2-methylglutaric acid

Acute Toxicity: oral

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

2-methylglutaric acid

EC Number:

210-521-7

EC Name:

2-methylglutaric acid

Cas Number:

617-62-9

Molecular formula:

C6H10O4

IUPAC Name:

2-methylglutaric acid

Test material form:

solid: crystalline

Test animals

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.

Administration / exposure

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.

Results and discussion

Effect levels

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

Applicant's summary and conclusion

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.