2-methylglutaric acid

Endpoint summary

Description of key information

No data available.
Absorption expected by the oral route
Distribution expected in hydrophilic tissues
No metabolisation expected
Excretion expected in urine

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No human data are available and no specific toxicokinetic (TK) study using2-Methylglutaricacid (MGA) has been performed. Therefore, the assessment of absorption, distribution, metabolism and excretion of 2-Methylglutaric acid is based on the physico-chemical properties of the test substance and on the results of the available toxicity studies.

 

Physico-chemical properties:

- The test substance is a non-pulverulent solid with a low volatility as evidenced by its vapor pressure ≤ 5.6x10^-4 Pa at 20°C.

- The estimated partition coefficient in n-octanol/water is <-1.3 at pH=7.

- The estimated water solubility is >1000 g/L.

- Molecular Weight: 146.143 g/mol

 

Absorption

Inhalation route

While theoretically possible considering its high water solubility and small size, absorption of the substance through inhalation is highly unlikely as the substance is a non-pulverulent solid and non-volatile as evidenced by its vapor pressure ≤ 5.6x10^-4 Pa at 20°C.Moreover, generation of droplet or aerosols is not expected in any of the substance expected use.

Oral route

 

Considering its high water solubility and small size, absorption of 2-Methylglutaric acid by the oral route is expected.

 

In an acute rat oral toxicity (Beerens, 2014) LD50 was estimated to be between 300 mg/kg bw and 2000 mg/kg bw. During this study two out of three rat administered with 2000 mg/kg bw died while all the rat administered with 300 mg/kg bw survived. However, macroscopic examination showed the absence of observation on the surviving animals, while only strong local effects on GI tract were observed on the dead animals. Therefore, no conclusion can be made on MGA oral absorption from this study.

 

A 90 days rat oral toxicity study was performed on 2-Methylglutaric acid (Beerens, 2015). In this study, the initial high dose was 1000 mg/kg bw/day but was reduced to 600 mg/kg/bw/day from day 7 based on the mortality of four animals, severe body weight loss and clear clinical signs.

At 600 mg/kg bw/day, the results showed the absence of systemic treatment related effects.

On the 4 dead animals which were treated at 1000 mg/kg bw/day, macroscopic examination revealed mostly the presence of strong local effects. However, on two out of 4 animals a moderate basophilia of the tubules with slight degeneration and cellular sloughing was observed in the kidney which were considered treatment related. However slight these observation is consistent with an absorption of MGA following administration by the oral route.

 

In an in vivo micronucleus test (Veerbaan, 2014), mice were treated orally with doses of 2-Methylglutaric acid up to 2000 mg/kg bw for males and up to 1750 mg/kg bw for females. No macroscopic observation of the animals was performed. While no clastogenic or aneugenic effects were observed, male animals treated for 48 hours and dosed with 2000 mg/kg bw showed a decrease in the ratio of polychromatic to normochromatic erythrocytes compared to the concurrent vehicle control group, indicating effects of this test substance on erythropoiesis. This observation is consistent with an absorption of 2-Methylglutaric acid upon administration by the oral route.

 

Dermal Route

 

As 2-Methylglutaricacid is corrosive to the skin, it is not relevant to evaluate its dermal penetration.

  

Distribution

 

As described in oral absorption section:

-         During the rat 90 days oral toxicity some slight effects were observed on the kidney at the high dose.

-         In the in vivo micronucleus test, effects on erythropoiesis were observed upon oral administration of 2000 mg/kg of MGA

 

These results showed that 2-Methylglutaric acid is at least able to reach kidneys and bone marrow upon absorption. Together with the very high water solubility, these observations seem indicative of a systemic distribution of MGA at least in the hydrophilic tissues. 

 

Metabolisation

 

2-Methylglutaric acidis not expected to be metabolized.

Several in-vitro genotoxicity studies were performed in presence or absence of metabolic activation. However, as the results were negative with or without metabolic activation in every test, these results are inconclusive concerning metabolisation.

  

Excretion

 

Owing to the low molecular weight and the high water solubility of 2-Methylglutaric acid, it is possibly excreted in the urine.

 

Conclusion

 

Based on the data currently available in the data set, both from the physico-chemical properties and toxicological data, absorption and distribution of the substance following oral exposure was suggested by the occurrence of slight effects on some organs (kidney, bone marrow) observed in rats administered with 2-Methylglutaricacid.

 

Considering its physical state and low vapor pressure, 2-Methylglutaricacid absorption through the lungs by inhalation is unlikely.

 

Considering its strong corrosive properties, dermal absorption cannot be evaluated.

 

The parent substance is not expected to be metabolized.

 

No indication of the test substance excretion was obtained but it is expected that 2-Methylglutaricacid is excreted in the urine.