Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
analytical purity of test substance not specified, limited documentation, only organogenesis covered (days 6-15 of gestation)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1972
Report Date:
1972

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(analytical purity of test substance not specified, limited documentation, only organogenesis covered (days 6-15 of gestation))
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: fine tan powdered material

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 206-215 g
- Housing: individually in mesh bottom cages
- Diet (ad libitum)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- temperature and humidity-controlled quarters

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 1 to 3 mL/kg bw
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6-15 of gestation
Frequency of treatment:
daily
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
9 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
185 mg/kg bw/day (actual dose received)
Dose / conc.:
855 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
23 (control group, 185 mg/kg bw/d dose group, 250 mg/kg bw/d Aspirin)
21 (9 mg/kg bw/d)
22 (40, 855 mg/kg bw/day)
Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg bw/d Aspirin

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 11, 15, and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- daily observation, but no recording

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 (caesarean section under surgical anesthesia)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes
- Number of resorptions: Yes
- Other: number of live and dead fetuses was recorded and the urigenital tract of each dam was examined in detail for anatomical normality
Fetal examinations:
Number of live and dead fetuses were recorded and body weights of the live pups were recorded.
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [one-third per litter]
- Skeletal examinations: Yes: [two-thirds per litter]
- Head examinations: Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: no treatment-related effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 855 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: no treatment-related effects

Details on embryotoxic / teratogenic effects:
Besides the effects listed in Table 1-3 (see " Any other information on resutls incl. tables"), the following soft tissue abnormalities were found in the positive control group pups delivered by different dams: acrania, craniocele; spina bifida, subcutaneous edema.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 855 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: Average maternal body weights (in g)

 Day

 

0

6

11

15

20

Dose group

 

 

 

 

 

Sham

206

236

260

283

352 (23)

Positive Control

214

236

252

270

309 (23)

9 mg/kg bw TS

209

230

246

275

344

(21)

40 mg/kg bw TS

215

240

262

286

351

(22)

185 mg/kg bw TS

207

227

250

273

243

(23)

855 mg/kg bw TS

207

229

246

277

343

(22)

- TS: test substance

- number of surviving dams in parentheses

Table 2: Litter response (caesarean section data)

Dose group

Sham

Positive Control

9 mg/kg bw TS

40 mg/kg bw TS

185 mg/kg bw TS

855 mg/kg bw TS

Pregnancies

 

 

 

 

 

 

Total No.

23

23

21

22

23

22

Died or aborted (before day 20)

0

0

0

0

0

1

To term (on day 20)

23

23

21

22

23

22

Corpora lutea

 

 

 

 

 

 

Total No.

268

270

244

267

265

253

Average/dam mated

11.2

11.3

10.2

11.1

11.0

10.5

Live litters

 

 

 

 

 

 

Total No.

23

15

21

22

23

22

Implant Sites

 

 

 

 

 

 

Total No.

253

256

233

253

251

252

Average/dam

11.0

11.1

11.1

11.5

10.9

11

Resorptions

 

 

 

 

 

 

Total No.

12

106

8

15

6

4

Dams with 1 or more sites resorbed

6

16

6

11

5

3

Dams with all sites resorbed

0

8

0

0

0

0

% partial resorptions

26.1

69.6

28.6

50.0

21.7

13.6

% complete resorptions

--

34.8

--

--

--

--

Live fetuses

 

 

 

 

 

 

Total No.

240

150

225

238

245

248

Average/dam

10.4

6.52

10.7

10.8

10.7

10.8

Sex ratio (M/F)

0.81

0.95

0.67

0.68

0.55

0.76

Dead Fetuses

 

 

 

 

 

 

Total No.

1

0

0

0

0

0

Dams with 1 or more dead

1

--

--

--

--

1

Dams with all dead

0

--

--

--

--

--

% partial dead

4.35

--

--

--

--

--

% all dead

--

--

--

--

--

--

Average fetus weight (g)

3.91

2.63

3.81

3.81

3.92

3.75

Table 3: Summary of skeletal findings

Dose group

Sham

Positive Control

9 mg/kg bw TS

40 mg/kg bw TS

185 mg/kg bw TS

855 mg/kg bw TS

Live Fetuses (at term)

161/23

99/15

148/21

159/22

164/23

167/22

Sternebrae

 

 

 

 

 

 

Incomplete oss.

15/11

94/16

10/9

8/7

11/8

13/9

Scrambled

--

--

--

--

--

--

Bipartite

--

1/1

--

1/1

--

--

Fused

--

--

--

--

--

--

Extra

--

--

--

--

--

--

Missing

2/1

64/14

--

--

--

--

Other

--

--

--

--

--

--

Ribs

Incomplete oss.

1/1

12/6

--

--

--

--

Fused/Split

3/2

4/3

--

--

--

--

Wavy

5/2

27/11

12/8

12/6

4/3

1/1

Less than 12

--

3/3

--

1/1

--

1/1

More than13

--

26/9

--

--

--

--

Other

--

--

--

--

--

--

Vertebrae

Incomplete oss.

3/1

75/14

3/3

--

2/1

4/4

Scrambled

--

--

--

--

--

--

Fused

--

2/2

--

--

--

--

Extra ctrs. oss.

--

--

--

--

--

--

Scoliosis

--

7/4

--

--

--

--

Other

--

--

--

--

--

--

 Skull            
 Incomplete closure  19/11 69/13  16/10  28/10  14/8  20/10 
 Craniostosis  -- 1/1  --  --  --  -- 
 Miscellaneous            
 Hyoid; missing  9/4 73/15  11/6  13/8  9/7  15/9 
 Hyoid; reduced  3/2 1/1  --  --  1/1  -- 

Applicant's summary and conclusion

Conclusions:
The test substance had no effect on intrauterine development.