Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
other: expert assessment
Adequacy of study:
weight of evidence
Study period:
14 December 2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment was performed based on literature data on the substance and literature data on an analogous substance.

Data source

Reference
Reference Type:
other: expert assessment
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
An assessment was performed based on literature data on the substance and literature data on an analogous substance.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
fertility
Effect level:
1 720 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
fertility
Effect level:
1 960 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
gross pathology
histopathology: non-neoplastic

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
As the conclusion of this assessment, it is proposed to use a NOAEL(fertility) of 1,720 mg/kg bw/day of glutaric acid for the male rats and 1,960 mg/kg bw/day for the female rats as they represent a worst-case scenario compared to the values derived from the chronic study on adipic acid (the value derived from the evaluation of adipic acid on female rats was not considered due to the low concentration tested).

With regard to the pre-natal developmental toxicity, the NOAEL(maternity toxicity) and NOAEL(developmental toxicity) of 250 mg/kg bw/day obtained on rabbits with adipic acid could be considered as representing a worst-case scenario as they were the highest concentrations tested and did not induce any observable effects. This approach is considered as conservative, as higher NOAELs were derived from a pre-natal developmental toxicity study performed on glutaric acid and deemed as reliable by US EPA (2001).
Executive summary:

The reproductive toxicity of glutaric acid was assessed using a read-across from the analogous substance adipic acid supported by available experimental data on glutaric acid.

Horn et al. (1957) investigated the effects of adipic acid on the sexual organs of rats as part of a chronic study. When tested up to concentrations of 5% in diet for males and 0.1% for females, equivalent respectively to 3,450 mg/kg bw/day for the males and 80 mg/kg bw/day for the females, adipic acid did not induce observable effects to the sexual organs,. These values may be used to derive the NOAEL(fertility) of adipic acid: 3,450 mg/kg bw/day for the males and 80 mg/kg bw/day for the females. However, the result for female rats cannot be considered as relevant since the highest concentration tested was only 0.1% of adipic acid in diet.

Litton Bionetics, Inc. (1973, 1974) performed developmental toxicity studies on adipic acid using a method similar to OECD Testing Guideline 414 with deviations. Studies were performed on rats, rabbits, mice, and hamsters, with the one on rabbits being considered as the most relevant and conservative. It allows to obtain a NOAEL(maternity toxicity) and a NOAEL(developmental toxicity) of 250 mg/kg bw/day of adipic acid, as it was the highest concentration tested in rabbits and did not induce observable adverse effects.

These results were supported by the historical uses of adipic acid in foodstuff, feed and industrial processes.

The experimental data on adipic acid are supported by the consistent results obtained from two subchronic studies on glutaric acid performed by Solutia Inc. (1977a, 1977b) and two pre-natal developmental toxicity studies performed by Sterling-Winthrop Research Institute (1984) and used as a weight of evidence for the purpose of this assessment.

Effects of glutaric acid on sexual organs was investigated as part of the subchronic studies. The substance was tested up to concentrations of 2% in the diet in male and female rats, and up to 5% in diet in male and female dogs without inducing any observable adverse effects to the sexual organs. Results from the subchronic study on rats were considered for the purpose of deriving the NOAEL(fertility) as rats represent a more relevant species for the purpose of this evaluation. Therefore, it is proposed a NOAEL(fertility) of 1,720 mg/kg bw/day of glutaric acid for the males and 1,960 mg/kg bw/day for the females.

Pre-natal developmental toxicity of glutaric acid was investigated on rats and rabbits, which are the most relevant species for the purpose of this evaluation. Based on the results of these studies it is proposed to use a NOAEL(maternal toxicity) and a NOAEL(developmental toxicity) of 400 mg/kg bw/day as they are representing a worst-case scenario.

These results are supported by the fact that glutaric acid is naturally produced in the human body during the metabolisation of several amino acids.

As the conclusion of this assessment, it is proposed to use a NOAEL(fertility) of 1,720 mg/kg bw/day of glutaric acid for the male rats and 1,960 mg/kg bw/day for the female rats as they represent a worst-case scenario compared to the values derived from the chronic study on adipic acid (the value derived from the evaluation of adipic acid on female rats was not considered due to the low concentration tested).

With regard to the pre-natal developmental toxicity, the NOAEL(maternity toxicity) and NOAEL(developmental toxicity) of 250 mg/kg bw/day obtained on rabbits with adipic acid could be considered as representing a worst-case scenario as they were the highest concentrations tested and did not induce any observable effects. This approach is considered as conservative, as higher NOAELs were derived from a pre-natal developmental toxicity study performed on glutaric acid and deemed as reliable by US EPA (2001).