Registration Dossier

The toxicity of glutaric acid following short-term repeated oral exposure was assessed using a read-across from the analogous substance adipic acid supported by available experimental data on glutaric acid.

Horn et al. (1957) derived a NOAEL of 3% for adipic acid in the diet for male rats following a chronic exposure, and above 0.1% of adipic acid in the diet for female rats as it was the highest concentration evaluated. These values are equivalent respectively to 2,070 mg/kg bw/day and 80 mg/kg bw/day. No specific target organ toxicity was identified, as the only adverse effects observed were a reduced body weight and a lower body weight gain in the groups receiving the highest concentrations of adipic acid in the diet when compared to the control groups, related to a reduced food consumption. These results were supported by Moody et al. (1978) who did not observe any significant effects when focusing on the liver of male rats exposed to 2% of adipic acid in the diet for three weeks – considered as equivalent to 2,000 mg/kg bw/day – and 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 used as a weight of evidence for the purpose of this assessment. Results from these studies were used to derive a NOAEL above 2% in the diet for the male rats and 1% for the females following subchronic exposure to glutaric acid, equivalent to 1,720 mg/kg bw/day for the males and 980 mg/kg bw for the female rats. No specific target organ toxicity has been identified as the only significant effect observed was a reduction of the body weight of the female rats. These results are supported by the fact that glutaric acid is naturally produced in the human body during the metabolisation of several amino acids.

The overall conclusion for this Registration Assessment Report, is a proposed NOAEL of 1,720 mg/kg bw/day of glutaric acid in the diet for male rats and 980 mg/kg bw/day of glutaric acid in the diet for female rats. These values are deemed to be conservative because they are derived from the results of longer-term exposure to glutaric acid while the purpose of this assessment is to assess the toxicity of glutaric acid following a short-term exposure. These values are also lower than those derived from the testing performed on the analogous substance adipic acid. No specific target organ toxicity was identified.

Reference

Endpoint:

short-term repeated dose toxicity: oral

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.

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

Sex:

male/female

Key result

Dose descriptor:

NOAEL

Effect level:

1 720 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

Key result

Dose descriptor:

NOAEL

Effect level:

980 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Critical effects observed:

no

Conclusions:

The overall conclusion for this Registration Assessment Report, is a proposed NOAEL of 1,720 mg/kg bw/day of glutaric acid in the diet for male rats and 980 mg/kg bw/day of glutaric acid in the diet for female rats. These values are deemed to be conservative because they are derived from the results of longer-term exposure to glutaric acid while the purpose of this assessment is to assess the toxicity of glutaric acid following a short-term exposure. These values are also lower than those derived from the testing performed on the analogous substance adipic acid. No specific target organ toxicity was identified.

Executive summary:

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

Horn et al. (1957) derived a NOAEL of 3% for adipic acid in the diet for male rats following a chronic exposure, and above 0.1% of adipic acid in the diet for female rats as it was the highest concentration evaluated. These values are equivalent respectively to 2,070 mg/kg bw/day and 80 mg/kg bw/day. No specific target organ toxicity was identified, as the only adverse effects observed were a reduced body weight and a lower body weight gain in the groups receiving the highest concentrations of adipic acid in the diet when compared to the control groups, related to a reduced food consumption. These results were supported by Moody et al. (1978) who did not observe any significant effects when focusing on the liver of male rats exposed to 2% of adipic acid in the diet for three weeks – considered as equivalent to 2,000 mg/kg bw/day – and 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 used as a weight of evidence for the purpose of this assessment. Results from these studies were used to derive a NOAEL above 2% in the diet for the male rats and 1% for the females following subchronic exposure to glutaric acid, equivalent to 1,720 mg/kg bw/day for the males and 980 mg/kg bw for the female rats. No specific target organ toxicity has been identified as the only significant effect observed was a reduction of the body weight of the female rats. These results are supported by the fact that glutaric acid is naturally produced in the human body during the metabolisation of several amino acids.

The overall conclusion for this Registration Assessment Report, is a proposed NOAEL of 1,720 mg/kg bw/day of glutaric acid in the diet for male rats and 980 mg/kg bw/day of glutaric acid in the diet for female rats. These values are deemed to be conservative because they are derived from the results of longer-term exposure to glutaric acid while the purpose of this assessment is to assess the toxicity of glutaric acid following a short-term exposure. These values are also lower than those derived from the testing performed on the analogous substance adipic acid. No specific target organ toxicity was identified.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

980 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 the analogous substance adipic acid.

Reference

Endpoint:: short-term repeated dose toxicity: inhalation
Data waiving:: exposure considerations
Justification for data waiving:: a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion:

no study available

Reference

Endpoint:: short-term repeated dose toxicity: inhalation
Data waiving:: exposure considerations
Justification for data waiving:: a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion:

no study available

Reference

Endpoint:: short-term repeated dose toxicity: dermal
Data waiving:: exposure considerations
Justification for data waiving:: a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion:

no study available

Reference

Endpoint:: short-term repeated dose toxicity: dermal
Data waiving:: exposure considerations
Justification for data waiving:: a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion:

no study available

An assessment was performed based on literature data on the substance and literature data on the analogous substance adipic acid. The overall conclusion for this assessment is a proposed NOAEL of 1,720 mg/kg bw/day of glutaric acid in the diet for male rats and 980 mg/kg bw/day of glutaric acid in the diet for female rats. These values are considered to be conservative for the purpose of this assessment because they are derived from the results of longer-term exposure to glutaric acid. No specific target organ toxicity was identified. The only significant adverse effects observed was a reduction of the body weight in female rats receiving 1,960 mg/kg bw/d, a dose higher than the limit dose recommended by the current version of the OECD Testing Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents). Glutaric acid did not meet the criteria for classification according to Regulation (EC) No.1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures.