Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (respiratory tract)
Route of original study:
By inhalation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Toxicokinetics

Information regarding the toxicokinetics and percutaneous absorption of cyclic anhydrides is available in the published literature. Toxicokinetics data on hexahydrophthalic anhydride and phthalic anhydride indicate that cyclic anhydrides are readily hydrolysed to the corresponding dicarboxylic acid, which is mainly excreted in the urine and to a lesser extent in expired air after exposure via the inhalation route. Cyclic anhydrides share structural and physicochemical properties such that succinic anhydride would also be expected to show low systemic availability, particularly following inhalation exposure.

Cyclic acid anhydrides, such as succinic anhydride, are readily hydrolysed to the corresponding dicarboxylic acids. The hydrolysis product of succinic anhydride is succinic acid. Succinic acid is ubiquitous in prokaryotic and eukaryotic cells, it is an approved food additive in the EU, and is naturally found in beer and wine.

The hydrolysis product of succinic anhydride is succinic acid, an endogenous substance and food ingredient, that is expected to be effectively excreted in urine. Percutaneous absorption of cyclic anhydrides was investigated using hexahydrophthalic anhydride as the test material. Hexahydrophthalic anhydride was shown to be minimally absorbed across human skin and similar results would be expected with succinic anhydride. Additional toxicokinetic testing is not required for succinic anhydride.

Acute toxicity

Succinic anhydride is slightly toxic (LD50 = 1794.9 mg/kg bw for male and female Sprague-Dawley rats) when tested in a guideline-comparable study of acute oral toxicity. When tested in a guideline study for acute dermal toxicity the acute dermal median lethal dose for succinic anhydride was found to exceed the limit dose level in rats, >2000 mg/kg bw.

Acute inhalation testing is not required. The results of the granulometry test indicate the L10 value for particle size was 377 µm and the L50 was greater than 1100 µm. On the basis of these results it is clear there is no respirable material present in the batch of succinic anhydride. The particles are not in the respirable size range for rats or humans and so no inhalation exposure is likely. Given the result can be predicted from the physical-chemical properties, an inhalation toxicity study can not be justified on animal welfare grounds. Since human exposure via inhalation is unlikely, due to particle size, according to Annex VIII, column 2 conducting an animal study to confirm the negative result is not justified.

Irritation and sensitisation

In vitro skin corrosion test with succinic anhydride on a human three dimensional epidermal model EpiDerm (EPI-200). The possible corrosive potential of succinic anhydride was tested through topical application for 3 minutes and 1 hour. The study procedures described in this report were based on the most recent OECD and EC guidelines. BatchLEBA3A7021 of succinic anhydride consisted of white flakes with a purity of 99.7 %. Succinic anhydride was crushed and ground in a mortar with pestle. Twenty-five mg of succinic anhydride was applied directly on top of the skin tissue which was moistened with 25 μL of Milli-Q water. Skin corrosion is expressed as the remaining cell viability after exposure to the test substance. The relative mean tissue viability obtained after 3-minute and 1-hour treatments with succinic anhydride compared to the negative control tissues was 96 % and 12 %, respectively. Because the mean relative tissue viability for succinic anhydride was below 15 % after the 1-hour treatment, it is considered to be corrosive.

In a guideline-similar study for eye irritation, succinic anhydride caused severe eye injury (over 5.0) to rabbits when applied undiluted (0.005 mL) and as a 15 % solution. A score of 5.0 corresponds to necrosis, visible only after staining and covering about 75 % of the surface of the cornea; or a more severe necrosis covering a smaller area.

Succinic anhydride caused severe injury to rabbit eyes when applied undiluted and as a 15 % solution for an 18–24 hour exposure; a 5 % solution did not cause this eye damage grade. Succinic acid was graded in the same effect group.

Another cyclic anhydride was also tested in this scheme for eye injury. Maleic anhydride was scored as grade 10 for injury to the rabbit eye and a solution of 1 % yielded an injury score of over 5.0.

In a GLP study conducted according to OECD guideline 429, succinic anhydride dissolved in dimethylformamide was administered to the ears of mice once a day on three consecutive days at concentrations of 10, 25, or 31.3 % w/w. Incorporation of radiolabeled 3HTdR was determined with the SIs of the test substance groups between 9.2 and 11.6 (a weak/moderate sensitiser). Although no clear concentration related response was observed, succinic anhydride is regarded as a sensitiser in the LLNA since the SIs of all examined test concentrations were greater than 3. This study does not provide information that can be used for quantitative risk assessment.

Repeated dose toxicity

Two studies comparable to OECD guideline 408 showed mortality and toxic signs in rats and mice administered succinic anhydride at concentrations of 200 mg/kg and 300 mg/kg, respectively, for 13 weeks. In rats, compound-related deaths at doses of 200 mg/kg or higher may have arisen from central nervous system depression due to metabolic acidosis resulting from the administration of succinic anhydride. The NOAEL for rats was approximately 100 mg/kg bw/day and the NOAEL for mice was approximately 150 mg/kg bw/day.

The risks associated with subchronic dermal toxicity of succinic anhydride can be assessed using the results of subchronic oral studies plus dermal absorption data on hexahydrophthalic anhydride, a structurally related compound. The 13-week repeat dose oral study in the rat resulted in a NOAEL of 100 mg/kg/day. Assuming that oral dose administration results in 100 % absorption and that dermal absorption of succinic anhydride is less than 5 %, the NOAEL for a 13-week dermal toxicity study would be greater than 2000 mg/kg/day.

The risks associated with subchronic inhalation toxicity of succinic anhydride can be assessed by extrapolation of the oral NOAEL in rats to a NAEC in humans. The conversion of the oral NOAEL of 100 mg/kg/day results in a DNEL of 3.5 mg/m³ that can be used for the assessment of inhalation risk to the general population. Succinic anhydride is expected to be irritating to the respiratory tract in rodents and the conduct of a repeated dose inhalation toxicity study would cause unnecessary suffering to laboratory animals. Based on the available information, no further repeat dose toxicity testing is necessary for hazard identification or risk assessment purposes.

Genetic toxicity

In two separate laboratory studies, succinic anhydride was non-mutagenic in the Ames assay with and without metabolic activation at doses of up to 10000 µg/plate in Salmonella typhimurium strains TA97, TA98, TA100, TA1535 and TA1537. In two additional laboratory studies, succinic anhydride did not induce sister chromatid exchanges or chromosomal aberrations in cultured CHO cells in the presence or absence of exogenous metabolic activation. Data from a gene mutation assay with maleic acid are presented. In the absence of any other indications of genotoxicity for succinic anhydride, the negative result for maleic acid (a structual analogue for the hydrolysis product of succinic anhydride that is ubiquitous in cellular energy production) can be used to read across to succinic anhydride and provide further supporting evidence of no mutagenicity potential.

Reproductive/developmental toxicity

In a multigeneration study with maleic anhydride, a cyclic anhydride which shares structural and physicochemical properties with succinic anhydride, treatment-related mortality in the F0 and F1 generations occurred primarily at concentrations of 150 mg/kg/day. No significant reduction in the percentage of pregnant females or the percentage of fertile males was observed with maleic anhydride at doses up to 55 mg/kg/day over two generations. At 150 mg/kg/day, maleic anhydride was toxic to parental animals. No adverse effects on litter size or pup survival were observed at doses up to 150 mg/kg/day in F1a and F1b litters or 55 mg/kg/day in F2a and F2b litters. Sufficient information on the reproductive toxicity of maleic anhydride is available for a read-across approach and succinic anhydride would be expected to show similar effects.

The teratogenic effects of succinic anhydride were investigated in three studies using pregnant CD-1 mice. In one study, pregnant CD-1 mice given i.p. injections of succinic anhydride on days 8–10 of gestation showed malformations only at doses nearly lethal to adults. The median effective teratogenic dose, tD50, was 79 mg/kg/day and the minimum teratogenic dose, tD05, was 31 mg/kg/day. In two other studies, i.p. injections of 50 mg/kg and 25 mg/kg succinic anhydride given to CD-1 mice on gestation days 8–10, or gestation days 11–13, respectively, produced a significant increase in defects. When considered together, succinic anhydride appears to induce a significant increase in malformations predominantly at doses in the adult toxic range. Succinic anhydride was considered more potent than phthalic or maleic anhydride but was less active than propionic or acetic anhydride. These data suggest there may be a correlation between acylating ability and teratogenic potential.

The available information on the read-across partner maleic anhydride suggests effects on fertility only at high concentrations and may be considered outside the criteria which lead to classification. Developmental toxicity appears as a secondary consequence of maternal toxicity such that classification may not be necessary. Futhermore, the developmental toxicity studies were conducted using intraperitoneal injection, which is not considered an appropriate route of administration which relates to potential human exposure. Based on existing data and the fact that the hydrolysis product, succinic acid, is ubiquitous in mammalian cells, classification of succinic anhydride as a reproductive toxicant is not triggered.

DNEL derivation

Skin sensitisation is the most sensitive endpoint. Whereas no clear concentration related response was observed in the LLNA with succinic anhydride, the SIs of all examined test concentrations were greater than 3. This study does not provide information that can be used for quantitative risk assessment. Therefore, no DNEL can be derived. Since sensitisation is considered a serious effect because of its irreversibilty and long term consequences, a qualitative approach to minimise risks is applied.

The sensitising potency for skin is assessed to be weak/moderate, with the SI indices being between 9.2 and 11.6.

The respiratory sensitisation potency cannot be determined, but given the large particle sizes found in the granulometry test in combination with the weak/moderate potency for skin sensitisation, the risk for respiratory sensitisation is estimated to be low.

Succinic anhydride is classified with H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled and H 317: May cause an allergic skin reaction.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Substance is only used in industrial and professional settings.