Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

There are no studies available for the assessment of the fertility endpoint with the target substance, succinic anhydride. Therefore, data from a suitable read-across partner, maleic anhydride was used to assess the reproductive toxicity of succinic anhydride. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

In a multigeneration reproductive toxicity study (similar to OECD TG 416) in rats treated with maleic anhydride no treatment-related effects on reproduction were observed at doses of up to 55 mg/kg bw/day. Based on the results, the NOAEL for reproductive toxicity is considered to be 55 mg/kg bw/day, which corresponds to a NOAEL of 56 mg/kg bw/day for the target substance succinic anhydride.

For more details on the assessment of reproductive toxicity based on read-across to cyclic anhydrides, succinic acid and maleic acid, please refer to the assessment report (DEC 2014.025 FL Succinic anhydride, effects on fertility, read across with Meleic anhdyride, Maleic acid and Succinic acid) attached to Section 13.2 in IUCLID.

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
A few cases of respiratory rales occured. Clinical appearance and behavior of P0 rats were similar to controls.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
For further details see section "Details on results" below
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Histopathological findings: neoplastic:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
CLINICAL SIGNS (PARENTAL ANIMALS): With the exception of a few cases of respiratory rales, the clinical appearance and behaviour of all treated animals were not remarkably different from the controls.

MORTALITY (PARENTAL ANIMALS): Mortality of adult males and females was 0 to 10% in the low and mid dose group and 65 to 70% in the high dose group.Intubation error was the cause of death for both low and mid dose rats and a single high dose male.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): P/F0 body weights in the high-dose group were significantly reduced by week 11 (males: -14.1%; females: -10.4%) in both sexes and this reduction increased as the generation progressed (males: -19.7% on study week 32; females: -18%). The mid-dose group means were low but not statistically significantly different from the controls, except at the end of the generation in the females. No effects in the low dose group in either sex during both generations. Mean maternal body weight gain during gestation and lactation during the Fla and Flb matings was unaffected by the administration of Maleic anhydride at all treatment levels tested.
No treatment-related effects on food consumption were observed in any group during the study (a slight decrease in mean female food consumption (both g/rat/day and g/kg/day) was observed throughout the P/F0 generation in the 20 mg/kg/day group, but this was considered as not treatment-related.

ORGAN WEIGHT (PARENTAL ANIMALS):
There were no obvious toxicologically significant variations in either mean absolute or relative (% body weight) organ weights for animals receiving 20, 55 or 150 mg/kg/day of maleic anhydride. There were statistically significant differences observed primarily for mean relative weights. The differences were contributed to the decrease in body weight gain and were not the result of a direct effect on the organs. There was also a statistically significant variation in the mean absolute and relative weight of the thyroid/parathyroid complex for females in the 20 mg/kg/day dosage group. there were no remarkable findings, however, microscopically. A biological significance is therefore doubtful.

GROSS PATHOLOGY (PARENTAL ANIMALS)/HISTOPATHOLOGY (PARENTAL ANIMALS):There were compound"related changes observed during postmortem examination of animals dying on study (DOS) or sacrificed at its termination (SAC). The changes included hydronephrosis/dilated pelvis, mottled kidneys/irregular surface and urinary calculi. Although, the incidences were small and randomly distributed among males and females (DOS/SAC) in the 20, 55 and 150 mg/kg bw/day dosage groups. Their toxicological significance was confirmed during microscopic examination. There was also a remarkaible incidence of gastric thickening, ulcerations, erosions and gaseous distension observed during macroscopic examination among animals in the 55 and 150 mg/kg bw/day dosage groups. A variety of gastritides were observed during microscopic examination. The primary cause(s), however, was not established. Thelesions were thereefore considered to be equivocally compound-related. There were other macroscopic changes observed in various organs. they were considered to be incidental and unrelated to the adminstration of maleic anhydride.
There were compound-related degenerative/inflammatory changes observed histologically in the kidney and urinary bladder of animals in the FO generation which died on study (DOS) or were sacrificed at the termination (SAC). In addition, there were inflammatory changes observed in the stomach of males and females (SAC/DOS) which had received 20, 55 or 150 mg/kg bw/day of maleic anhydrideThe changes were considered to be equivocally compound-related because their pathogenic origin was not clearly established.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Male and female fertility indices were reduced in the 20 and 150 mg/kg bw/day groups in the F1a mating when compared with the control group. The relation of these findings to treatment is doubtful since the F1b mating fertility indices were generally comparable at all treatment levels. No difficulties were observed at parturition among the treated and control females in either the F1a or F1b matings. There were no significant differences in the mean length of gestation between the 20, 55 and 150 mg/kg bw/day females and control group females in the F1a and F1b matings.
Key result
Dose descriptor:
NOAEL
Remarks:
(fertility)
Effect level:
55 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: No effects; highest dose tested without complete maternal mortility
Dose descriptor:
LOAEL
Remarks:
(systemic)
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Dose descriptor:
LOEL
Remarks:
(local)
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: inflammatory changes in stomachs (it was not possible to conclude they were directly related to maleic anhydride)
Critical effects observed:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
For further details see section "Details on results" below
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
CLINICAL SIGNS: Clinically, in both parental generations (P0/P1), respirator rales was observed with increased frequency among treated animals when compared to the control group. In addition, treated P1/F1 parental rats vigorously resisted the physical dosing procedure.

MORTALITY: Most of these deaths were attributed to gavage-related injuries . If these deaths are omitted, then a 0 to 10% mortality was observed in both the low and mid dose groups, and significant mortality was produced only in the high dose group (100% among high-dose females). As a result of poor survival, the high dose group was terminated in the F1 generation, and the study was reduced from a three generation to a two generation study

BODY WEIGHT:
At the 20 mg/kg/day level, no effect on mean male body weight was observed throughout the F1 generation (percentage difference -2 .6 on study week 61). The 55 mg/kg bw/day group exhibited moderate to slight decreases in mean male body weight which decreased in magnitude as the F1 generation progressed (i.e., percentage difference -10 and -5 .4 on study weeks 41 and 61, respectively). Marked reductions in mean male body weight were observed at the 150 mg/kg/day level (percentage difference -12 .9 on study week 41) prior to sacrifice of the remaining males.
Females in the 20 and 55 mg/kg bw/day groups showed no adverse effects/regarding mean body weight throughout the F1 generation ; values for these treated groups generally exceeded corresponding control group values . At the 150 mg/kg bw/day level, slight to moderate inhibition of mean female body weight was observed until study week 42 when mortality reached 100% . Percentage differences for these females ranged from -12 .5 to -6 .2% on weeks 30 and 35, respectively . No statistical significance was observed at any of the F1 points of analysis .
Mean maternal body weight gain during gestation in the 20 and 55 mg/kg bw/day groups was comparable to the control group during the F2 matings (F2a and F2b). The 20 mg/kg/day group exhibited mean maternal body weight gain in excess of the control group during lactation in the F2a mating and mean loss in maternal body weight during lactation in the F2a . mating . Slight reduction of mean maternal body weight gain and no gain in mean maternal body weight were observed during lactation in the F2a and F2b mating respectively, at the 55 mg/kg bw/day level.

ORGAN WEIGHT AND HISTOPATHOLOGY: In the F1 generation, kidney weights were significantly increased in females from the low and mid dose group ; however, there were no microscopic changes observed in these kidneys.

REPRODUCTIVE PERFORMANCE:
Male and female fertility indices for the 20 and 55 mg/kg bw/day groups for the F2a and F2b mating were comparable to those of the control group . In addition, these values were generally within the range of historical control values. It was noted that fertility in this study was reduced in all groups including the control when compared to control groups of previous studies. However, this generalized reduction is not considered an effect of treatment since the control group also had reduced fertility indices. The general reduction in fertility observed throughout the P0 and P1 generations and mortality contribute to a significant reduction in the available sample size of the data with regard to reproductive and litter parameters . In the P1 generation, 17 litters were available at the 55 mg/kg bw/daylevel with 100% mortality among the 150 mg/kg bw/day females by the time of the first F1 mating.
Findings with regards to parturition and length of gestation for the Fl generation were similar to the FO generation.No dystocia was observed of the F2a and F2b matings and the mean length of gestation of the treated females was comparable to the control group during both matings of the F1generation.
Key result
Dose descriptor:
NOAEL
Remarks:
(fertility)
Effect level:
55 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: Since 100% mortality was observed among female rats at 150 mg/kg bw/day.The high dose group was terminated in the F1 generation, and and 55 mg/kg bw/day was the highest dose tested in the F1 generation.
Remarks:
Since 100% mortality was observed among female rats at 150 mg/kg bw/day.The high dose group was terminated in the F1 generation, and and 55 mg/kg bw/day was the highest dose tested in the F1 generation.
Key result
Dose descriptor:
LOAEL
Remarks:
(systemic)
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
no
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Histopathological findings:
no effects observed
Other effects:
no effects observed
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
MORTALITY/VIABILITY (OFFSPRING):
- Pup viability (birth):There were no biologically meaningful or statistically significant differences between the treated and control rats in the mean numbers of viable or stillborn pups on lactation day 0 in the F1a and F1b litter.
- Pup survival to weaning:Treeatment with maleic anhydride at levels of 20, 55 or 150 mg/kg bw/day had no apparent adverse affect on pup survival to weaning in the F1a or F1b litters.

BODY WEIGHT: In the F1a litters, mean pup body weight at birth was comparable to the control group at the 20 and 55 mg/kg bw/day levels but significantly reduced (p<0.01) in the 150 mg/kg/day group. This effect was not observed in the F1b litters; mean pup body weight at birth in all treated groups of the F1b litters was comparable to the control groups.
Pup growth during lactation was unaffected by treatment with Maleic anhydride at dosage levels of 20 and 55 mg/kg bw/day in both mating of the P0 generation. However, at the 150 mg/kg/day level, inhibition of pup body weight was observed throughout lactation [with statistical significance on days 7, 14 and 21 (by sex),] in the F1a litters and after day 7 of lactation in the F1b litters.

ORGAN WEIGHTS (OFFSPRING): In the F1 generation, the absolute kidney weights of adult females in the low- and mid-dose groups were significantly increased to 108 and to 111%, respectively, of the control value.

GROSS PATHOLOGY (OFFSPRING)/HISTOPATHOLOGY (OFFSPRING): - F1: Low incidence of mineralization (2/12 males; 3/21 females) and nephrosis (2/12 males ; 5/21 females) in the kidney of animals receiving 150 mg/kg/day. There were no microscopic changes in these kidneys.

OTHER FINDINGS (OFFSPRING): No treatment-related effects were observed on indices of fertility for males and females in the F1 generation. No adverse effects on litter size and on pup survival were observed at doses up to 150 mg/kg bw/day in the F1 litters, or at 55 mg/kg bw/day in the F2 litters.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects on litter size and on pup survival were observed with maleic anhydride at doses up to 150 mg/kg/day in F1 a and F1b litters
Critical effects observed:
no
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The high-dose group was terminated during the second generation due to treatment-related mortality in adults.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
For further details see section "Details on results" below
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Description (incidence and severity):
The examination of tissues from F2b pups revealed no compound-related changes in incidences of microscopic lesions.
Other effects:
not specified
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
MORTALITY/VIABILITY:
- Pup viability (birth): Very slight reductions in the mean number of viable pups at birth in the F2a litters were observed at the 20 and 55 mg/kg bw/day levels; there was no similar increase in the mean number of stillborn pups. These very slight reductions were not considered to represent a test article-related effect since values for both the 20 and 55 mg/kg bw/day groups (12.2 and 12.0, respectively) were comparable to the historical control value (12.3) and no similar decreases were noted in theF2b litters. The mean numbers of viable and stillborn pups at birth in the 20 and 55· mg/kg bw/day groups were comparable to the. control group in the F2b litters.
- Pup survival:There were no statistically significant differences in pup survival to weaning between treated and control litters in both matings of the FI generation at doses of 55 mg/kg/day and less.

BODY WEIGHT: Mean pup body weight at birth of treated litters in both matings of the Fl generation was statistically comparable to the control group. In the F2a litters, mean pup body weights In the low and intermediate dose groups were generally comparable to the control through lactation. However, in the F2b litters, slight to moderate reductions in mean pup body weight were observed in the 20 and 55 mg/kg/day groups throughout lactation. These reductions were statistically significant on days 14 (combined weights) and 21 (females only) of lactation in the 20 mg/kg/day group and days 4 before reduction (females only) and 21 (females only) of lactation at the 55 mg/kg/day level.
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
55 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
sexual maturation
Remarks on result:
other: Since 100% mortality was observed among parental F1 female rats at 150 mg/kg bw/day. The high dose group was terminated in the F1 generation, and 55 mg/kg bw/day was the highest dose tested in the F1 and F2 generation.
Reproductive effects observed:
no

The high dose group (150 mg/kg bw/day) during the second generation was terminated due to treatment-related mortality in F1. The lack of adverse findings in the reproductive toxicity study with maleic anhydride is also seen in1 carcinogenicity studies with succinic anhydride. No adverse findings in reproductive organs were observed in rats or mice in 2-year studies with succinic anhydride (NTP, 1990). No treatment-related effects on reproduction were observed with maleic anhydride at doses up to 55 mg/kg bw/day over two generations.

Table 1. Mortality and body weight of adult rats treated with maleic anhydride during a multigeneration reproduction study

   

          Maleic anhydride (mg/kg/day)

 F0 generation    0 20 55 150 
 Males  Mortalitya  0 (0) 10 (10)  10 (0)  70b (60)b 
   Body weightc 143, 502, 700 142, 524, 697  143, 506, 666  143, 431b, 562b 
 Females  Mortalitya  0 (0) 0 (0)  5 (0)  65b (65)b 
   Body weightc  129, 289, 368 130, 281, 345  130, 280, 337  127, 259b,317b 
 F1 generation          
 Males  Mortalitya  20 (0)  40 (40)b  40 (0)  75b (58)b
   Body weightd  113, 495, 722 107, 500, 703  103, 445, 683  85b, 431,-- 
 Females  Mortalitya  20 (0) 30 (5)   52b (10)  100b (14)
   Body weightd  96, 265, 334 100, 272, 343  95, 265, 347  84, 247, -- 
a Total dead/total treated x 100 (% mortality minus gavage-related deaths). Groups contained 10 to 12 males and 20 to 21 females; bSignificantly different from the appropriate control; cBody weight (g/rat) at weeks 0, 11 and 32 of study; dBody weights (g/rat) at weeks 30, 41 and 61 of study.  

Table 2. Fertility of rats treated with maleic anhydride during a multigeneration reproduction study

 

          Maleic anhydride (mg/kg/day)

   0 20 55 150 
 Females  F1a  14/20 (70)a 7/20 (35)b 14/20 (70) 7/20 (35)b
  F1b 10/20 (50) 8/2 (40) 11/19 (58) 6/10 (60)
 F2a  14/20 (70) 13/15 (87)  9/11 (82)  --
   F2b  12/16 (75) 12/14 (86) 8/10 (80) --
Males  F1a  8/10 (80)c 5/10 (50)  9/10 (90)  4/10 (40)b 
   F1b  6/10 (60)  5 /9 (56)  7/10 (70)  5/9 (56)
   F2a  9/10 (90) 6/6 (100) 6/6 (100) --
   F2b  8/8 (100) 7/7 (100)   5/5 (100)  --
a Number pregnant/number mated x 100 (% pregnant); bSignificantly different from control; c Number fertile/number mated x 100 (% fertile)

Table 3. Litter size of rats treated with maleic anhydride during a multigeneration reproduction study

              Maleic anhydride (mg/kg/day)
 Litter  Days after birth  0 20  55  150 
 F1a

 0

4

21

12.2a

12.0 (9.9)b

9.9 

11.0

10.5 (9.3)

9.3 

11.6

11.2 (9.3)

8.8 

13.1

13.4 (10.0)

10.0 

 F1b

 0

4

21

13.3

13.0 (9.8)

9.8 

10.3

9.6 (9.0)

8.9 

13.4

13.2 (9.9)

9.8 

11.3

10.8 (9.7)

9.3 

 F2a

 0

4

21

13.4

13.1 (9.9)

9.9

12.2

11.6 (10.0)

9.9 

12.0

11.8 (9.8)

9.8 

------
 F2b

 0

4

21

10.5

10.4 (8.2)

8.2 

13.6

13.3 (9.8)

9.7 

14.0

13.8 (10.0)

9.0 

------ 

aMean live pups/litter on indicated day. The number of pregnant females that gave birth on day 0 is presented in Table 2; bMean live pups/litter before litter reduction (mean live pups/litter after reduction to five pups/sex/litter when possible) 

Table 4. Body weight of pups from rats treated with maleic anhydride during a multigeneration reproduction study

            Maleic anhydride (mg/kg/day)
 Litter  Days after birth  0 20  55  150 
 F1a

 0

4

21

6.7a

12 (11)c

58 (56) 

6.6

11 (11)

54 (53) 

6.7

12 (11)

58 (55) 

5.8b

10 (9)

46b(44)b

 F1b

 0

4

21

6.4

11 (10)

53 (50) 

7.1b

12 (12)

54 (54)

6.2

11 (10)

51 (50) 

6.3

10 (10)

47 (46) 

 F2a

 0

4

21

6.6

11 (10)

47 (45)

6.4

10 (10)

47 (46)

6.7

10 (10)

46 (45) 

------
 F2b

 0

4

21

6.8

11 (11)

50 (57)

6.4

10 (9)

45 (44)b

6.1

9 (9)

43 (44)b

------ 
aMean weight (g) of both males and females; bSignificantly different from control; cMean weight (g) of males (mean weight (g) of females) 
Conclusions:
With reference to fertility, neither a dose-related reduction nor a pattern (during the two consecutive matings) within the parental (P0/F0) generation suggested a treatment-related effect. In F1 generation 100% mortality was observed among female rats at 150 mg/kg bw/day. Therefore, the high dose group was terminated and 55 mg/kg bw/day was the highest dose tested in the F1 generation and therefore F2 generation pups. No adverse effects on fertility were observed. Based on these observations the NOAEL (fertility) was derived at 55 mg/kg bw/d (highest dose tested under the conditions of this study).
Executive summary:

In a multigeneration generation reproduction study (similar to OECD Guideline 416) maleic anhydride (purity 99%) was administered to 10 male and 20 female rats/dose in by gavage at dose levels of 0, 20, 55 or 150 mg/kg bw/day). The rats were mated to produce two generations, each with two litters. Groups of the same size from the second litter were used for subsequent generations and were given the same dose of maleic anhydride as were their parents.Since 100% mortality was observed among parental F1 female rats at 150 mg/kg bw/day. The high dose group was terminated in the F1 and 55 mg/kg bw/day was the highest dose tested in the F1 generation and therefore F2 generation pups. The study was reduced from a three generation to a two generation study..

Renal cortical necrosis occurred in high-dose P/F0 males and females. Increased kidney weights were observed in low- and mid-dose adult F1 females. Therefore, no NOAEL could be determined and the LOAEL (systemic) was regarded as 20 mg/kg bw/day. With reference to fertility, neither a dose-related reduction nor a pattern (during the two consecutive matings) within the parental (P0) generation suggested a treatment-related effect. In F1 generation 100% mortality was observed among female rats at 150 mg/kg bw/day. Therefore, the high dose group was terminated and 55 mg/kg bw/day was the highest dose tested in the F1 generation. No adverse effects on fertility was observed. Based on these observations the NOAEL(fertility) was considered to be at 55 mg/kg bw/d (highest dose tested under the conditions of this study, equivalent to 56 mg/kg bw/day succinic anhydride).

This study is acceptable and satisfies the guideline requirement for a 2-generation reproductive study OECD 416 in rats.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
56 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
comparable to guideline study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no studies available for the assessment of the reproductive toxicity endpoint with the target substance, succinic anhydride. The target substance is a cyclic anhydrides and therefore shares similar structural and physiochemical properties with other cyclic anhydrides compound such as maleic anhydride. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

In a multigeneration generation reproduction study (similar to OECD Guideline 416) maleic anhydride (purity 99%) was administered to 10 male and 20 female rats/dose in by gavage at dose levels of 0, 20, 55 or 150 mg/kg bw/day). Since 100% mortality was observed among parental F1 female rats at 150 mg/kg bw/day. The high dose group was terminated in the F1 and 55 mg/kg bw/day was the highest dose tested in the F1 generation and therefore F2 generation pups. The study was reduced from a three generation to a two generation study.

No treatment-related effects on reproduction were observed with maleic anhydride at doses up to 55 mg/kg/day over two generations. Renal cortical necrosis was seen in F0 animals at this dose level. Increased kidney weights were observed in the low- and mid-dose adult F1 females. 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. 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.

Furthermore, in carcinogenicity studies with succinic anhydride no adverse findings in reproductive organs were observed in rats or mice (NTP, 1990). Therefore, the available data is sufficient to show an absence of reproductive toxicity hazard for succinic anhydride and additional studies in animals cannot be justified either scientifically or in terms of animal welfare.

Effects on developmental toxicity

Description of key information

There are no studies available with the target substance succinic anhydride for the assessment of the developmental toxicity endpoint following a likely route of human exposure such as the oral route. Therefore, data from suitable read-across partners maleic anhydride and adipic acid were used to assess the developmental toxicity of succinic anhydride on rats and rabbits following oral route. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

In an oral developmental toxicity study conducted similar to OECD TG 414 with maleic anhydride in rats, no effects on any development parameters were recorded at any dose. Based on the results, the NOAEL for developmental toxicity is considered to be 140 mg/kg bw/day, which corresponds to a NOAEL of 143 mg/kg bw/day for the target substance succinic anhydride.

In an oral developmental toxicity study conducted similar to OECD TG 414 with adipic acid in rabbits, the source substance adipic acid did not induce effects on the development up to the highest tested dose of 250 mg/kg bw/day. Based on the results, the NOAEL for developmental toxicity is considered to be 250 mg/kg bw/day, which corresponds to a NOAEL of 171 mg/kg bw/day for the target substance succinic anhydride.

For more details on the assessment of reproductive toxicity based on read-across to cyclic anhydrides, succinic acid and maleic acid, please refer to the assessment report (DEC 2014.025 FL Succinic anhydride, effects on fertility, read across with Meleic anhdyride, Maleic acid and Succinic acid) attached to Section 13.2 in IUCLID.

Link to relevant study records

Referenceopen allclose all

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:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
The general appearance and behavior of rats were not altered by treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
While one adult died in each of the experimental groups, the overall survival in these groups was 96%.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Dams in the experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Dams from all test groups produced normal-sized litters, and there was no evidence of postimplantation loss
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The number of resorptions/dam was not altered after treatment.
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
The number of viable fetuses/dam was comparable between treatment groups and control.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
There was a minimal reduction in the ratio of pregnant animals to the number of treated animals between control (23/25) and the low (24/25), mid (20/25) and high dose (21/25) treated animals.
Other effects:
not examined
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Respiratory involvement and red nasal discharge were observed in all dosage groups. The incidence of these was higher in the treated groups, though not in a dose-related pattern. No treatment-related deaths (one rat in each dosage group died during the first part of treatment; the cause of death was not determined) nor abnormal behavior was observed in any of the maleic anhydride treated groups. Mean body weight gain was reduced in the 30 mg/kg/day dosage group for the first three days of treatment. There was a slight mean body weight loss in the 90 and 140 mg/kg/day dosage groups for the first three days of treatment. These reductions in weight gains resulted in reduced mean body weight gains over the entire treatment period in all treatment groups compared to the control (however, mean weight of all groups was within 5% of control on days 15 and 20. No biologically meaningful differences in the mean number of viable fetuses, implantations, post implantation losses, corpora lutea, or in the male to female sex ratio between any of the maleic anhydride treated groups and the control group. The general appearance and behavior of rats were not affected by treatment.
Dose descriptor:
NOAEL
Effect level:
140 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Only slight effects on the body weight in the 90 and 140 mg/kg treatment groups. These effect were reversible, and there were no statistically significant effects on body weight at any of the times examined.
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Compared with concurrent controls, fetal body weights were slightly reduced for all test groups, but the reductions were statistically significant only in the low- and high-dose groups, However, this is not considered to be compound-related, because fetal weights for concurrent control and all treated groups were slightly greater than the values for historical controls.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The number of viable fetuses/dam was not affected by treatment.
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Dams from all test groups produced normal-sized litters.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation.
The fetal variations were comparable both in type and frequency in the control and treated groups.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation.
The fetal variations were comparable both in type and frequency in the control and treated groups.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation.
The fetal variations were comparable both in type and frequency in the control and treated groups.
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Mean fetal body weights were lower in the treatment groups than in the control group. This was not considered compound related due to the unusually high mean fetal body weight in this concurrent control group (mean: 4 g). External evaluation, internal examination, and skeletal observations of fetuses from all three treatment groups showed no anomalies in fetal development which could be attributed to maleic anhydride (slight increase in fetal malformations in the 30 (2/23 litters) and 140 mg/kg/day dosage group (3/21 litters) when compared to the control group (1/23 litters) is considered due to random occurrence due to the variety of abnomalities observed).
Dose descriptor:
NOAEL
Effect level:
140 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
140 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetotoxicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
In developmental toxicity study (equivalent to OECD 414) maleic anhydride (>99% purity) was administered to 25 female Wistar rats/dose in corn oil at dose levels of 0, 30, 90 or 140 mg/kg bw/day from days 6 through 15 of gestation. On day 20 of gestation the animals were sacrificed. Based on the results, the NOAEL for both maternal toxicity and fetal toxicity of maleic anhydride in this study is considered to be to 140 mg/kg bw/day.
Executive summary:

In a developmental toxicity study (equivalent to OECD 414), CD rats (25 mated females/group) were treated orally with 30, 90, or 140 mg/kg/day of maleic anhydride from Day 6 through Day 15 of gestation. Mated females in the control group were treated in a similar manner with 14 mL/kg of corn oil. All females were sacrificed with carbon dioxide on Day 20 of gestation, and the fetuses were delivered by cesarean section. All fetuses were weighed and examined for external abnormalities. Approximately one-third of the fetuses were placed in Bouin’s fixative and examined for soft tissue abnormalities . The remaining fetuses were fixed in alcohol, cleared with potassium hydroxide, stained with Alizarin Red S and examined for skeletal abnormalities.

There were no changes in appearance or behavior attributable to treatment with maleic Anhydride at dosage levels of 30, 90 and 140 mg/kg bw/day. Respiratory involvement and red nasal discharge were observed in all dosage groups. The incidence of these was higher in the treated groups, though not in a dose-related pattern. One rat in each dosage group dl.dd during the first part of treatment. The cause of death was not determined. There were reduced mean maternal body weight gains during the first three days of treatment in the 30 mg/kg bw/day dosage group when compared to the control group. In the 90 and 140 mg/kg bw/day dosage groups mean body weight losses were observed for the first 3 days of treatment. These reductions in weight gains resulted in reduced mean weight gains over the entire treatment period in all treatment groups when compared to the control group. There were no biologically meaningful differences in the mean number of viable fetuses, implantations, post implantation losses, corpora lutea or in the male to female sex ratio between any of the maleic anhydride treated groups and the control group. Based on the results, the NOAEL for maternal toxicity is considered to be 140mg/kg bw/day (equivalent to 143 mg/kg bw/day succinic anhydride).

There were no treatment-related effects in developmental parameters. Therefore, based on the result the developmental NOAEL is also considered to be 140 mg/kg bw/day (equivalent to 143 mg/kg bw/day succinic anhydride).

 

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

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:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Analytical verification of doses or concentrations:
not specified
Statistics:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal in the positive control group and one animal the lower mid dose died before day 29.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects observed on average body weights.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
One animal in the positive control group and one animal the lower mid dose died or aborted before day 29. No other animal showed signs of abortion prior to the scheduled sacrifice. For further information please refer to Table 2/3 in box "Any other information on results incl. tables".
Pre- and post-implantation loss:
not examined
Description (incidence and severity):
No test item-related effects were noted for number of implantation sites. For further information please refer to Table 2 in box "Any other information on results incl. tables".
Total litter losses by resorption:
not specified
Description (incidence and severity):
No test item-related effects were noted for number of total resorptions. For further information please refer to Table 2 in box "Any other information on results incl. tables".
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Description (incidence and severity):
For further information please refer to Table 2 in box "Any other information on results incl. tables".
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Successful mating resulted in 13/10 pregnancies in the LD group, 16/11 in the LMD group, 15/10 in the HMD group and 20/14 in the HD group when compared to 19/11pregnancies in the control group. For further information please refer to Table 3 in box "Any other information on results incl. tables".
Other effects:
not examined
Details on maternal toxic effects:
The administration of up to 250 mg/kg bw/day of the compound to pregnant rabbits for 13 consecutive days had no effect on nidation or on maternal survival.
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: no adverse toxic effects up to the highest dose tested
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No test-item related effects were observed for fetal body weight changes in comparison to the control.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No test item-related effects were noted for number of live foetuses. For further information please refer to Table 2 in box "Any other information on results incl. tables".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No test item-related effects were noted for sex ratio. For further information please refer to Table 2 in box "Any other information on results incl. tables".
Changes in litter size and weights:
not examined
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
No test item-related effects were noted in comparison to the control.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No test item-related effects were noted in comparison to the control.
Visceral malformations:
no effects observed
Description (incidence and severity):
No test item-related effects were noted in comparison to the control.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
The administration of up to 250 mg/kg bw/day had no effect on fetal survival. The number of abnormalities seen in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. No difference between treatment and control groups were found for total no. of fetuses, total no. of live litters and fetal weights.
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: no adverse effects observed up to the highest dose tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table 2: Reproduction data

Dose mg/kg bw

Control 6-AN** 2.5 12.0 54.0 250.0
 
Pregnancies 11 13 10 11 10 14
Total  0 1 0 1 0 0
Died or aborted (before day 29) 11 12 10 10 10 14
 
Corpora lutea            
Total 104 108 108 108 107 152
average/dam mated  9.45 9.00 10.8 9.82 11.9 10.1
 
Liver litters            
Total* 11 8 9 9 8 12
 
Implantation sites            
Total 77 103 90 86 88 102
average/dam* 7.00 8.58 9.00 8.60 8.80 7.29
 
Resorptions            
Total* 10 56 9 14 13 16
Dams with 1 or more sites resorbed 4 10 5 5 3 6
Dams with all sites resorbed - 4 - 1 1 1
Per cent partial resorptions 36.4 83.3 50.0 50.0 30.0 42.9
Per cent complete resorptions - 33.3 - 10.0 10.0 7.14
 
Live Fetuses            
Total 67 46 73 67 65 78
Average/dam* 6.09 3.83 7.30 6.70 6.50 5.57
Sex ratio (M/F) 0.72 1.56 1.03 1.03 1.03 0.66
 
Dead Fetuses          
Total* - 1 8 5 10 8
Dams with 1 or more dead - 1 2 3 1 1
Dams with all dead - - 1 - 1 1
Per cent partial dead - 8.33 20.0 30.0 10.0 7.14
Per cent all dead - - 10.0 - 10.0 7.14
 
Average Fetus Weight, g 42.3 36.5 38.1 40.0 39.4 41.4
*Included only those dams examined at term            
** Positive Control: 2.5 mg/kg of 6-aminonicotinamide dosed on Day 9         

Table 3: Fate summary

Material  Dose ** (mg/kg) Total 
Mated
Total
Pregnant
Surviving at term
Total
Surviving at term
Pregnant
Control 0.0 19 11 19 11
6-AN* 2.5 16 13 15 12
FDA 71-50 2.5 13 10 13 10
FDA 71-50 12.0 16 11 15 10
FDA 71-50 54.0 15 10 15 10
FDA 71-50 250.0 20 14 20 14

* positive Control: 2.5 mg/kg of 6-aminonicotinamide dosed on Day 9
** Administered as a water solution

Conclusions:
Under the given conditions, the NOAEL for maternal and developmental toxicity is considered to be 250 mg/kg bw/day.
Executive summary:

In a developmental toxicity study adipic acid (purity not specified) was administered to 10-14 pregnant female rabbits/dose by gavage at dose levels of 0, 2.5, 12, 54 or 250 mg/kg bw/day from days 6 through 18 of gestation.

There were no treatment-related effects on maternal toxicity. The maternal NOAEL is considered equal or higher to 250 mg/kg bw/day. There were no treatment-related effects in developmental parameters. The developmental NOAEL is considered to be 250 mg/kg bw/day (equivalent to 171 mg/kg bw/day succinic anhydride)

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
143 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
comparable to guideline study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no reliable developmental toxicity studies available with the target substance, succinic anhydride. The target substance is a cyclic anhydrides and therefore shares similar structural and physiochemical properties with other cyclic anhydrides compounds such as maleic anhydride. In addition, like other cyclic anhydrides, succinic anhydride is readily hydrolysed in water to the underlying dicarboxylic acid, succinic acid (half-life in water: 5 min). Adipic acid, a dicarboxylic acid compound structurally similar to succinic acid (one additional CH2 group in the aliphatic chain of the source substance) is therefore used as a read-across partner. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

The first key study is a developmental toxicity study conducted equivalent to OECD 414 with the source substance maleic anhydride. In this study, CD rats (25 mated females/group) were treated orally with 30, 90, or 140 mg/kg/day from day 6 through day 15 of gestation. All females were sacrificed with carbon dioxide on Day 20 of gestation, and the fetuses were delivered by cesarean section.

The results showed, that the general appearance and behaviour of rats were not altered by maleic anhydride. While one adult died in each of the experimental groups, the overall survival in these groups was 96%. Dams in the experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined. Dams from all test groups produced normal-sized litters, and there was no evidence of post implantation loss. Compared with concurrent controls, fetal body weights were slightly reduced for all test groups, but the reductions were statistically significant only in the low- and high-dose groups, However, this is not considered to be compound-related, because fetal weights were slightly greater than the values for historical controls. Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation. The fetal variations were comparable both in type and frequency in the control and treated groups.

Based on the results obtained, the maternal and developmental NOAEL can be considered to be 140 mg/kg bw/day (equivalent to 143 mg/kg bw/day succinic anhydride).

The second key study is also a developmental toxicity study conducted equivalent to OECD 414 with adipic acid. In this study, Dutch-belted rabbits (10-14 pregnant females/group) were treated orally with 0, 2.5, 12, 54 or 250 mg/kg/day adipic acid from day 6 through day 18 of gestation. All females were sacrificed on Day 29 of gestation.

The results did not show treatment-related effects on maternal toxicity or any assessed developmental parameter. The NOAEL for maternal or developmental toxicity is therefore considered to be 250 mg/kg bw/day (equivalent to 171 mg/kg bw/day succinic anhydride).

Furthermore, in one teratogenicity study, pregnant CD-1 mice given ip injections of succinic anhydride on days 8 -10 of gestation showed malformations only at doses which were lethal to adults. Only structural defects were included in the evaluation of teratogenic potential and the median effective teratogenic dose, tD50, was 79 mg/kg/day and the minimum teratogenic dose, tD05, was 31 mg/kg/day. As the effects occur together with maternal toxicity, the effects needs to be considered as secondary. The median teratogenic dose, tD50, for succinic anhydride was 0.8 mmol/kg/day and the tD05 was 0.3 mmol/kg/day. The relative teratogenic index, defined as the ratio of minimum lethal dose (LD01) to minimum teratogenic dose (tD05), was 1.0. The reliability of this study is limited because only major structural defects were included in the evaluation of teratogenic potency. Also, intraperitoneal injection is not a relevant route of human exposure. Additionally, this route is also not relevant for chemicals with low chemical stability in aqueous solutions because anticipated exposure by the oral, dermal or inhalation route will not result in the parent compound reaching the conceptus due to the rapid hydrolysis of succinic anhydride.

These findings were also observed in  two other studies investigating the teratogenicity and chemical reactivity of selected anhydrides, ip injections of 50 mg/kg (Fabro et al, 1976) and 25 mg/kg (Brown et al, 1978) succinic anhydride given to CD-1 mice on gestation days 8 -10, or gestation days 11 -13, respectively, produced a significant increase in defects. 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. These studies were not conducted under GLP. There is only limited information and only the abstracts have been published. Therefore, these studies are of very limited reliability and a klimisch score of 4, not assignable, may be appropriate.

In conclusion, the key studies are reliable and sufficient to show an absence of developmental toxicity hazard for succinic anhydride.

Justification for classification or non-classification

Based on the existing data, the target substance does not warrant classification for reproductive/developmental toxicity in accordance with CLP Regulation 1272/2008.

Additional information