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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The study by Onodera et a. (1978) is referenced as a key study for the assessment of teratogenicity of benzoic acid in the expert evaluation fo benzoic acid by ECHA/RAC (2012)

Data source

Reference
Reference Type:
other: Background document for RAC oppinion on benzoic acid
Title:
Background document to the Opinion proposing harmonised classification and labelling at EU level of Benzoic acid, CHL report
Author:
Committee for Risk Assessment, RAC
Year:
2012
Bibliographic source:
Background document to the Opinion proposing harmonised classification and labelling at EU level of Benzoic acid, CHL report, Committee for Risk Assessment, RAC, November 2012, ECHA/RAC/CLH-O-0000001687-65-02/A1
Report date:
2012

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was referenced as a key study of teratogenicity in benzoic acid in the expert evaluation fo benzoic acid by ECHA/RAC (2012)
GLP compliance:
no
Remarks:
Study was performed before 1. of June 2008

Test material

Constituent 1
Chemical structure
Reference substance name:
Benzoic acid
EC Number:
200-618-2
EC Name:
Benzoic acid
Cas Number:
65-85-0
Molecular formula:
C7H6O2
IUPAC Name:
benzoic acid
Test material form:
not specified

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
Oral, dietary, from day 1 to 20 of gestation
Duration of treatment / exposure:
day 1 to 20 of gestation
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
600 mg/kg bw/day
Dose / conc.:
1 130 mg/kg bw/day
Dose / conc.:
1 610 mg/kg bw/day
Dose / conc.:
1 820 mg/kg bw/day
No. of animals per sex per dose:
12-18

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality increased at 1610 mg/kg/day
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Bodyweight was decreased at 1610 mg/kg/day
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food comsumption was decreased at 1610 mg/kg/day

Maternal developmental toxicity

Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
Perinatal survival was decreased at 1610 mg/kg/day maternal dose

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 130 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
mortality

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal weight was decreased at 1610 mg/kg/day maternal dose
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Fetal weight was decreased at 1610 mg/kg/day maternal dose
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Perinatal survival decreased at 1610 mg/kg/day maternal dose
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
8-wk offspring survival decreased at 1130 mg/kg/day (4.5 %, mortality: 1/22)
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
More than tenfold increase in skeletal malformations in the offsprings were increased at 1610 mg/kg/day maternal dose
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
More than tenfold increase in soft tissue malformations in the offsprings were increased at 1610 mg/kg/day maternal dose

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in postnatal survival

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: skeletal and soft tissue malformations
Description (incidence and severity):
Malformations in the offsprings were increased at 1610 mg/kg/day maternal dose

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 610 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The teratogenicity of benzoic acid (sodium benzoate doses converted to benzoic acid equivalents) was investigated by Onodera et al. (1978) and reffered to in ECHA/RAC (2012). No increase in offspring variations and malformations was observed up to doses of ~1130 mg/kg bw/d benzoic acid administered with the food during the whole gestational period. However, a slight reduction (4.5 %, mortality: 1/22) in offspring survival was noted at this dose level. Higher doses led to reduced maternal survival, maternal bw loss, reduction in the number and weight of viable foetuses, reduced perinatal survival and a more than tenfold increase in skeletal and soft tissue malformations. A NOAEL of 1130 mg/kg bw/d benzoic acid equivalents for maternal and developmental effects and a more conservative NOAEL of 600 mg/kg bw/d for other effects on offspring is concluded.
Executive summary:

The teratogenicity of benzoic acid (sodium benzoate doses converted to benzoic acid equivalents) was investigated by Onodera et al. (1978) and reffered to in ECHA/RAC (2012). No increase in offspring variations and malformations was observed up to doses of ~1130 mg/kg bw/d benzoic acid administered with the food during the whole gestational period. However, a slight reduction (4.5 %, mortality: 1/22) in offspring survival was noted at this dose level. Higher doses led to reduced maternal survival, maternal bw loss, reduction in the number and weight of viable foetuses, reduced perinatal survival and a more than tenfold increase in skeletal and soft tissue malformations. A NOAEL of 1130 mg/kg bw/d benzoic acid equivalents for maternal and developmental effects and a more conservative NOAEL of 600 mg/kg bw/d for other effects on offspring is concluded.