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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: very concise study summary is available

Data source

Reference
Reference Type:
publication
Title:
Studies on effects of sodium benzoate on fetuses and offspring of Wistar rats
Author:
Onodera H, Ogiu T, Matsuoka C, Furuta K, Takeuchi M, Oono Y, Kubota T, Miyahara M, Maekawa A, Odashima S
Year:
1978
Bibliographic source:
Eis Shik Hok, 96: 47-54

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pregnant Wistar rats, 15 to 17 weeks old, were given sodium benzoate throughout their whole gestation period.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Sodium benzoate
EC Number:
208-534-8
EC Name:
Sodium benzoate
Cas Number:
532-32-1
IUPAC Name:
sodium benzoate
Details on test material:
- Name of test material (as cited in study report): Sodium benzoate

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 15 to 17 weeks old

Administration / exposure

Route of administration:
oral: feed
Duration of treatment / exposure:
whole gestation period
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1, 2, 4, 8 %
Basis:
nominal in diet
No. of animals per sex per dose:
12-18 females per dose
Control animals:
yes

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: yes
- Organs examined: thymus, spleen, heart, lung, liver, adrenal, testis, ovary, kidney
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes
- Skeletal examinations: Yes: [91-142 per litter ]
- Head examinations: No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In 4 and 8 % groups, food consumption of pregnant rats was much lower than those of the other experimental and control groups. The body weight of rats in 8 % group decreased and that in 4 % group increased slightly.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 330 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 257 mg/kg bw/day
Based on:
other: methyl benzoate
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Many abnormalities of organs and skeletal systems were found in fetuses in 4 and 8 % groups.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 330 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
1 257 mg/kg bw/day
Based on:
other: methyl benzoate
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Observation of mother rats and fetuses at the 20th gestation day

Group

No. of mother rats

No. of implants

No. of dead fetus & resorbed embryo

No. of viable fetuses

Sex ratio (Male:Female)

Av. body weight of viable fetuses

(g ± SD)

Total

Average ± SD

Control

15

194

12.93 ± 1.73

13 (6.7 %)

181

0.95 (88:93)

370 ± 0.40

1 %

15

179

11.93 ± 3.66

20 (11.2 %)

159

1.15 (85:74)

3.71 ± 0.37

2 %

16

194

12.13 ± 3.80

11 (5.7 %)

183

1.18 (99:84)

3.68 ± 0.35

4 %

18

213

11.89 ± 4.09

62 (29.1 %)

151

1.25 (84:67)

2.62 ± 0.32

8 %

12

141

11.75 ± 2.62

24 (17.0 %)

117

0.98 (58:59)

2.22 ± 0.42

Table 2. External and internal observation of fetuses

Group

External observation

Internal observation

No. of fetuses examined

No. of fetuses with abnormality

Type and No. of abnormality

No. of fetuses examined

No. of fetuses with abnormality

Type and No. of abnormality

Control

181

0

 

41

0

 

1 %

159

0

 

33

1

B-AO 1

2 %

183

0

 

41

1

U-PE 1

4 %

151

17

slight edema 17

36

12*

U-MO 5

B-MO 1

U-AO 2

HC 3

B-PE 2

U-RHP 1

8 %

117

1

slight edema 1

26

11**

U-MO 6

 

 

 

 

 

 

U-AO 1

 

 

 

 

 

 

HC 3

 

 

 

 

 

 

CHP 1

 

 

 

 

 

 

B-PE 2

Key to abbreviation:    B-AO, bilateral anophthalmia; U-PE, unilateral pyelectasis;

                                  U-MO, unilateral microphthalmia; U-AO, unilateral anophthalmia;

                                  B-MO, bilateral microphthalmia; HC, hydrocephalus;

                                  B-PE, bilateral pyelectasis; U-RHP, unilateral renal hypoplasia;

                                  CHP, cerebral hypoplasia.

*One had U-AO and HC, and another one had U-AO and U-MO.

**One had B-PE and HC, and another one had U-AO and HC.

Table 3. Skeletal observation of fetuses

Group

No. of mother rats

No. of fetuses examined

Ossification state

No. of fetuses with abnormal bones

No. of ossified sacral and caudal vertebrae (Average ± SD)

Lumbar ribs

Cervical ribs

Varied stenebrae

Others

Control

15

140

8.61 ± 0.92

32

0

50

Spincule 1

Fusion of thoracic arches 1

Small pubis 1

1 %

14

126

8.48 ± 0.84

29

0

47

 

2 %

15

142

8.47 ± 0.69

45

0

51

Fusion of thoracic arches 1

Shortning of cervical arches 1

Waved rib 1

4 %

15

115

5.58 ± 1.60

49

5

112

Fusion of cervical arches 5

Lack of cervical centrum 1

Waived rib 4

Deformed centrums 3

Fusion of ribs 1

8 %

12

91

4.89 ± 1.68

15

4

91

Fusion of cervical arches 1

Deformed centrums 1

Shortning of rib 1

Lack of rib 1

Table 4. Delivering rate, lactation rate and survival rate at 8-week-old in offspring rats

Group

No. of mother rats

No. of implants

No. of born offspring (delivering rate)

Rate of perinatal death

Lactation rate

Survival rate at

8-week-old

Control

5

64

48 (75.0 %)

0 %

100 %

100 %

1 %

5

61

49 (80.3 %)

0 %

100 %

100 %

2 %

4

55

45 (81.8 %)

0 %

97.8 %

95.5 %

4 %

4

52

26 (50.0 %)

100 %

0 %

0 %

8 %

5

49

4 (8.2 %)

100 %

0 %

0 %

Table 5. Abnormality of skeletal systems and other pathological findings in offspring rats

Group

Animal No. (mother rat)

No. of offspring rats examined

No. of offspring rats with abnormality

Skeletal abnormality and No. of rats

Pathological findings

Control

1

9

1 (11.1 %)

Cervical rib

1

 

2

12

2 (16.7 %)

Cervical rib

2

 

3

12

6 (50.0 %)

Cervical rib

5

 

Lumbar rib

1

 

4

4

1 (25.0 %)

Lumbar rib

1

 

5

11

1 (9.1 %)

Lumbar rib

1

 

1 %

6

8

3 (37.5 %)

Cervical rib

3

 

7

11

2 (18.2 %)

Cervical rib

2

Inhibited growth 1

8

12

9 (75.0 %)

Cervical rib

7

 

Varied sternebrae

2

 

9

12

7 (58.3 %)

Cervical rib

6

 

Lumbar rib

1

 

10

6

3 (50.0 %)

Cervical rib

3

 

2 %

11

10

4 (40.0 %)

Cervical rib

4

 

12

12

4 (33.3 %)

Cervical rib

4

 

13

12

6 (50.0 %)

Cervical rib

6

Delay of opening eyelids 3

Urinary bladder stones 1

14

8

4 (50.0 %)

Cervical rib

3

Delay of opening eyelids 1

Detachment of dorsal nodules of servical vertebra

1

 

Applicant's summary and conclusion

Conclusions:
A NOAEL of 2 % (1330 mg/kg bw/day) of sodium benzoate or 1257mg/kg bw/day of methyl benzoate for maternal and developmental effects is concluded.
Executive summary:

Pregnant Wistar rats, 15 to 17 weeks old, were exposed orally to sodium benzoate via food throughout their whole gestation period. The concentration of the chemical in diet was 1, 2, 4 and 8 %, respectively. Effects of the chemical on pregnant rats, prenatal foetuses and offspring were studied. In 4 and 8 % groups, food consumption of pregnant rats was much lower than that of the other experimental and control goups. The body weight of rats in 8 % group decreased, and that in 4 % group increased slightly. Many abnormalities of organs and skeletal systems were found in foetuses in 4 and 8 % groups. The rate of perinatal death was 100 % in both high dose groups. In 1 and 2 % groups, organ abnormality was found in few foetuses and bone abnormality was observed in few foetuses. No significant statistical difference was detected, however, between control and these 2 experimental low dose groups. Growth of offspring rats in these 2 groups was similar to that of the control. Based on the study results, a NOAEL of 2 % (1330 mg/kg bw/day) of sodium benzoate or 1257 mg/kg bw/day of methyl benzoate for maternal and developmental effects is proposed.