Octadecanedioic acid, 1,18-dimethyl ester

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was performed between 23 November 2011 and 15 May 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

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 (incl. QA statement)

Remarks:

Date of inspection 2011-06-27 to 2011-07-21; Date of signature 2011-08-15

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

methyl 9-decenoate

EC Number:

662-772-0

Cas Number:

25601-41-6

Molecular formula:

C11H20O2

IUPAC Name:

methyl 9-decenoate

Details on test material:

- Name of test material (as cited in study report): 9-decenoic acid, methyl ester (9DAME)
- Physical state: clear colourless liquid
- Analytical purity: > 99 %
- Lot/batch No.: 184-113
- Date received: 2011-10-12
- Storage condition of test material: room temperature in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females).

Frequency of treatment:

Test item was administered daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 300 and 1000 mg/kg bw/day. Treatment volume (4 ml/kg) corresponding to concentrations of 7.5, 75 and 250 mg/ml respectively
Basis:

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Statistics:

Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05. Statistical analysis was performed on the following parameters: Grip Strength, Motor Activity, Body Weight, Body Weight Change, Food Consumption during gestation and lactation, Haematology, Blood Chemistry, Absolute Organ Weights, Body Weight- Relative Organ Weights

Data were analysed using the decision tree from the ProvantisTM Tables and Statistics Module

Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analysed using Bartlett’s test. Intergroup variance were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any transformed data were analysed to find the lowest treatment level that showed a significant effect, using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found, but the data shows non-homogeneity of means, the data were analysed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was
performed using the Student t-test (parametric) or the Mann-Whitney U test (nonparametric).

Data not analysed by the Provantis data capture system were assessed separately using the SPSS statistical package.
Probability values (p) were calculated as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p?0.05 (not significant)

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: oral administration of test substance was well tolerated at dosage levels of 30, 300, and 1000 mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The oral administration of 9-decenoic acid, methyl ester (9DAME) to rats by gavage, at dose levels of 30, 300 and 1000 mg/kg bw/day did not result in any toxicological significant effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day.

Executive summary:

A 28 day repeat dose oral toxicity study combined with a reproduction/ developmental toxicity screening test of the test item was performed in the Wistar rat, according to OECD Guideline 422, in compliance with GLP. The test item, 9-decenoic acid, methyl ester was administered by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 30, 300 and 1000 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP).
Clinical signs, behavioural assessments, body weight change, food and water consumption were monitored during the study. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.
The oral administration of 9-decenoic acid, methyl ester (9DAME) to rats by gavage did not result in any toxicologically significant effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day (Harlan Laboratories Ltd, 2012).