Dimethyl itaconate

Endpoint summary

Description of key information

Acute toxicity: 
- oral: LD50 > 2000 mg/kg bw, OECD TG 420; Bradshaw / 2014 / rat
- inhalation: waiver
- dermal: waiver

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 2014-09-05 to 2015-01-07

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according guideline (OECD 420) under GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8 to 12 weeks of age
- Weight at study initiation: 152 - 172 g
- Fasting period before study: an overnight
- Housing: in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.79 mL/kg

DOSAGE PREPARATION (if unusual): the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.

Doses:

2000 mg/kg

No. of animals per sex per dose:

one animal for the sighting study and 4 animals for the main study

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: for clinical observations: 1/2, 1, 2 and 4 hours after dosing and then daily for fourteen days. For weighing: on Days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic observations

Statistics:

No data

Sex:

female

Dose descriptor:

discriminating dose

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 0/5 deaths at 2000 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths (see Table 1).

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period (see Table 1).

Gross pathology:

No abnormalities were noted at necropsy (see Table 3).

Table 1. Individual Clinical Observations and Mortality Data

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0 =   No signs of systemic toxicity

Table 2 . Individual Body Weights and Body Weight Changes

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week
		0	7	14	1	2
2000	1-0 Female	172	188	211	16	23
	2-0 Female	152	179	193	27	14
	2-1 Female	160	172	189	12	17
	2-2 Female	159	176	188	17	12
	2-3 Female	153	169	179	16	10

Table 3. Individual Necropsy Findings

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	1-0 Female	Killed Day 14	No abnormalities detected
	2-0 Female	Killed Day 14	No abnormalities detected
	2-1 Female	Killed Day 14	No abnormalities detected
	2-2 Female	Killed Day 14	No abnormalities detected
	2-3 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight.

Executive summary:

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat according to OECD TG 420 and under GLP. Following a sighting test at a dose level of 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test item at a dose level of 2000 mg/kg body weight. There were no deaths and no signs of systemic toxicity. All animals showed expected gains in body weight. No abnormalities were noted at necropsy. The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Study according guideline (OECD 420) under GLP

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

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:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

- acute toxicity: oral

The test substance was not toxic in acute oral test (OECD TG 420). The LD50 value was greater than 2000 mg/kg bw after single oral (gavage) administration of the test substance.

- acute toxicity: inhalation

Based on maximal classified concentration of aerosol (5 mg/mL) and vapour pressure of the test substance (4.05 Pa at 20 °C), the calculated dose level is at least 2 times lower than for acute oral toxicity test, where no rat mortality was observed.

- acute toxicity: dermal

According to Competent Authorities for REACH and CLP (CARACAL), the test substance is considered as not toxic in acute oral test (LD50 > 2000 mg/kg), therefore no dermal acute toxicity data is required.

Justification for selection of acute toxicity – oral endpoint
Only one reliable study is available for this endpoint.

Justification for classification or non-classification

Acute oral toxicity:

Based on the above stated assessment dimethyl itaconate is not toxic acutely via oral route according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Acute inhalation toxicity:

As no data on acute inhalation toxicity is available for dimethyl itaconate a classification is not possible according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Acute dermal toxicity:

As no data on acute dermal toxicity is available for dimethyl itaconate a classification is not possible according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.