2-methylglutaric acid

Endpoint summary

Description of key information

The LD50 by oral route was determined to be between 300 and 2000 mg/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2014-05-20 to 2014-08-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study, OECD 423 compliant

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

06 May 2013

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Species: Rat, Wistar strain Crl:WI (Han) (outbred, SPF-Quality). Recognized by international guidelines as the recommended test system (e.g. OECD, EC).
Source: Charles River Deutschland, Sulzfeld, Germany.
Number of animals: 9 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.
Age and body weight: Young adult animals (approx. 8-9 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
Identification: Earmark and tail mark
Health inspection: At least prior to dosing. It is ensured that the animals were healthy and without any abnormality that might affect the study integrity.

ENVIRONMENTAL CONDITIONS
Conditions
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

Accommodation
Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).

Water
Free access to tap water.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Method: Oral gavage, using plastic feeding tubes. Test substance (formulations) were stirred on a magnetic stirrer during dosing.
Fasting: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.
Frequency Single dosage on Day 1.

Dose level (volume): 2000 mg/kg (10 mL/kg) body weight.
300 mg/kg (10 mL/kg) body weight.

Doses:

300 and 2000 mg/kg

No. of animals per sex per dose:

3 animals at 2000 mg/kg
6 animals at 300 mg/kg

Control animals:

no

Details on study design:

The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

OBSERVATIONS
Mortality/Viability: Twice daily.

Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).

Necropsy: The animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Sex:

female

Dose descriptor:

LD50

Effect level:

300 - 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg, two animals were found dead on Day 2.
At 300 mg/kg, no mortality occurred.

Clinical signs:

other: At 2000 mg/kg, hunched posture and piloerection were noted for all animals between Days 1 and 4 (or until death). At 300 mg/kg, hunched posture and/or piloerection were noted among the animals on Days 1 and/or 2.

Gross pathology:

At 2000 mg/kg, abnormalities of the stomach (many reddish foci in the glandular mucosa) and duodenum (many dark red foci) were found at macroscopic post mortem examination in both animals that died during the study.
Macroscopic examination of the animals at 300 mg/kg and the surviving at animal 2000 mg/kg did not reveal any abnormalities

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 value of 2-Methylglutaric acid in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

Executive summary:

Assessment of acute oral toxicity with 2-Methylglutaric acid in the rat (Acute Toxic Class Method) was realised according to the OECD 423 guideline and under GLP conditions.

Initially, 2-Methylglutaric acid was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 300 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

At 2000 mg/kg, two animals werefound dead on Day 2.At 300 mg/kg, no mortality occurred.

 

At 2000 mg/kg, hunched posture and piloerection were noted for all animals between Days 1 and 4 (or until death).

At 300 mg/kg, hunched posture and/or piloerection were noted among the animals on Days 1 and/or 2.

At 2000 mg/kg, abnormalities of the stomach (many reddish foci in the glandular mucosa) and duodenum (many dark red foci) were found at macroscopic post mortem examination in both animals that died during the study. Macroscopic examination of the animals at 300 mg/kg and the surviving animal at 2000 mg/kg did not reveal any abnormalities.

Based on these observations, it is concluded that the death of the two deceased animals is likely to be related to corrosive effects of the substance on the GI tract.

The oral LD50 value of Methylglutaric acid in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral

Assessment of acute oral toxicity with 2-Methylglutaric acid in the rat (Acute Toxic Class Method) was realised according to the OECD 423 guideline and under GLP conditions.

Initially, 2-Methylglutaric acid was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 300 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

At 2000 mg/kg, two animals were found dead on Day 2. At 300 mg/kg, no mortality occurred.

 

At 2000 mg/kg, hunched posture and piloerection were noted for all animals between Days 1 and 4 (or until death).

At 300 mg/kg, hunched posture and/or piloerection were noted among the animals on Days 1 and/or 2.

At 2000 mg/kg, abnormalities of the stomach (many reddish foci in the glandular mucosa) and duodenum (many dark red foci) were found at macroscopic post mortem examination in both animals that died during the study. Macroscopic examination of the animals at 300 mg/kg and the surviving animal at 2000 mg/kg did not reveal any abnormalities.

Based on these observations, it is concluded that the death of the two deceased animals is likely to be related to corrosive effects of the substance on the GI tract.

The oral LD50 value of 2-Methylglutaric acid in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

Inhalation:

This study was waived. The acute inhalation study does not need to be conducted as the substance is classified as corrosive in contact with the skin and exposure of humans via inhalation is 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.

Dermal:

2-Methylglutaric acid was found corrosive in a Corrositex study (OECD 435) and is classified Skin corrosion Category 1C.

According to the column 2 of the Annex VIII of the Regulation (EC) No. 1907/2006 (REACh) (section 8.5.3), an acute dermal toxicity study does not need to be conducted if the substance is classified as corrosive to the skin. In addition, as mentioned in the Guidance on the application of Regulation (EC) No 1272/2008, a skin corrosive substance is considered to also cause serious eye damage which is indicated in the hazard statement for skin corrosion (H314: causes severe skin burns and eye damage).

Justification for selection of acute toxicity – oral endpoint
GLP study, OECD 423 compliant, quoted Klimish 1 and selected as key study.

Justification for selection of acute toxicity – inhalation endpoint
In accordance with column 2 of REACH Annex VIII, the acute inhalation study does not need to be conducted as the substance is classified as corrosive in contact with the skin, an acute toxicity study is available and no significant exposure is expected as MGA is a non-pulverulent solid and has a low volatility as evidenced by it vapor pressure of 5.6.10-4 Pa at 20°C.

Justification for selection of acute toxicity – dermal endpoint
2-Methylglutaric acid was found corrosive in a Corrositex study (OECD 435) and is classified Skin corrosion Category 1C.
According to the column 2 of the Annex VIII of the Regulation (EC) No. 1907/2006 (REACh) (section 8.5.3), an acute dermal toxicity study does not need to be conducted if the substance is classified as corrosive to the skin.

Justification for classification or non-classification

Based on the acute oral study, with a LD50 between 300 and 2000 mg/kg, 2-Methylglutaric acid is classified as harmful by ingestion (H302), according to the CLP 1272/2008 criteria.