Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

To assess reproductive/development toxicity an experimental result has been read across from a supporting substance, structural analogue 9-decanoic acid, methyl ester (EC 662-772-0):

A short-term repeat dose oral toxicity study combined with a reproduction/ developmental toxicity screening test was performed in the rat in accordance with GLP and OECD Guideline 422 . 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. There were no treatment related effects observed on mating, fertility or gestation length at any dose level. The offspring litter size, sex ratio, viability, growth and development were all comparable to controls and no adverse effects were noted. Since no treatment-related effects were observed for reproduction, a NOEL for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
The study was performed between 23 November 2011 and 15 May 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
KL2 due to RA
Justification for type of information:
Read-across justification: A comparison target substance (9DDAME) and the read-across substance (9DAME) shows that the two substances share structural similarities, increasing from a chain length of C10 to C12 with similar functional groups and also have ‘mechanistic action’ similarities.
Reason / purpose for cross-reference:
read-across source
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
Species:
rat
Strain:
Wistar
Sex:
male/female
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
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
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.

Due to the preponderance of non-normally distributed data, reproductive parameters (implantation losses, offspring sex ratio and offspring surface righting) were analysed using non-parametric analyses.

Probability values (p) were calculated as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p?0.05 (not significant)
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Remarks:
Sytemic toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The oral administration of the test substance at dose levels of 30, 300 and 1000 mg/kg mg/day did not result in any toxicologically significant effects.
Dose descriptor:
NOEL
Remarks:
Reproductive toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no treatment-related effects on mating performance
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Developmental immunotoxicity:
no effects observed
Dose descriptor:
NOAEL
Remarks:
Reproductive toxicity
Generation:
F1
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment related effects on litters when compared to controls
Critical effects observed:
no
Reproductive effects observed:
not specified
Conclusions:
The 'No Observed Effect Level' (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day. The NOAEL for systemic toxicity was also considered to be 1000 mg/kg bw/day.
Executive summary:

The reproductive toxicity of the test item 9-dodecenoic acid, methyl ester via the oral route has been read-across from the substance 9-decenoic acid, methyl ester from the following study:


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. There were no treatment related effects observed on mating, fertility or gestation length at any dose level. The offspring litter size, sex ratio, viability, growth and development were all comparable to controls and no adverse effects were noted. Since no treatment-related effects were observed for reproduction, a NOEL for reproductive toxicity was considered to be 1000 mg/kg bw/ day (Harlan Laboratories Ltd, 2012). Based on the results of the read across study, a similar NOEL can be expected for the test item.


 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

Refer to description of OECD 422 results in effects on fertility section.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Under the conditions of the OECD 422 study, conducted on a structural analogue substance, the test item administered to male and female rats up to a dose level of 1000 mg/kg bw/day for a period of up to 8 weeks is not toxic to reproduction and has no effect on fertility or development. No treatment-related effects were observed for reproduction; hence, a NOEL for reproductive toxicity was considered to be 1000 mg/kg bw/day.

Based on these results, octadecanedioic acid, 1,18-dimethyl ester

does not warrant classification according to the criteria described in Regulation (EC) No 1272/2008.

Additional information