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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:
1990-1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Experimental data (GLP, per guideline)

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1992
Report Date:
1992
Reference Type:
secondary source
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
volume: 5 ml/kg bw
Details on mating procedure:
Each female mated with 1 stud male. After coitus females were injected with 10 I.U. chorionic gonadotrophin i.v. The day of insemination is taken as day 0 of gestation.
Duration of treatment / exposure:
day 7 to 19 of gestation
Frequency of treatment:
once daily
Duration of test:
Day 0 to day 29 of gestation
No. of animals per sex per dose:
16

Examinations

Maternal examinations:
mortality (twice daily), clinical signs (daily), body weight (day 0, 7, 8, 9, 12, 19, 24, 29 of gestation), food consumption.
Necropsy data: Liver, Lung, Skin, Foot, Uterus, but no observation of gastrointestinal tract =no local effects reporded).
Ovaries and uterine content:
pregnancy status, numer of corpora lutea, number, status and intrauterine position of implantations.
Fetal examinations:
external foetal malformations, foetal weight, foetal sex.
Statistics:
groups means, standard deviations and reproductive indices where appropriate.
Indices:
reproductive indices where appropriate
Historical control data:
yes

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(65-68%)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(65-68%)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(65-68%)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(65-68%)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(65-68%)
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(65-68%)
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

 

Group/Dose Level (mg/kg/day)

1

(0)

2

(10)

3

(30)

4

(100)

Number of animals mated

16

16

16

16

Number pregnant

16

16

16

15

Pregnancy frequency as %

100

100

100

93.8

   Died / Killed

0

0

1

1

   With total resorptions

1

1

0

0

   With live foetuses at Day 29

15

15

15

14*

Group mean body weight (kg)
Day of gestation
 
0
7
8
9
12
19
24
29

Group mean body weight gain significantly lower than control

Days 7 to 9.  * p<.05. Kruskal-Wallis, Wilcoxon rank sum test

      12 to 19. ** p<.01, Analysis of variance, Dunnett's test



3.37
3.69
3.71
3.72
3.78
3.96
4.07
4.14

 



3.41
3.72
3.74
3.75
3.82
3.96
4.02
4.09

 



3.42
3.77
3.79
3.80
3.87
4.03
4.15
4.14

 



3.41
3.76
3.73
3.73*
3.75
3.76**
3.90
3.95

 

% body weight change days 0-29

22.8

19.9

21.1

15.8

% body weight change days 7-19

7.3

6.5

6.9

0.5

Group mean food intake (g/animal/day)
days of gestation
0-7
7-8
8-9
9-12
12-19
19-24
24-29

Group mean food intakeoverperiod signif. lower than control

AnalysIs of variance, Dunnett's test:

Days 7 to 9, * p<.05

        9 to 12, * p<.01
      12 to 19, *** p<.00l



185
197
185
180
174
166
119

 

 



184
194
189
185
172
153
125

 

 



192
194
185
189
178
171
109

 

 



202
159
153*
134**
109***
155
129

 

 

Mean intake /g/day) days 0-29

168

166

170

148

Mean intake /g/day) days 7-19

179

178

183

123

Mean intake /g/day) days 19-29

143

139

140

142

Number of females with live foetuses on GD 29

15

15

15

14

Number of corpora lutea
Mean number per female

134
8.5

134
7.9

142
9.5

129
9.2

Number of implantations
Mean number per female

127
8.5

119
7.9

127
8.5

106
7.6

% pre-implantation loss

5.2

11.2

10.6

17.8 DR*

Number of male foetuses

67

69

61

57

Number of female foetuses

56

41

60

45

% male foetuses

54.5

62.7

50.4

55.9

Mean litter weight (g)

355.8

327.4

348.4

317.1

Mean foetal weight (g)

43.0

45.0

43.6

43.7

Mean foetal weight (g) – males only

44.3

45.3

42.9

44.0

Mean foetal weight (g) – females only

43.0

44.2

44.1

43.5

 

DR* = significant increasing dose response (p<.05, Terpstra-Jonckheere test)

Applicant's summary and conclusion

Conclusions:
The technical substance (65%) caused developmental effects in rabbits at maternally toxic doses in a range-finding and main developmental study after oral administration. The effects observed, included postimplantation loss and eye and limb malformations, justify the NOAEL (maternal, fetotoxicity) = 30 mg/kg bw/day.