Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: expert assessment
Adequacy of study:
weight of evidence
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetics behaviour of the substance was performed using results from existing toxicological studies and information from an analogue substance.

Data source

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

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
An assessment of the toxicokinetics behaviour of the substance was performed using results from existing toxicological studies and information from an analogue substance.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
There is evidence of absorption following an oral exposure. No evidence on absorption following an inhalation or dermal exposure was identified.
Type:
distribution
Results:
Distribution is expected through the water compartments but the substance is not expected to accumulate in tissues.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral exposure: Glutaric acid is a water soluble dicarboxylic acid with a low molecular weight therefore dissolution and absorption in the gastrointestinal tract is likely. The substance being a weak acid, the absorption is likely to occur in the stomach. Available in vivo data supports the conclusion that glutaric acid is absorbed following oral exposure.
Inhalation Exposure: Glutaric acid particles are expected to dissolve in the respiratory tract, this combined with the low molecular weight mean absorption following exposure by inhalation cannot be excluded. No in vivo data was identified investigating the effects of glutaric acid following an inhalation exposure. Oral exposure: No dermal absorption is expected taking into account the particle size of agglomerated glutaric acid as manufactured. These particles are not expected to significantly dissolve in contact with the skin. Available in vivo data does not allow to if the substance is absorbed following a dermal exposure.
Details on distribution in tissues:
Being a hydrophilic substance with a low molecular weight, glutaric acid is expected to be well distributed in a mammalian body through the water compartments but is not expected to accumulate in tissues. Systemic effects were observed during in vivo studies, providing evidence to suggest that the substance was absorbed. No effects were observed relating to specific target organs or systems, therefore it is not possible from these results to derive information on the distribution of glutaric acid.
Details on excretion:
Glutaric acid is expected to be excreted mainly by respiration in the form of CO2. Other metabolites and unchanged glutaric acid are expected to be eliminated in the urine and faeces.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Glutaric acid is naturally present in the human body as a degradation product of several amino acids. The main metabolic processing of the substance involves the formation of acetoacetate and acetate. Ketoglutaric acid was also identified as a metabolite of glutaric acid but the pathway leading to this metabolite is not considered as the major metabolic pathway.
Glutaric acid is expected to undergo the same metabolic processes as the analogue substance adipic acid, another dicarboxylic acid composed of a linear alkane of four carbons (compared to the three carbons for glutaric acid) with a carboxylic acid group at each end of the chain. CO2, urea, glutamic acid, lactic acid, citric acid, and ketoadipic acid were identified as the ultimate degradation products of adipic acid. The same ultimate degradation products can be expected during metabolisation of glutaric acid, with the exception of ketoadipic acid which would be replaced with ketoglutaric acid.
It is therefore reasonable to conclude that the main metabolic pathway of glutaric acid involves the formation of acetoacetate and acetate with ultimate degradation products of CO2 urea, glutamic acid, lactic acid, citric acid, and ketoglutaric acid.

Applicant's summary and conclusion

Conclusions:
An assessment of the toxicokinetics behaviour of the substance was performed using results from existing toxicological studies and information from an analogue substance.
Executive summary:

The absence of specific toxicokinetic data from animal testing means that it is not possible to make firm conclusions concerning the absorption, distribution, and excretion of glutaric acid. However, it was possible to use existing data on the physico-chemical and toxicological properties of the substance, as well as data available for the similar substance adipic acid, to determine the likely toxicokinetic behaviour of glutaric acid. Data on the metabolisation of the substance was identified in the literature and used for the purpose of this assessment.

According to the available information, glutaric acid is expected to be absorbed mainly in the stomach following an oral exposure. Absorption via the dermal or inhalation routes cannot be excluded, but there is no data from which to draw a conclusion regarding these routes. Glutaric acid being a hydrophilic compound with a low molecular weight can be expected to be well distributed in the water compartments of the body, but the adverse effects observed following an exposure to the substance do not allow a conclusion regarding specific target organs. The substance is not expected to accumulate in the body. Glutaric acid has been shown to be metabolised to mainly acetate and acetoacetate, with production of ketoglutaric acid as an alternative metabolisation route. The elimination route for glutaric acid is mainly in the form of CO2 by inhalation, with other metabolites eliminated through the urine and the faeces.

It is not considered appropriate to perform further animal studies on this substance to investigate its toxicokinetic behaviour.