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.

Repeated dose toxicity: oral

Administrative data

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

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

2003

Reference 2

Reference Type:

secondary source

Title:

Bis(2-ethylhexyl) azelate

Author:

OECD

Year:

2006

Bibliographic source:

SIDS Initial Assessment Report for SIAM 22, Paris, France, 18-21 April, 2006

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-ethylhexyl) azelate

EC Number:

203-091-7

EC Name:

Bis(2-ethylhexyl) azelate

Cas Number:

103-24-2

IUPAC Name:

bis(2-ethylhexyl) azelaate

Details on test material:

- Name of test material (as cited in study report): Bis(2-ethylhexyl)nonanedioate
- Analytical purity: 77.2%
- Impurities (identity and concentrations):
Bis(2-ethylhexyl)glutarate 2.2%,
Bis(2-ethylhexyl)adipate 2.4%,
Bis(2-ethylhexyl)pimelate 2.8%,
Bis(2-ethylhexyl)suberate 3.8%,
Bis(2-ethylhexyl)sebacate 3.3%,
Bis(2-ethylhexyl) 1-,9-nonamethylenedicarboxylate 5.3%,
Bis(2-ethylhexyl)1-,10-decamethylenedicarboxylate 0.6%,
Bis(2-ethylhexyl)1-,11-undecamethylenedicarboxylate 0.3%
- Lot/batch No.: N-31101

Test animals

Species:

rat

Strain:

other: Crj:CD(SD)IGS

Sex:

male/female

Administration / exposure

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

Doses / concentrations

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

Results and discussion

Effect levels

1

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

2

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.