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Description of key information

Succinic anhydride was slightly toxic when tested in a guideline-comparable study of acute oral toxicity.  When tested in a guideline-similar study for acute dermal toxicity, maleic anhydride, a structural analogue of succinic anhydride, showed very low toxicity.  A similar absence of effects was reported in a recent study with succinic anhydride - the median lethal dermal dose exceeded the limit of 2000 mg/kg bw. 
Acute inhalation testing is not required. The results of the granulometry 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 only a very small portion of respirable material present in the batch of succinic anhydride. The particles are not in the respirable size range for rats or humans and so inhalation exposure is not likely. Given the result can be predicted from the physical-chemical properties, an inhalation toxicity study cannot be justified also because of animal welfare reasons.

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:
11 March 1981 to 27 March 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline- and GLP- compliant study.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
standard protocol for determination of acute median lethal oral dose.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
After an acclimation period of at least 7 days, animals were assigned to groups of two males and two females at five dose levels for the preliminary study and five males and five females at six dose levels for the principal study. Animals were individually housed in wire mesh bottom cages in environment controlled rooms.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Animals were fasted overnight prior to receiving a single oral dose of the test article at five dosing levels. The test article was administered at a constant concentration and the volume of dosing solution did not exceed 5 mL per animal, where possible.
Doses:
Preliminary study: 50, 139, 387, 1078 and 3000 mg/kg Principal study: 1214, 1500, 1854, 2291, 2832, and 3500 mg/kg
No. of animals per sex per dose:
Preliminary study: 2 males and 2 females per dosePrincipal study: 5 males and 5 females per dose
Control animals:
no
Details on study design:
All animals on the main study were observed for at least 14 days or until all signs of reversible toxicity subsided, whichever occurred later. Animals were observed three times a day on the day of dosing and twice daily for the remainder of the study. All gross or visible toxic or pharmacological effects were recorded. Body weights were recorded initially and on days 8 and 15 or at death. All animals that died and all animals sacrificed at termination were subject to gross necropsy.
Statistics:
No details but graphical representations indicate probit analysis used to determine the median lethal dose
Preliminary study:
The preliminary dose range -finding study gave mortality results at dose levels of 50 (0/4); 139 (0/4); 387 (0/4); 1078 (0/4) or 3000 (4/4) mg/kg bw
Sex:
male
Dose descriptor:
LD50
Effect level:
2 157.2 mg/kg bw
95% CL:
1 722.2 - 2 758.6
Sex:
female
Dose descriptor:
LD50
Effect level:
1 510.5 mg/kg bw
95% CL:
1 086.9 - 1 816.7
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 794.9 mg/kg bw
95% CL:
1 505 - 2 071.5
Mortality:
For male rats, cumulative mortality at dose levels of 1214, 1500, 1854, 2291, 2832, and 3500 mg/kg was 0/5, 1/5, 2/5, 3/5, 3/5 and 5/5, respectively. For female rats, cumulative mortality at the same dose levels was 1/5, 3/5, 3/5, 5/5, 5/5 and 5/5, respectively.
Clinical signs:
In males at dose levels of 1500 mg/kg and higher, decreased activity and death was seen. Soft stools were reported for males dosed at 2291 mg/kg and ataxia was observed for males at the two highest dose levels. In females, decreased activity and death was observed at all dose levels. Soft stools were observed in females dosed at 1214 mg/kg and ataxia was observed at doses of 1500 mg/kg and higher.
Body weight:
See Table 2 below.
Gross pathology:
Black pylorus in stomach and intestines containing a blood-like substance were seen in males at doses of 2291 mg/kg and above. At the highest dose, green areas on the lungs were seen in males at necropsy. In females, black stomach pyloric and intestines containing a blood-like substance were seen at doses of 1854 mg/kg and higher. At necropsy, green areas on the lungs were seen in females dosed at 2291 and 3500 mg/kg.
Other findings:
No data

Table 1. Mortality

 

     Time of Death        

 
  Dose level (mg/kg)  Day 1  Day 2  Day 3  Day 8  Day 15  Cumulative mortality
 Males                 

 1214

 0  0 0/5 
 1500  0 1/5 
 1854  1 2/5 
 2291 0 3/5 
 2832 3/5 
 3500 --  -- --  --  5/5 
 Females                 
 1214 1/5 
 1500  0 3/5 
 1854 3/5 
 2291 --  --  --  5/5 
 2832  5 --  --  --  --  5/5 
 3500  5 --  --  --  --  5/5 

Table 2. Summary of body weights

 

          Body weights (mean + SD)

 Dose level (mg/kg)  Initial*  8 days  15 days  at death
 Males           
 1214#  188.8 + 14.9  254.4 + 11.4 281.6 + 12.5  -- 
 1500  319.8 + 23.3 346.3 + 40.4  365.3 + 38.5  294.0 
 1854  322.8 + 8.3 348.0 + 19.1  372.7 + 16.3  307.0 + 35.4 
 2291 324.8 + 24.5  359.5 + 12.0  386.0 + 5.7  308.7 + 12.1 
 2832 318.0 + 16.1  364.5 + 12.0  385.5 + 13.4  312.7 + 19.4 
 3500  306.0 + 20.4 --  --  306.0 + 20.4 
 Females           
 1214# 191.2 + 6.4  226.0 + 12.3  227.0 + 12.3  188.0 
 1500 222.0 + 15.7  239.0 + 7.1  249.0 + 9.9  208.7 + 17.2 
 1854  214.4 + 9.3  247.0 + 15.6 255.0 + 24.0  210.0 + 11.1 
 2291  230.4 + 28.2 --  --  227.2 + 25.2 
 2832  225.6 + 8.6 --  --  225.6 + 8.6 
 3500  231.2 + 19.8 --  --  231.2 + 19.8 
      *Fasted body weight   # Dosed on a different day    
Interpretation of results:
harmful
Remarks:
Migrated informationCriteria used for interpretation of results: EU
Conclusions:
Succinic anhydride was found to be slightly toxic when tested for acute oral toxicity via OECD test guideline 401.Although succinic anhydride is an endogenous material in humans and associated with succinic acid/succinate in the Kreb's cycle, nonetheless the effects observed particularly in female rats suggest that some acute oral toxicity is probable at levels much higher than normally encountered physiologically, but still within the classification range for "harmful if swallowed" materials.
Executive summary:

The LD50 value for succinic anhydride following administration of a single gavage dose to male and female Sprague-Dawley rats was 2157.2 and 1510.5 mg/kg bw, respectively. At the highest dose level in males (3500 mg/kg bw) and the three highest dose levels in females (2291, 2832 and 3500 mg/kg bw), all test animals died by day 2 of the study. Clinical signs included a decreased activity, ataxia and soft stools. Gross necropsy revealed blackening of the pyloric region of the stomach and a blood-like, viscous substance in the intestines.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 794.9 mg/kg bw

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:
16 to 30 March 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Proprietary GLP guideline-compliant study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Remarks:
OECD; self-certified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The animals were male and female Crl:CD(SD) rats, obtained from Charles River Deutschland GmbH. Females were nulliparous and non-pregnant. The males were approximately 8 weeks old and the females were approximately 12 weeks old at the time of administration. The rats were acclimatised for at least 7 days.A health inspection was performed prior to commencement of the study to ensure that the animals were in good health. Special attention was paid to the skin, which was confirmed to be intact and free from any abnormality. Room temperature ranged from 19.96 to 20.99°C. Relative humidity ranged from 45.08 to 58.78%. There were 12 air changes per hour, and artificial light was provided on a 12 hour light/dark cycle. The rats were housed singly in Makrolon type III cages with wire mesh lids. Autoclaved Aspen wood chips were provided as bedding. Nibbling wood bricks and nesting material from the same material and source as the bedding material were also provided. Ssniff R/M-H maintenance diet for rats and mice was provided ad libitum (Ssniff Spezialdiäten GmbH, Germany). Tap water was provided ad libitum. Individuals were identified with felt-tipped pen on the tails.
Type of coverage:
semiocclusive
Vehicle:
corn oil
Details on dermal exposure:
A single dermal administration was performed by applying the test substance to an area of least 10% of the estimated body surface. The test site was located on the dorsal thoracic region. An area of 6.5 cm x 8 cm (52 cm²) was marked.The hair of the dorsal trunk was clipped with an electric hair clipper one day before test substance application. Test substance amounts were calculated and weighed for each rat using individual body weights determined on the day of administration.A cellulose patch (Pehazell, Hartmann AG) with the correct amount of test substance on the surface and soaked in corn oil (to get optimal contact with the skin) was applied to the test site and held in place with non-irritating tape (Blenderm 3M). The test site was covered by a semi-occlusive dressing (Fixomull Stretch).At the end of the exposure period the dressing, the tape and the patch were removed. Residual test substance was wiped off using wet cellulose tissue, if necessary.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 rats/sex
Control animals:
not required
Details on study design:
Observations were performed 0-0.5, >0.5-1, >1-2, >2-4 and >4-6 hours after administration, then at least once daily for a total of 2 weeks. Observations included but were not limited to changes in skin, fur, eyes, the occurrence of secretions and excretions, autonomic activity, changes in gait, posture and the presence of convulsions. Body weights were determined immediately prior to administration, then 7 and 14 days after administration. All animals were sacrificed at the end of the observation period by CO2 inhalation and subjected to a necropsy including a gross pathological examination.
Statistics:
Formal statistical analysis was not required.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
No clinical signs were observed in any animal during the observation period.
Body weight:
All rats gained weight in the first and second week of the observation period.
Gross pathology:
No abnormalities were detected at necropsy.
Other findings:
3/5 males and all females exhibited erythema and eschar formation at the application site. These local effects were observed 1 day after administration lasting until a maximum of 7 days post administration.

The acute dermal LD50 of succinic anhydride is greater than 2000 mg/kg bw in rats. Comparison of the dermal toxicity results for succinic and maleic anhydrides, suggest that succinic anhydrides is less toxic than other anhydrides.

Interpretation of results:
not classified
Remarks:
Migrated informationCriteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 of succinic anhydride is greater than 2000 mg/kg bw in rats.
Executive summary:

The acute dermal toxicity of succinic anhydride was determined in rats, according to OECD test method 402. The test substance was administered once to the shaved dorsal skin of 5 male and 5 female Sprague-Dawley rats at a dose of 2000 mg/kg bw. The test site was covered by a semi-occlusive dressing, held in place for 24 hours. The rats were observed for 14 days.

There were no effects on body weight; all animals gained weight during the observation period. No systemic signs of toxicity were noted, however local irritation at the test site (erythema and eschar formation) were observed 1 to 7 days after administration. No abnormalities were detected at necropsy.

It was therefore concluded that the acute dermal LD50 of succinic anhydride is greater than 2000 mg/kg bw in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

The single dose oral toxicity of succinic anhydride in Sprague-Dawley rats was reported as 1794.9 mg/kg bw for males and females. The acute dermal median lethal dose for succinic anhydride was found to exceed the limit dose level in rats, >2000 mg/kg bw.

Clinical signs included reduced appetite and activity, increasing weakness, collapse and death inalbino rabbits following acute dermal administration of maleic anhydride. The LD50 is between 1600 and 2600 mg/kg/day. Macroscopic evaluation showed enlarged gall bladder, discoloration of spleen and kidneys, and gastrointestinal inflammation. Similar results would be expected with succinic anhydride

Acute inhalation testing is not required. The results of the granulometry indicate the L10 value for particle size was 377 µm and the L50 was greater than 1100 µm.

On the basis of these results only a very small part of the particles in the batch of succinic anhydride may be smaller than 100 µm and may be respirable. The lager part of 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.

Justification for classification or non-classification

It is not proposed to classify succinic anhydride for acute dermal toxicity based on experimental results. Classification for acute inhalation toxicity is not appropriate - the results of granulometry testing indicate there are no respirable particles present in the test material.

Based on the available acute oral toxicity results, female rats are slightly more susceptible to succinic anhydride toxicity. While the males are less susceptible, and based on male data alone, no classification would be required, yet the combined value using male and female data results in an LD50 value of less than 2000 mg/kg bw. It is therefore proposed to classify succinic anhydride as R22 "Harmful if swallowed" according to Directive 67/548/EEC. It is classified as H302 "Harmful if sawllowed, the signal word Warning and the pictogram GHS07.