Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981-03-11 to 1981-04-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report date:
1981

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted 12 May 1981
Deviations:
no
Principles of method if other than guideline:
standard protocol for determination of acute median lethal oral dose.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Succinic anhydride
EC Number:
203-570-0
EC Name:
Succinic anhydride
Cas Number:
108-30-5
Molecular formula:
C4H4O3
IUPAC Name:
succinic anhydride
Specific details on test material used for the study:
Succinic anhydride appeared as white solid flakes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system 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.

Administration / exposure

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 dose; Principal 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

Results and discussion

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
Effect levelsopen allclose all
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. (see Table 1 in section "Any other information on results incl. tables" for details on mortality data)
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:
For details on body weight see Table 2 in section "Any other information on results incl. tables" .
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

Any other information on results incl. tables

Table 1. Mortality data

 

     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    

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The results of this study indicate that succinic anhydride is of low acute oral toxicity when tested according to OECD test guideline 401. The combined LD50 for males and females is 1794.9 mg/kg bw. This result would indicate classification for acute toxicity Cat.4, H302 (Harmful if swallowed) according to the CLP criteria as set out in Regulation (EC) 1272/2008 may be appropriate.
Executive summary:

In an acute oral toxicity study performed according to OECD TG 401, groups of 5 fasted Sprague-Dawley rats/sex were given a single oral dose of succinic anhydride by gavage at doses of 1214, 1500, 1854, 2291, 2832 and 3500 mg/kg bw and observed for at least 14 days.

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.

The oral LD50 value was 2157.2 mg/kg bw for males and 1510.5 mg/kg bw for females. The combined oral LD50 was 1794.9 mg/kg bw.

Clinical signs included decreased activity in males at dose levels of 1500 mg/kg and higher. 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 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.

Black pylorus in stomach and intestines containing a blood-like substance were seen in males at doses of 2291 mg/kg and above and in females at doses of 1854 mg/kg and higher.

At the highest dose in males, green areas on the lungs were seen at necropsy. In females, these effects were observed at doses levels of 2291 and 3500 mg/kg.

Succinic anhydride is of low toxicity based on the combined LD50 of 1794.9 mg/kg bw. Classification to Category 4 for acute oral toxicity is warranted according to the CLP criteria as set out in Regulation (EC) 1272/2008.