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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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
review article or handbook
Title:
Final Report on the Safety Assessment of Malic Acid and Sodium Malate
Author:
Fiume MZ, Bergfeld WF, Belsito DV, Klaassen CD, Schroeter AL, Shank RC, Slaga TJ, Snyder PW, and Andersen FA
Year:
2001
Bibliographic source:
Int J Toxicol 20 (Suppl 1): 47-55

Materials and methods

GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
days 6 through 15 of gestation
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
3.5 mg/kg bw/day
Dose / conc.:
16.2 mg/kg bw/day
Dose / conc.:
75.4 mg/kg bw/day
Dose / conc.:
350 mg/kg bw/day
No. of animals per sex per dose:
25-29
Control animals:
yes

Examinations

Ovaries and uterine content:
The number of implantation sites, resorption sites, and live and dead neonates was determined on day 20 of gestation.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Mortality:
no mortality observed
Description (incidence):
All animals except three of the 350 mg/kg test group (two were gravid) survived until study termination.
Body weight and weight changes:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
The researchers concluded that "the administration of up to 350 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
At gross examination, 20/25, 21/29, 22/25, and 26/28 animals of the 3.5, 16.2, 75.4, and 350 mg/kg dose groups, respectively, were gravid.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day
Basis for effect level:
other: highest dose level tested was without effects

Results (fetuses)

Fetal body weight changes:
not specified
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The researchers concluded that "the administration of up to 350 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival.
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The number of abnormalities seen in skeletal tissues of the test groups did not differ from the number occurring spontaneously in sham-treated controls."
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The number of abnormalities seen in soft tissues of the test groups did not differ from the number occurring spontaneously in sham-treated controls."

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day
Basis for effect level:
other: highest dose level tested was without effects

Applicant's summary and conclusion