females were allowed to give birth and bring up the offspring until sacrifice on PND 4 or 13. The stability of these preparations was demonstrated over a period of 7 days under ambient conditions. Analyses confirmed the overall accuracy of the prepared concentrations and the homogeneity of the test substance in the vehicle. Regarding clinical examination, no test substance related, adverse signs of (systemic) toxicity were observed up to limit dose of 1000 mg/ kg bw/d. Most of the high- and mid-dose and single low-dose animals showed temporary salivation after dosing during the entire study. Salivation occurred immediately after dosing (up to 2 hours post dosing), and also afterwards (between 2 and 5 hours post dosing). It is most likely, that this temporary finding was induced by a bad taste of the test substance or local affection of the upper digestive tract. It is, however, not considered to be an adverse toxicologically relevant finding. Neither body weight development nor food consumption were adversely affected in any of the tested dose groups. Concerning clinical pathology, no treatment-related, adverse effects were observed up to a dose of the compound of 1000 mg/kg bw/d. Regarding pathology, target organ was the liver in female animals of test group 3 which showed an increased mean relative weight. This was considered possibly treatment-related, but not adverse due to the absence of histopathological findings. All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

Target organ of both substances is the liver although the effects observed with C13-C15 are less severe. However CAS 10042-59-8 can serve as a worst case estimate and hence the read-across is valid.

Justification for classification or non-classification

Based on the available information the substance does not need to be classified for oral repeated dose toxicity, as in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.