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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:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights or copora lutea not determined One third used for visceral examination; should be 50% Test substance identification (Batch etc) missing No details on housing conditions/source of animals Administration only during periods of organogenesis, not until day before pregnancy
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1973
Report Date:
1973

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
Adult female golden hamsters were mated with mature males (1:1). Observation of motile sperm in the vaginal smear was considered as Day 0 of gestation. Dosing by oral intubation with a control (Vehicle at level equivalent to group receiving the highest dose or aspirin at 250 mg/kg) or test article in a water suspension at 1.66, 7.71, 35.8 and 166.0 mg/kg was carried out daily on Days 6 to 10 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 14 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Genital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
GLP compliance:
no
Remarks:
Study predates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): FDA 71-61 (sodium acid pyrophosphate)
- Physical state: Fine white powdered material

Test animals

Species:
hamster
Strain:
other: Golden
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 122.2 - 133.4 g
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data

IN-LIFE DATES: No data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: 1:1 mating
- Proof of pregnancy: appearence of motile sperm in vaginal smear
Duration of treatment / exposure:
5 days (Day 6 to Day 10 of gestation)
Frequency of treatment:
Daily
Duration of test:
14 days
No. of animals per sex per dose:
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 22 20
Aspirin 250 22 21
FDA 71-81 1.66 22 20
7.71 24 20
35.8 22 21
166.0 22 22
Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg aspirin

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 8, 10 and 14.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: uterus and genital tract
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
No data
Indices:
No data
Historical control data:
No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 166 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 166 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects noted

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin

1.66

7.71

35.8

166.0

Pregnancies

 

 

 

 

 

 

Total No.

20

21

20

20

21

22

Died or aborted (before Day 14)

0

0

0

0

1

1

To term (on Day 14)

20

21

20

20

20

21

Live litters

 

 

 

 

 

 

Total No.*

20

21

20

20

20

21

Implant Sites

 

 

 

 

 

 

Total No.

298

311

292

289

290

300

Average/dam*

14.9

14.8

14.6

14.5

14.5

14.3

Resorptions

 

 

 

 

 

 

Total No*

1

8

1

1

1

8

Dams with 1 or more sites resorbed

1

6

1

1

1

5

Dams with all sites resorbed

--

--

--

--

--

--

Per cent partial resorptions

5.00

28.6

5.00

5.00

5.00

23.8

Per cent complete resorptions

--

--

--

--

--

--

Live foetuses

 

 

 

 

 

 

Total No

295

303

291

288

289

292

Average/dam*

14.8

14.4

14.6

14.4

14.5

13.9

Sex ratio (M/F)

0.89

0.94

0.81

0.78

0.75

0.75

Dead Foetuses

 

 

 

 

 

 

Total No.*

2

--

--

--

--

--

Dams with 1 or more dead

2

--

--

--

--

--

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

10.0

--

--

--

--

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

1.70

1.72

1.72

1.82

1.82

1.75

* Includes only those dams examined at term

** Positive control: 250 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

1.66

7.71

35.8

166.0

Live foetuses examined (at term)

204/20

209/21

200/20

199/20

202/20

202/21

Sternebrae

 

 

 

 

 

 

Incomplete oss.

131/20

85/20

124/20

69/17

88/18

80/20

Scrambled

 

 

 

 

 

 

Bipartite

18/9

16/11

22/14

20/11

15/9

25/13

Fused

 

 

 

 

 

 

Extra

8/2

 

1/1

6/3

5/3

 

Missing

53/14

48/13

49/12

39/10

33/10

51/14

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

 

 

 

 

2/1

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

62/17

56/13

46/16

69/17

38/13

60/16

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

2/2

15/5

 

1/1

 

8/2

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

 

 

 

 

 

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other

 

 

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

4/4

17/6

 

6/4

 

13/3

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

6/6

14/6

5/4

4/2

2/1

13/3

Hyoid; reduced

7/7

6/5

9/7

7/3

6/5

8/6

* Numerator = Number of foetuses affected; Denominator = Number of litters affected

** Positive control: 250 mg/kg

 

Table 4 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

Sham

0.0

S 5908

1

Meningoencephalocele

 

 

S 5914

1

Hydrocephalus

Aspirin

250.0

A 5912

1

Hepatomegaly

FDA 71-61

1.66

M 5013

1

Hydrocephalus

FDA 71-61

166.0

M 5092

4

Hydrocephalus

 

 

 

2

Hydromyelia

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the test material administered to pregnant hamsters for 5 days up to a dose level of 166 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 166 mg/kg bw.