Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The toxicity to fertily of the registered substance was assessed using literature data on the substance and on an analogous substance. No study investigating the toxicity of the substance to reproduction was identified, but the effects of the substance to reproductive organs was investigated as part of unpublished subchronic repeated-dose toxicity studies on rats and dogs respectively. No significant adverse effect was identified. As rats are considered the more relevant species for reproductive toxicity testing than dogs, it is proposed to use a NOAEL(fertility) of 1,720 mg/kg bw/day of glutaric acid for male rats and 1,960 mg/kg bw/day for female rats obtained during the subchronic repeated-dose toxicity study performed on rats, as they were the highest dose evaluated and did not induce significant adverse effects. These values are supported by the results of the subchronic repeated-dose toxicity study performed on dogs using the registered substance and the chronic toxicity study on rats using the analogous substance adipic acid.

The developmental toxicity of the registered substance was assessed using literature data on the substance and on an analogous substance. Two unpublished studies were identified investigating the developmental toxicity on the registered substance, performed on rats and rabbits respectively. The only significant adverse effects observed was an increase of the number of resorptions at 1,300 mg/kg bw/d in rats, which was the highest dose investigated and was above the limit of 1,000 mg/kg bw/d recommended by the OECD Testing Guideline 414. Two developmental toxicity studies were performed on the analogous substance adipic without identifying adverse effects at up to 250 mg/kg bw/d in rabbits, 288 mg/kg bw/d in rats, 263 mg/kg bw/d in mice, and 205 mg/kg bw/d. None of these doses induced maternal toxicity. Rabbits being the most relevant species for this endpoint, it is proposed to set a NOAEL for maternity toxicity and a NOAEL for developmental toxicity of 250 mg/kg bw/day considering that these values are conservative compared to the results obtained on the registered substance.

Link to relevant study records
Reference
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.
Reference:
Composition 0
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 information:
Composition 1
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
Remarks on result:
not measured/tested
Critical effects observed:
no
Key result
Reproductive effects observed:
no
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).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 720 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
An assessment was performed based on literature data on the substance and literature data on an analogous substance.
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

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

The toxicity to fertily of the registered substance was investigated using information on the effects on reproductive organs induced by the registered substance and the analogous susbtance adipic acid. No significant adverse effects were identified.

The pre-natal developmental toxicity of the registered substance was investigated using studies performed on the registered substance and the analogous substance adipic acid. The only significant adverse effects observed was an increase of the number of resorptions in rats treated at 1,300 mg/kg bw/d of the registered substance, a dose above the limit dose of 1,000 mg/kg bw/d recommended by the OECD Testing Guideline 414.

It is concluded that the registered substance does not meet the criteria for classification according to Regulation (EC) No.1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures.