Registration Dossier

Administrative data

Endpoint:
two-generation reproductive 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:
not specified
Remarks:
weanling albino rats
Sex:
male/female

Administration / exposure

Route of administration:
oral: unspecified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
9 wks prior to mating for the F1A litter, through weaning of the F1B litter
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 ppm
Dose / conc.:
10 000 ppm
No. of animals per sex per dose:
10 males, 20 females
Control animals:
yes, sham-exposed
Details on study design:
The F1A litters were culled to a maximum of eight pups, reproductive indices were monitored, and after 21 days, approximately one-third of the pups were
necropsied. One wk after weaning of the last F1A litter, the P1 parents were remated to produce the F1B litter, which was also culled and monitored.
After 21 days, 10 male and 20 female weanlings from each group were selected for the P2 generation. Approximately one-third of the remaining pups were nacropsied. The P2 generation was fed the appropriate diet and mated when the animals reached approximately 100 days of age to produce the F2A generation, and the same procedures were followed as above. One-half of the F2B litters were delivered naturally end held until weaning, while the other half were delivered
by Caesarean section on day 19 of gestation.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Appearance and behavior were similar for P1 test and control rats.
Mortality:
no mortality observed
Description (incidence):
Survival was similar for test and control animals. None of the P1 animals died during the F1A or F1B phase.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Prior to mating of the P1 generation, body weight gains of males of the test groups were slightly decreased compared to control animals; female body weights were comparable.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Feed consumption was similar for test and control animals.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Behavior was similar for P1 test and control rats.

Reproductive function / performance (P0)

Reproductive performance:
no effects observed
Description (incidence and severity):
For all litters, the various indices, litter sizes, and pup body weights were comparable among test and control animals.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
10 000 ppm
Sex:
male/female
Basis for effect level:
other: no effects at the highest dose level tested

Results: P1 (second parental generation)

General toxicity (P1)

Description (incidence and severity):
The P2 test and control animals were similar throughout the study; wheezing was observed in all groups during the F2B phase.

Results: F1 generation

General toxicity (F1)

Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the F1A litters, all of the necropsied pups In three of the low-dose litters had rough surfaces on the spleen.

Results: F2 generation

General toxicity (F2)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the F2A litters, the number of pups that were weak or had labored respiration during lactation was increased in the high-dose group.
In the F2B litters, weakness and labored respiration were reported for a few low-dose pups.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the F2A litters, renal discoloration (two animals), dark renal medullas (four animals), rough surfaces on the spleen (four animals), and white loci on the spleen (three animals) were found in Iow-dose weanling animals and renal discoloration (three animals), dark red corticomedullary zones (three animals), dark renal medullas (three animals), rough surfaces on the spleen (two animals), and a firm, enlarged, irregularly-shaped cecum with a hole penetrating it (one animal) were found in high-dose weanling animals at necropsy.
In the F2B litters, weakness and labored respiration were reported for a few low-dose pups, and the renal pelvis of one high-dose pup was dilated at necropsy.

Details on results (F2)

The animals of the F2B generation delivered by Caesarean section had no "meaningful differences" between test and control animals in the number and placement of implantation and resorption sites or in the number, weight, or length of live neonates, and none of the neonates died. The skeletal development of the F2B neonates was similar between test and control animals. Slight differences in developmental indices were "considered to be within the range of normal variations in fatal development. No trends toward lesser or greater skeletal development were observed."

Applicant's summary and conclusion