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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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well conducted and sufficiently described

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1968

Materials and methods

Principles of method if other than guideline:
Impact of administration of ZnO via diet for 21 days prior to mating until day 15 of gestation or from day 0 to day 15, 16, 18 or day 20 of gestation but not prior to mating.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Zinc oxide
EC Number:
215-222-5
EC Name:
Zinc oxide
Cas Number:
1314-13-2
IUPAC Name:
oxozinc

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
CFE strain of Sprague-Dawley rats obtained from Carworth, New City, New York
Ranging weight: 160-190 g
Individually housed in wire cages
feed and distilled water ad libitum

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
The composition of the basal diet was as follows: (in % ) casein, 20; sucrose, 63; cellulose,5 2; corn oil, 10; salt mixture, 4; and vitamin mixture, 1. Excess zinc diets were made by the incorporation of either 0.2 or 0.4% zinc as zinc oxide into the basal diet. The diets contained 7.5 ppm of copper and 230 ppm of iron.
Details on mating procedure:
the day sperm was found in the vaginal smear was designated as 0 day age of the fetus
Duration of treatment / exposure:
21 days prior to mating until day 15 of gestation
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.2 and 0.4% of Zn2+ as ZnO (corresponding to 100 and 200 mg Zn2+/kg bw/day, respectively)
Basis:
nominal in diet
No. of animals per sex per dose:
10 or 20 females
Details on study design:
Experiment 1. Ten female rats were fed the 0.4% zinc diet and ten were fed the basal diet beginning at 0-day age of the fetus. At each fetal age of 15 and 16 days, 5 experimental and 5 basal rats were killed.
Experiment 2. Twenty female rats were treated according to the same regimen as described in experiment 1 with the exception that the animals were killed at fetal ages of 18 and 20 days.
Experiment 3. Twenty female rats were subjected to the same regimen as stated in experiment 1 with the exception that the rats were fed the diets for 21 days before mating and continued to be fed the diets during the development of the fetus.
Experiment 4. Ten female rats were subjected to the same regimen as given in experiment 3 with the exceptions that the experimental diet contained 0.2% zinc, and the rats were killed only at a fetal age of 15 days.

Examinations

Maternal examinations:
Maternal liver and fetuses removed via abdominal incision.
All specimens were dried to a constant weight at 100°. The dried samples were wet-digested with nitric and sulfuric acid, and analyzed for zinc, copper and iron.
Fetal examinations:
External anatomical examination
Maternal liver and fetuses removed via abdominal incision. Because of fetal size, the 15- and 16-day old fetuses from individual mothers were pooled. For the 18- and 20-day-old fetuses, the liver was removed from each fetus and the livers and the bodies of the fetuses from each mother were pooled separately. All specimens were dried to a constant weight at 100°. The dried samples were wet-digested with nitric and sulfuric acid, and analyzed for zinc, copper and iron.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
impaired copper balance

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Excess zinc (0.4% ) in the diet of the maternal rat beginning at 0-day age of the fetus caused a significant reduction in growth (in terms of dry matter) of the
15- to 20-day-old fetus. Growth reduction was also reflected by a significantly smaller liver size of the 18- and 20-day-old fetus. Fetal resorptionoccurred with this regimen (4-29%). Extension of the feeding of 0.4% zinc to 21 days before mating caused 100% resorptionof the 15-and 16-day-old fetuses. In trials to determine at what fetal age resorption was initiated on the regimen of 0.4% zinc beginning at 21 days before mating, 36 and 40% resorption was found for the 12-
and 14-day-old fetus, respectively. Feeding a 0.2% zinc diet beginning at 21 days before mating did not affect fetal growth in terms of dry matter, cause any significant degree of resorption,nor cause any anatomical malformations in 15-day-old fetuses.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

In rats, the administration of 0.4% of Zn2+ as ZnO (corresponding to 200 mg Zn2+/kg bw/day) via diet for 21 days prior to mating until day 15 of gestation resulted in resorption of all foetuses. Administration of 0.4% dietary Zn2+ from day 0 to day 15, 16, 18 or day 20 of gestation, but not prior to mating, resulted in decreased live fetal body weights and in 4-29% fetal resorptions. When the concentration of Zn2+ in the feed was reduced to 0.2% (corresponding to 100 mg Zn2+/kg bw /day), starting 21 days prior to mating until day 15 of gestation no resorptions or effects on fetal body weights were observed. Treatment with dietary zinc did not result in external malformations, irrespective of dose level or treatment regimen. A dose-related significant increase in liver total zinc and liver zinc concentration and a significant decrease in the liver copper concentration was found in foetuses and mothers on all zinc regiments. No other information was given with respect to the health status of the mother animals. Although some of the animals were exposed from day 21 before mating up to study termination, no data were provided on possible consequences for female fertility.