Reaction product with n-butanol of high-boiling stream resulting from the hydroxylation, oxidative cleavage and hydrolysis of vegetable oil saturated and unsaturated C16-C22 triglycerides.

Endpoint summary

Description of key information

A conservative NOAEL of 218 mg/kg bw/d was determined for FAV-ES based on effects observed in a combined repeated dose / reprotox screening test performed on one of the read-across substances.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: recent GLP and OECD guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crj:CD(SD)IGS

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Males: 14 days before mating, 28 days afterwards Females: total of 42-53 days beginning 14 days before mating to day 4 of lactation

Frequency of treatment:

7 days/week

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

13

Control animals:

yes, concurrent vehicle

Dose descriptor:

LOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical chemistry; body weight; organ weight

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical chemistry; body weight; organ weight

Critical effects observed:

not specified

CLINICAL SIGNS AND MORTALITY: There was no mortality related to the test substance treatment. No changes were observed on general clinical observation, nor were scores obtained by detailed clinical observations between control and the test substance-treated groups.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was suppressed in males of the 1000 mg/kg bw/day-treated group (see Table 1)

FOOD CONSUMPTION
No effects were observed in males and females of the test substance-treated groups.

HAEMATOLOGY
No effects were observed in males of the test substance-treated groups. A decrease in white blood cells (WBC) and a shorter activated partial thromboplastin time were observed in females of the 1000 mg/kg bw/day dose group. But these change were not considered as adverse effects because of no accompanying changes. A decrease in WBC was observed in females of the 1000 mg/kg bw/day dose group.

CLINICAL CHEMISTRY
An increase in albumin/globulin (A/G) ratio was found in males at 1000 mg/kg bw/day and in females at 300 mg/kg bw/day and higher. Decreases in total protein, creatinine and calcium were observed in females at 1000 mg/kg bw/day. The increase in A/G ratio noted in females at 300 mg/kg bw/day was not considered as an adverse effect because of no accompanying changes (see Table 2). Decreases in glucose and alkaline phosphatase observed in females of 100 mg/kg bw/day group and 300 mg/kg bw/day, respectively, were incidential observations and thus considered non-adverse.

NEUROBEHAVIOUR
No neurobehavioural abnormalities were observed in the test substance-treated groups.

ORGAN WEIGHTS
Increases in a relative weight of liver and absolute and relative weights of kidney for males and increases in relative weights of liver and kidney for females were observed in the 1000 mg/kg bw/day group (see Table 3).

GROSS PATHOLOGY
No adverse effects were observed for males and females.

HISTOPATHOLOGY: NON-NEOPLASTIC
Tendency of increase in hypertrophy of centrilobular hepatocytes and a reduction in the grade of periportal fatty change were observed in males of the 1000 mg/kg bw/day group

Conclusions:

Based on the findings observed at 1000 mg/kg bw/day, the NOAEL for repeated dose toxicity was considered to be 300 mg/kg bw/day.

Executive summary:

The repeated dose toxicity of bis(2-ethylhexyl) azelate was studied in a combined repeated dose and reproductive / developmental toxicity screening test according to the OECD 422 guideline. Male animals (13 per dose) received the test substance every day, starting 14 days before mating until 28 days afterwards. Female animals (13 per dose) received the test substance every day, starting 14 days before mating until day 4 of lactation. Total exposure duration therefore is between 42 and 53 days. The daily dose was 100, 300 or 1000 mg/kg bw/d.

Based on findings of increased relative liver and kidney weights, a tendency for increase in hypertrophy of centrilobular hepatocytes and a reduction in the grade of periportal fatty change observed in animals of the highest dose group, a NOAEL of 300 mg/kg bw/d was established.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

218 mg/kg bw/day

Study duration:

subacute

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

Literature publications are available in which the repeated dose toxicity data of a number of read-across substances has been described:

The repeated dose toxicity of dibutyl adipate was examined in a 28d test similar to the OECD 407 guideline (28-day test in rodents). The test substance was administered to male and female SD rats at doses of 0, 20, 140 and 1,000 mg/kg/day via oral gavage for 14 days. Test groups consisted of 6 animals per sex per dose. No test substance-related changes were noted in clinical observations, body weight gains, food consumption, and the findings obtained from hematology testing, blood chemical examination, urinalysis, and pathological examination. The NOAEL of dibutyl adipate therefore is considered to be 1000 mg/kg/day in both sexes.

The repeated dose toxicity of dibutyl sebacate was examined for a period of 2 years, in which groups of male Sprague-Dawley rats were treated with the test item offered via feed. 16 animals per dose level were used. The tested dose levels were 0.01, 0.05, 0.25, 1.25 and 6.25%. No test substance-related changes were noted in clinical observations, body weight gains, food consumption, and the findings obtained from hematology testing, blood chemical examination, urinalysis, and pathological examination. The NOAEL for dibutyl sebacate was considered to be 6000 mg/kg/day.

The repeated dose toxicity of butyl stearate was examined for a period of 2 years, in which groups of male Sprague-Dawley rats were treated with the test item offered via feed. 16 animals per dose level were used. The tested dose levels were 0.01, 0.05, 0.25, 1.25 and 6.25%. No test substance-related changes were noted in clinical observations, body weight gains, food consumption, and the findings obtained from hematology testing, blood chemical examination, urinalysis, and pathological examination. The NOAEL for butyl stearate was considered to be 6000 mg/kg bw/day.

The repeated dose toxicity of medium- and long chain triacylglycerol (MLCT) was examined for a period of 6 weeks, in which 6-week old Wistar rats received a daily dose of ca. 3500 mg/kg bw via the diet. A limited number of examinations were performed. From this study, a NOAEL of 3500 mg/kg bw/d was determined for MLCT.

 

The repeated dose toxicity of medium chain triglycerides (MLT) to dogs was examined by daily dietary exposure of male and female beagle dogs via the diet for a period of 91 days. The dogs were fed a diet containing medium chain triglycerides at levels of 0%, 5%, 10%, and 15% MCT added to conventional feed. There were no signs of toxic effects observed in any of the animals that were related to feed, and the animal viability was 100% at the end of the study. Based on examination of clinical signs, body weight measurements, food consumption level, physical examinations, hematology and serum chemistry, ophthalmic examinations and urinalysis the NOAEL for medium chain triglycerides was found to be 15%, which was calculated to be approximately 3750 mg/kg bw/day.

 

The repeated dose toxicity of bis(2-ethylhexyl) azelate was studied in a combined repeated dose and reproductive / developmental toxicity screening test according to the OECD 422 guideline. Male animals (13 per dose) received the test substance every day, starting 14 days before mating until 28 days afterwards. Female animals (13 per dose) received the test substance every day, starting 14 days before mating until day 4 of lactation. Total exposure duration therefore is between 42 and 53 days. The daily dose was 100, 300 or 1000 mg/kg bw/d. Based on findings of increased relative liver and kidney weights, a tendency for increase in hypertrophy of centrilobular hepatocytes and a reduction in the grade of periportal fatty change observed in animals of the highest dose group, a NOAEL of 300 mg/kg bw/d was established.

 

Based on these data it can be reasonably assumed that FAV-ES will not exert distinct toxicity following repeated exposure. In accordance with the precautionary principle, the NOAEL derived for bis(2-ethylhexyl) azelate (300 mg/kg bw/d) can be converted to a NOAEL for FAV-ES. As FAV-ES is a UVCB substance, it has a broad molecular weight distribution, ranging from 300 to 1294 g/mol. Calculation of the NOAEL for FAV-ES taking into account the lowest molecular weight of 300 g/mol yields a NOAEL of 218 mg/kg bw/d, which is to be considered a (very) conservative value.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The read-across study with the lowest NOAEL was selected. Adverse effects were limited to increased relative liver and kidney weights, a tendency for increase in hypertrophy of centrilobular hepatocytes and a reduction in the grade of periportal fatty change.

Justification for classification or non-classification

Based on the results of the repeated dose toxicity testing performed on the read-across substances, FAV-ES should not be classified for Specific Target Organ Toxicity following Repeated Exposure (STOT-RE) according to the criteria described in EU Regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP). Likewise, classification for repeated-dose toxicity is not required under the conditions described in Directive 67/548/EEC (Dangerous Substances Directive).