Dimethyl succinate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Dimethyl succinate is metabolised by hydrolysis to form the corresponding dicarboxylic acid (succinic acid) and methanol. Succinic acid is an endogenous metabolite in the body and is a component of the Krebs cycle (Voet, D. & Voet, J.G., eds. (1990) Biochemistry, New York: John Wiley & Sons, pp. 506-527, 632-633, 690). Data on methanol are presented.

2. SOURCE AND TARGET CHEMICAL(S)
The source substance is a metabolite of the target substance.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

data documentation limited; extended copulation time (21 days); not all parameters mentioned in the guideline were investigated

Species:

rat

Strain:

Sprague-Dawley

Body weight and weight changes:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

1.3 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

other: Lack of effect on reproductive parameters

Key result

Critical effects observed:

no

Dose descriptor:

NOAEC

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Key result

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

0.13 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: Reproductive parameter

Key result

Dose descriptor:

LOAEC

Generation:

F1

Effect level:

1.3 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: Reproductive parameter

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEC

Generation:

F2

Effect level:

0.13 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: Reproductive parameter

Key result

Dose descriptor:

LOAEC

Generation:

F2

Effect level:

1.3 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: Reproductive paramter

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Reference 2

Endpoint:

one-generation reproductive toxicity

Type of information:

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

Adequacy of study:

weight of evidence

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

Dose descriptor:

LOAEC

Effect level:

0.16 mg/L air

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Critical effects observed:

yes

Lowest effective dose / conc.:

0.16 other: mg/L air

System:

respiratory system: upper respiratory tract

Organ:

nasal cavity

Treatment related:

yes

Dose response relationship:

yes

Dose descriptor:

NOEC

Generation:

F1

Effect level:

1 mg/L air

Sex:

male/female

Basis for effect level:

other: overall effects

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

296 mg/m³

Study duration:

subchronic

Experimental exposure time per week (hours/week):

140

Species:

rat

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a one-generation reproductive toxicity study (Kelly, et.al., 1998) rats were exposed, by inhalation, to a mixture of dibasic esters containing dimethyl succinate, dimethyl glutarate and dimethyl adipate. Groups of 20 male and 20 female rats were exposed to concentrations of 0, 0.16, 0.40 or 1.0 mg/L for 6 hours/day, 5 days/week for 14 weeks during a pre-breeding period followed by 7 days/week for 8 weeks throughout a mating, gestation, and lactation periods. No significant differences related to treatment were noted on mating performance, fertility, length of gestation, numbers of pups, pup anomalies and viability. Body weights of both parental rats and their pups were reduced at 1.0 mg/L. Relative liver weight was increased in parental animals treated at 0.4 or 1.0 mg/L and relative lung weight was increased at 1.0 mg/L. A treatment related increase in squamous metaplasia in the olfactory epithelium was observed in parental animals. The NOAEC is considered to be 1.0 mg/L for reproductive performance of parental animals and for development of the off-spring.

In a two-generation reproductive toxicity study (OECD, 2004) on methanol, a metabolite of the registered substance, rats were exposed by inhalation to concentrations of 0, 0.013, 0.13 or 1.3 mg/L for 19-20 hours/day during a breeding period covering two generations. No significant differences related to treatment were noted on mating performance, fertility, length of gestation, numbers of pups, pup anomalies and viability. Male pups of the F1 and F2 generations from the highest exposure group exhibited some post-natal morphological differentiation with respect to the descent of the testes occurring 0.5 to 1 days earlier. This time-dependent parameter was evaluated by relating the completion of downward migration of the testes (final length of the gubernaculum reached) to the post-natal body-weight gain. The meaning of an apparent shift of testis descent in male offspring in relation to body-weight development of the pups is unclear and this parameter showed considerable variation also within the control group. In addition, absolute and relative brain weights were significantly lowered in the high-dose group pups of either sex at an age of 8 and 16 weeks. Although there was no obvious pathological effect in the progeny of groups exposed to 1.3 mg/L, the effects observed may be considered as biologically relevant under the described test conditions and, therefore, 1.3 mg/L (equivalent to 2.96 mg/L dimethyl succinate and considering that one molecule of dimethyl succinate will be metabolised to release two molecules of methanol), is established as a LOAEL and 0.13 mg/L (equivalent to 0.296 mg/L dimethyl succinate) as a NOAEL for post-natal development while for parental effects, the NOAEL is 1.3 mg/L (equivalent to 2.96 mg/L dimethyl succinate).

Effects on developmental toxicity

Description of key information

Developmental toxicity: In a developmental toxicity study with rats by the inhalation route with animals exposed 6 hours/day from Day 7 to 16 of gestation the NOAEC for developmental toxicity was considered to be 1.0 mg/L/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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

Dose descriptor:

NOAEC

Effect level:

1 mg/L air

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

Abnormalities:

no effects observed

Dose descriptor:

NOAEC

Effect level:

1 mg/L air

Basis for effect level:

other: Lack of treatment-related effects

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 000 mg/m³

Study duration:

subacute

Experimental exposure time per week (hours/week):

42

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a developmental toxicity study (Alvarez et.al., 1995) rats were exposed by inhalation to a mixture of bibasic esters containing dimethyl succinate, dimethyl glutarate and dimethyl adipate. Groups of pregnant rats were exposed to concentrations of the mixture of 0.16, 0.4 or 1.0 mg/L by inhalation daily for 6 hours/day from Day 7 through to Day 16 of gestation (Day 1 being designated as the day in which evidence of mating was detected). A control group of pregnant rats was exposed to air only. All animals were killed on gestation Day 21 and the foetuses examined. The mixture was regarded as not causing developmental toxicity in the rat following inhalation exposures at concentrations as high as 1.0 mg/L during the period of organogenesis and the NOAEC was 1.0 mg/L.

Justification for classification or non-classification

Based on the available data, classification and labelling according to Directive 67/548/EEC or Regulation 1272/2008 is not required.