Dimethyl succinate

Endpoint summary

Description of key information

- Acute toxicity:
Oral: LD50: 6892 mg/kg for rat
Inhalation (4 hours) LD50: > 5900 mg / m3 in the rat for a mixture of dibasic esters containing 16.5% dimethylsuccinate

Dermal: LD50: > 2000 mg/kg for rat

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Study pre-dates test guidelines

Principles of method if other than guideline:

"Standard" LD50 test

GLP compliance:

no

Remarks:

Study pre-dates GLP regulations

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 82 - 115 g
- Fasting period before study: 16 hours
- Diet (e.g. ad libitum): Altromin R rat diet, ad-libitum except for a 16 hour fast prior to dosing and approximately 2 hours after dosing
- Water (e.g. ad libitum): Ad-libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

IN-LIFE DATES: From: Not reported To: Not reported

Route of administration:

oral: gavage

Vehicle:

vegetable oil

Remarks:

sesame oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25%
- Justification for choice of vehicle: Solubility miscibility
- Lot/batch no. (if required): Not reported
- Purity: Not reported

Doses:

4000, 6300, 8000, 10000 and 15000 mg/kg

No. of animals per sex per dose:

10 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations - Frequently following dosing followed by at least daily. Weighing - Weekly
- Necropsy of survivors performed: Not reported

Statistics:

Probit analysis

Sex:

female

Dose descriptor:

LD50

Effect level:

6 892 mg/kg bw

Based on:

test mat.

95% CL:

6 256 - 7 592

Mortality:

4000 mg/kg - 0 / 10 (0%)
6300 mg/kg - 3 /10 (30%)
8000 mg/kg - 8 / 10 (80%)
10000 mg/kg - 10 / 10 (100%)
15000 mg/kg - 10 / 10 (100%)

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose (LD50) of the substance following a single oral dose was determined to be 6892 mg/kg body weight

Executive summary:

The test susbtance was administered as a single dose, by gavage, to groups of 10 female rats. Animals were observed for 14 days following dosing for mortality and clinical signs. The incidence of mortality relative to dose was used to calculate the median lethal dose by probit analysis.

The median lethal dose (LD50) of the substance following a single oral dose was determined to be 6892 mg/kg body weight

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

6 892 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The US EPA, as part of the High Production Volume (HPV) Challenge Program has accepted a category proposal concerning bibasic esters. These are short, straight-chain dicarboxylic acid dimethyl esters that differ by one carbon atom (from four to six carbons) in chain length. The basis for considering dimethyl succinate, dimethyl glutarate, dimethyl adipate and a dibasic ester mixture containing all three as a Category is based upon the similarities of the three substances in structure, physicochemical properties and consistent responses in ecotoxicology and human health toxicology studies. The US EPA considers that the similarity in response makes read-across of data between members of the category both feasible and justifiable.

The source substance is a mixture containing the target substance, all being components of the mixture being dimethyl esters of acids which are metabolised to endogenous substances.

2. SOURCE AND TARGET CHEMICAL(S)
The source substance is a mixture consisting of 16.5% dimethyl succinate (the target substance), 17.0% dimethyl adipate and 66.0% dimethyl glutarate

Reason / purpose for cross-reference:

read-across source

Sex:

male

Dose descriptor:

LC0

Effect level:

>= 5 900 mg/m³ air

Exp. duration:

4 h

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 900 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From February 25,2010 to March 16,2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Lot No.of test material: T14B208335
- Production date: 30 Nov 2008
- Expiration date of the lot/batch: 31 December 2010

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy S.r.l., 33049 San Pietro al Natisone (UD), Italy
- Age at study initiation: 6 to 8 weeks old
- Weight at study initiation: 176 to 200 grams
- Housing: Polycarbonate cages measuring 42.5x26.6x18 cm with stainless steel mesh lid and floor.
- No. of animals/cage: Individually caged (both during acclimatisation and study)
- Cage tray control: Daily inspected and changed as necessary (at least 3 times/week)
- Diet:4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy) , ad libitum throughout the study
- Water :drinking water supplied to each cage via a water bottle , ad libitum.
- Acclimation period: At least 5 days
- Veterinary health check: After arrival
- Choise of species:The Sprague Dawley SD rat was used, being the species and strain of choice because it is accepted by many regulatory authorities and there is ample experience and background data on this species and strain.
- Choice of the route: The route of administration is a potential route of exposure during manufacturing, handling or use of the substance.
- Room lighting: Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours
- Air changes : Approximately 15 to 25 air changes per hour
- Temperature range:22°C ± 2°C
- Relative humidity range: 55% ± 15%
Actual conditions were monitored, recorded and the records retained. No relevant deviations occurred.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Exposure time :24 hours
Washing procedure:After exposure, the adhesive bandage and gauze patch were removed. The treatment area was cleaned by gentle swabbing of the skin with cotton wool soaked with lukewarm water.

Duration of exposure:

24 hours

Doses:

single dose at level of 2000/mg/kg bw

No. of animals per sex per dose:

5 animals /sex/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Allocation (Day-1), Days 1, 8 and 15
- Necropsy of survivors performed: yes
- Clinical signs: controlled on the Day of dosing (on dosing, approximately 1, 2 and 4 hours after dosing). Daily thereafter (14 days).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred and no clinical signs were observed in male or female animals during the observation period.

Clinical signs:

other: No clinical signs were observed in male or female animals during the observation period.

Gross pathology:

No abnormalities were found at necropsy examination performed on all animals at termination of the study.

Interpretation of results:

GHS criteria not met

Conclusions:

No mortality occurred following dosing and no signs of toxicity were observed.
These results indicate that the test item, Dimethyl Succinate (DMS), has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The lack of mortality demonstrates the LD50 to be greater than 2000 mg/kg.

Executive summary:

Acute dermal toxicity has been investigated according to OECD/EU test methods. No mortality occurred and no clinical signs were observed at a limit dose level of 2000 mg/kg, demonstrating the LD50 to be in excess of this value .

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

Classification with regard to acute oral and dermal toxicity is not justified based on the observed lack of mortality at a dose level of 2000 mg/kg.

Classification with regard to acute (4 hour) inhalation toxicity is not justified based on the observed lack of mortality at an exposure level of 5900 mg / m3