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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to GLP and guideline
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Calcium sulfate, dihydrate
- Analytical purity: 99.9%
- Lot/batch No.: Sigma Aldrich Corporation, LOT No. - 109H0166

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks
- Weight at study initiation: 254.2 - 297.8 g (males) and 182.7 - 208.2 g (females)

Administration / exposure

Route of administration:
oral: gavage
Details on mating procedure:
- M/F ratio per cage: 1:1 (from same test group)
- Length of cohabitation: 4 days
- Proof of pregnancy:sperm in vaginal smear
Duration of treatment / exposure:
Premating exposure period of 2 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300 and 1000 mg/kg/day
Basis:

No. of animals per sex per dose:
60
Control animals:
yes, concurrent no treatment
Details on study design:
A pre-treatment test was conducted with 0, 125, 250, 500 and 1,000 mg/kg/day of test substance for 7 days to determine the appropriate starting dose level.

Examinations

Parental animals: Observations and examinations:
Clinical observations performed and frequency: Clinical symptoms were observed once a day but were observed once a week in detail; a death rate was observed twice a day; and body weight was observed once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of gestation period, date of delivery, and 4 days after the delivery; consumption rate of fodder was observed once a week except mating period.







Litter observations:
Observation of F1:
The number of survivors and deaths during delivery
Body weight and Survival rate: measured on the day 0 and 4 after the delivery
Postmortem examinations (parental animals):
A number of implantation and corpus luteum: while female animals were necropsied, the number of corpus leteum and implantation were
counted; and the former was measured in the ovary and the latter was measured in the uterus.

Organ weight: testes, epididymider (all males) liver, kidney, adrenals, thymus, spleen, brain, and heart (5 male and female animals from each test group).

- Fixation: 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals, brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or tibial), bone marrow.






Statistics:
Statistical decision tree, but in case of recovery group, either two-side Students t-test or two-side Apsin Welch t-test was used. In case of categorical data, two-sided Fishers exact test was used.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

Pregnancy and delivery: There was no significant difference between the treatment groups and the control group in terms of delivery and; the number of corpus luteum and implantation. Some animals in the test groups including the control group had quite higher loss rate of the embryo prior to the implantation and the fetus after the implantation but significant difference was not observed between the treatment group and the control group. These higher loss rate were occurred spontaneously and no dose-response correlation, thus no influence under test substance.


Index of copulation, fertility and gestation: Every test group including control group was succeeded in the mating, but each animal from every group was not succeeded in the gestation. However, all pregnant female animals were succeeded in the delivery. Therefore, no significant difference between the treatment group and the control group was found.

- Clinical signs: In male control group, a case of salivation and bloodylike secretion was observed on the day 11 and 12. In the 1,000 mg/kg/day treatment group, a case of depilation, dcab and pus was observed on the left cheek between the day 25 and the closing day. However, the frequency of occurrence was low and no dose-response correlation. Thus these symptoms were not influenced by test substance. In female control group, a case of genitalia bloody-like secretion was observed at day 29. In the 100 mg/kg/day treatment group, each case of hypoactivity and depilation was observed on the day 8 and 9, and between day 44 and the closing day, respectively. However, these symptoms were disappeared in short, thus these symptoms did not have relationship with test substance.


Necropsy opinions: For male animals, in the control group within the recovery group, a case of left and right caput epididymis cyst was observed and the 1,000 mg/kg/day recovery group had symptom of right caput epididymis cyst. However, its frequency of occurrence was low and it was even observed at the control group within the recovery group, so it did not have relationship with test substance. For female animals, in the 300 mg/kg/day treatment group, each animal was dead on the day 7 and 14 and; each case of lung dark-red discolouration was observed, but white particles in a lobe of the lung was observed just from one of carcasses. A case of spleen white nodule was observed for an animal in the 300 mg/kg/day treatment group. There was a case of right adrenal gland white spots at the 1,000 mg/kg/day treatment group. In the control group within the recovery group, each case of right adrenal gland hemorrhagia and atrophy and liver adhesion with diaphragm was observed. However, their frequencies of occurrence were low and no dose-response correlation, so these did not have relationship with test substance.













Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
790 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: The result has been corrected to calcium sulfate anhydrous

Results: F1 generation

Details on results (F1)

Number of pups born, viability and sex ratio: No significant difference was observed between the treatment group and the control group at the time of the delivery and on the day 4 after the delivery. There were reconfirmed of sex ratio at the day 7 after the delivery since total 8 cases of sex were decided again. For instance, each 2 cases of misconfirmation of sex was found at the following three treatment groups such as 100, 300, 1,000 mg/kg/day as their sexes were replaced from male to female; and each case of mis-confirmation of sex was found at the 300 mg/kg/day and 1,000 mg/kg/day, for their sexes were replaced to male.(refer to table 1 for results)


Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
790 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: The result has been corrected fot calcium sulfate anhydrous

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1:

DOSE: (mg/kg)

0

100

300

1000

No. of mated males

Copulation index (%)

Fertility index (%)

No. of mated females

Copulation index (%)

Fertility index (%)

Gestation index (%)

No. of corpora lutea

Mean ± S.D

No. of implantations

Mean ± S.D

Mean % preimplantation loss

No. of embryo/fetal death

No. of live pups born

Mean ± S.D

Mean pregnancy period (day)

Viability index on day at birth(%)

Viability index on day 4 pp (%)

Body weights of pups (g)

Male (at birth)

4 DAY

Female (at birth)

4 DAY

12

100.0

91.7

12

100.0

91.7

100.0

17.2

2.6

15.1

2.5

11.6

1.5

13.5

2.2

21.8

99.0

98.0

 

6.49

9.78

6.19

9.44

12

100.0

91.7

12

100.0

91.7

100.0

17.0

3.4

13.6

4.1

20.2

1.0

12.6

4.0

21.7

99.4

98.3

 

6.42

9.86

6.06

9.13

10

100.0

90.0

10

100.0

90.0

100.0

17.4

3.5

15.7

1.9

9.0

0.7

15.0

1.8

22.0

98.0

97.8

 

6.56

9.70

6.23

9.37

12

100.0

91.7

12

100.0

91.7

100.0

17.2

1.9

15.4

4.3

10.3

0.7

14.6

4.5

22.0

100.0

97.6

 

6.55

9.52

6.26

8.74

Applicant's summary and conclusion

Conclusions:
According to the results of the reproductive toxicity test the NOAEL was the highest dose tests (1000 mg/kg) which was corrected to 790 mg/kg for calcium sulfate anhydrous. Calcium sulfate was not considered to be toxic to reproduction or development