Hexanoic acid, 3,5,5-trimethyl-, tin(2+) salt (2:1)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across from a publication which meets basic scientific principles

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1974

Report date:

1974

Materials and methods

Principles of method if other than guideline:

No guideline for method was reported. Rabbits were administered the test substance at four doses orally by gavage from gestation days 6 through 18. On Day 29, animals of all doses were subjected to Caesarean section.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tin dichloride

EC Number:

231-868-0

EC Name:

Tin dichloride

Cas Number:

7772-99-8

Details on test material:

- Name of test material (as cited in study report): FDA 71-33 Stannous chloride
- Physical state: crystalline

Test animals

Species:

rabbit

Strain:

Dutch

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: no data
- Housing: individually in mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Humidity (%): controlled

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: water solution
The test material was prepared and doses calculated according to the following table:

Dosage (mg/kg) Dose (mL/kg) Concentration (mg/mL)
251-500 2 125-250
501-750 3 133-250
751-1000 4 187-250
1001-1250 5 200-250
1251-1500 6 208-250
1501-1600 6.4 235-250


VEHICLE
-water

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

On Day 0 each doe was given an injection of 0.4 mL of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 mL of diluted semen from a proven donor buck using approximately 20 x 10E6 motile sperm.

Duration of treatment / exposure:

day 6-18 of gestation

Frequency of treatment:

once per day

Duration of test:

29 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0.42, 1.90, 8.90, and 41.5 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

females

Control animals:

yes, concurrent vehicle

other: positive control: 2.5 mg/kg of 6-aminonicotinamide dosed on Day 9

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: appearance and behavior

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 12, 18 and 29 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes - generally observed at cage side observation
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

POST-MORTEM EXAMINATIONS: No

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: urogenital tract was examined in detail for normality
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes
- Skeletal examinations: Yes: all per litter
- Head examinations: No data
- The live fetuses of each litter were placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed,
and all pups examined for visceral abnormalities.

Statistics:

No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects. Remark: No clearly discernible effect on nidation or on maternal survival.

Details on maternal toxic effects:
Total number of pregnant dams on Day 29/total pregnancies, by dose administered:
0 mg/kg:           10/10
0.42 mg/kg:       11/11
1.90 mg/kg:       11/12 
8.90 mg/kg:       10/11 
41.5 mg/kg:       10/11 
Positive control: 11/12 

Animals died or aborted before Day 29

The average numbers of corpora lutea per pregnant dam tended to increase  with increasing dose level 
(from 8.36 at 0 mg/kg bw/d to 9.67 at 41.5  mg/kg bw/d). (Positive control 7.87)

Total number of live litters was 10, 11, 10, 10, 9 at 0, 0.42, 1.9, 8.9 and 41.5 mg/kg bw/d respectively. (Positive control 11)

The average number of implantation sites per pregnant dam examined at  term was 4.30, 6.09, 4.91, 5.80 and 5.40  for the 0, 0.42, 1.90,  8.90 and 41.5 mg/kg bw/d, respectively. (Positive control 6.27))

Total numbers of resorptions in the 0.42, 1.90, 8.90, 41.5 mg/kg dose  groups were 0, 7, 5, 4, 7,  respectively. (Positive control 8)

The total number of live fetuses 0, 0.42, 1.90, 8.90, 41.5 mg/kg dose  groups  were 43, 57, 49, 54 and 47  respectively. (Positive control 61)

Average maternal body weights of surviving dams in all dose groups  increased over the study period.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

> 41.5 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Remark: The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Details on embryotoxic / teratogenic effects:
Male/female sex ratios of live fetuses in the 0, 0.42, 1.90, 8.90, 41.5 mg/kg bw/d dose groups were 1.26, 1.28, 1.45, 1.35 and 1.24, and 0.97, respectively.
(Positive control 0.97)
There were 3 dead fetuses in the 0.42 mg/kg bw/d dose group in one liter.

Average fetal body weights in the 0, 0.42, 1.90, 8.90, 41.5 mg/kg bw/d dose groups were 39.9, 38.5, 37.9, 38.2 and 42.3 g, respectively.
(Positive control 32.5)


Skeletal findings, by dose group:
0 mg/kg: 2 fetuses in one litter had incomplete ossification of the sternebrae; 1 fetus in 1 litter had scrambled or bipartite sternebrae; and 1 fetus in 1 litter
had fused sternebrae, 1 fetus in 1 litter had acrania.
0.42 mg/kg: 1 fetus in 1 litter had incomplete ossification of the sternebrae; 2 fetuses in 2 litters had fused sternebrae; and 4 fetuses in 1 litter had extra sternebrae; and 2 fetuses in 1 litter had missing sternebrae.
1.90 mg/kg: No skeletal abnormalities reported.
8.90 mg/kg: 3 fetuses in 3 litters had incomplete ossification of the sternebrae; 2 fetuses in 2 litters had fused sternebrae; and 4 fetuses in 2 litters had extra sternebrae.
41.5 mg/kg: 2 fetuses in 2 litters had extra sternebrae and 1 fetus in 1 litter had missing sternebrae.

Positive control group: 5 fetuses in 5 litters had incomplete ossification of the sternebrae; 2 fetuses in 2 litters had bipartite sternebrae; 5 fetuses in 3 litters had fused sternebrae; 1 fetus in 1 litter had extra sternebrae; 4 fetuses in 3 litters and fused or split ribs; 21 fetuses in 7 litters had scrambled vertebrae; 3 fetuses in 3 litters had scoliosis; 35 fetuses in 7 litters had tail defects; and 3 fetuses in 2 litters had incomplete closure of the skull.

Soft tissue abnormalities, by dose group:
0 mg/kg: 1 pup with cleft palate.
0.42 mg/kg: No abnormalities reported.
1.90 mg/kg: 1 pup had meningoencephalocele and 1 pup had medial rotation of hind limbs.
8.90 mg/kg: No abnormalities reported.
41.5 mg/kg: 1 pup had medial rotation of front limbs.
Positive control: Multiple abnormalities reported, including anopia, medial rotation of hind limbs, short tail, cleft palate, meningoencephalocele, and
umbilical hernia.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

> 41.5 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

2

Dose descriptor:

NOAEL

Effect level:

> 41.5 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The administration of up to 41.5 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discrenible
effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not
differ from the number occurring spontaneously in the untreated control.

Executive summary:

Virgin, adult, Dutch-belted rabbits were artificially inseminated and administered the test substance on days 6 through 18 of gestation. Females were dosed by gavage with a sham control, positive control, 0.42, 1.90, 8.90 and 41.4 mg/kg. On Day 29 all does were subjected to Caesarean section under surgical anesthesia. The test material had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the untreated control.