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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:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data from secondary source

Data source

Reference
Reference Type:
secondary source
Title:
one generation reproduction toxicity study in Wistar rats
Author:
European Food Safety Agency (EFSA)
Year:
2010
Bibliographic source:
Additional Report to the DAR for test material ,2010

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Developmental Toxicity study was performed on rabbits.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):2-naphthyloxyacetic acid
- Molecular formula (if other than submission substance):C12H10O3
- Molecular weight (if other than submission substance):202.208 g/mol
- Substance type:Organic

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% Carboxymethyl cellulose
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material dissolved in 0.5% Carboxymethyl cellulose

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test material dissolved in 0.5% Carboxymethyl cellulose
- Concentration in vehicle: 0, 3, 10,50mg/kg/day
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
No data available
Duration of treatment / exposure:
23(gestation day 6 to 28)
Frequency of treatment:
daily
Duration of test:
30 days
Doses / concentrations
Remarks:
0, 3, 10,50mg/kg/day.
No. of animals per sex per dose:
Total:100
0mg/kg/day: 25 female
3mg/kg/day:25 female
10mg/kg/day:25 female
50mg/kg/day:25 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: base on the preliminary range-finding study (0, 10, 60 and 300 mg/kg/day).
- Rationale for animal assignment (if not random):
- Other:

Examinations

Maternal examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: twice daily

BODY WEIGHT: Yes
Time schedule for examinations: Individual body weights were recorded on gestation days 0, 3, 5, 8, 11, 14, 17, 20, 23, 26, 29 and 30.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption per cage of animals were measured over the following periods during gestation: days 0-3, 3- 5, 5-8, 8-11, 11-14, 14-17, 17-20, 20-26, 26-29 and 29-30.
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes
- Skeletal examinations: Yes:
- Head examinations: Yes
Statistics:
The test parameters body weight, percent body weight change, feed consumption, prenatal data and foetal data will be analysed using statistical techniques like Bartlett’s test, ANOVA and Dunett’s and Student’s t tests. Foetal examination will be analysed using Chi-square test.
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
There were no maternal death
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a significant reduction in the body weight gain during the treatment period in the high dose group (50 mg/kg).The reduction in body weight during the treatment period was considered treatment related.

Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The food consumption was comparable to the vehicle control group.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
One rabbit aborted in the 50mg/kg dose group
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The maternal data parameters comprising of pre and post-implantation loss in all the treatment groups were comparable to the vehicle control group
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The maternal data parameters comprising of early and late resorptions in all the treatment groups were comparable to the vehicle control group
Early or late resorptions:
no effects observed
Description (incidence and severity):
The maternal data parameters comprising of early and late resorptions in all the treatment groups were comparable to the vehicle control group
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
effects observed, treatment-related
Description (incidence and severity):
There were 2 non pregnant rabbits in control, 4 in low dose group, 3 in mid dose group and 4 in the high dose group. There was one complete resorption in mid dose group.
Other effects:
not specified

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake
number of abortions
pre and post implantation loss
total litter losses by resorption
early or late resorptions
changes in number of pregnant
Remarks on result:
other: No toxic effects observed

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
Remarks on result:
other: No developmental toxic effects observed

Fetal abnormalities

Abnormalities:
not specified
Localisation:
other: not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

Main parameters of pregnant rabbits treated with test material during organogenesis period

Group

1

2

3

4

dose (mg/kg/d)

0

3

10

50

Maternal observations

Mortality

 

0/25

0/25

 

0/25

0/25

 

Day 0-6

6.80

8.06

 

8.85

6.44

Body

weight gain (%)

 

 

 

Day 6-30

15.67

10.62

18.99

9.28*

Day 0-30

20.55

17.54

25.32

14.74

No. of rabbits aborted

0

0

0

1

No. of non pregnant rabbits

2

4

3

4

No of pregnant rabbits

23

21

22

20

Dams with complete resorptions

0

1

0

0

Number of litter examined

23

20

22

20

* : Significantly different from vehicle control at p≤0.05

 

Main parameters of pregnant rabbits treated with test material during organogenesis period

Group

1

2

3

4

dose (mg/kg/d)

0

3

10

50

Litter observations

 

 

Number of Corpora lutea

8.43

8.24

8.77

6.70*

Pre-implantation loss (%)

9.00

11.33

6.37

19.43*

Post-implantation loss (%)

3.60

7.82

5.65

5.26

Early resorptions

0.35

0.24

0.36

0.25

Late resorptions

0.00

0.14

0.09

0.05

Mean litter size

7.70

7.52

8.27

5.50**

Fetus weight

(g)

Male

44.03

43.15

41.83

43.27

Female

42.28

40.82

42.10

42.85

Sex ratio- Male: Female

1:1.85

1:1.30

1:1.15

1:1.00

 

* : Significantly different from vehicle control at p≤0.05

**: Significantly different from vehicle control at p≤0.01

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 50 mg/kg/day, When female rabbits were treated with test material orally.
Executive summary:

The developmental toxicity study of test material was performed according toOECD guideline 414 on rabbits.Young adult nulliparous New-Zealand white strain female and male rabbits (Oryctolagus cuniculus) were used in study. The test material dissolved in 0.5% Carboxymethyl cellulose in dose concentration 0, 3, 10 and 50 mg/kg/day and adminstered by daily gavage through gestation day 6 to 28to mated females (25/dose group).The preliminary range-finding study (0, 10, 60 and 300 mg/kg/day) was performed,Based on preliminary range-finding study findings, 0, 3, 10 and 50 mg/kg/day were selected for the main study. Animals were observed twice daily for moribundity and mortality. Individual clinical signs were recorded at least once a day during the treatment period and once daily during the pre- and post-treatment periods. Individual body weights were recorded on gestation days 0, 3, 5, 8, 11, 14, 17, 20, 23, 26, 29 and 30. Food consumption per cage of animals were measured over the following periods during gestation: days 0-3, 3- 5, 5-8, 8-11, 11-14, 14-17, 17-20, 20-26, 26-29 and 29-30. On Day 29 of gestation, all the rabbits were sacrificed using intravenous injection of sodium thiopentone. Any gross pathological changes in all the visceral organs of dams were recorded. Organs with macroscopic findings and kidneys were preserved for possible histological evaluation. The ovaries, uteri and uterine contents were removed and examined to determine: the number of corpora lutea, the number of implantations, early and late resorptions, the weight of intact gravid uterus, the number and distribution of live foetuses, the number and distribution of intra-uterine dead foetuses, the individual foetal weight and sex, foetal abnormalities.

There were no maternal death or necropsy findings at any dose levels. There was a significant reduction in the body weight gain during the treatment period in the high dose group (50 mg/kg). The food consumption was comparable to the vehicle control grou. The reduction in body weight during the treatment period was considered treatment related. One rabbit aborted in the high dose group, there were 2 non pregnant rabbits in control, 4 in low dose group, 3 in mid dose group and 4 in the high dose group. There was one complete resorption in mid dose group. At the end, at least 20 litters were observed in each of the dose groups. The maternal data parameters comprising of implantations, early and late resorptions, pre and post-implantation loss in all the treatment groups were comparable to the vehicle control group. The mean number of corpora lutea, implantation and live foetus were significantly lower in high dose group (50 mg/kg body weight/day) when compared with the control group. Observed decrease in corpora lutea at 50 mg/kg body weight/day is considered as biological variation because the treatment was initiated after the implantation (gestation day 6). Therefore, the decrease observed in the absolute uterine weight, implantation and live foetus reported at this dose level are also considering as biological variation as these observations are directly correlated with the decrease in the number of the corpora lutea. Hence No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 50 mg/kg/day,When female rabbits were treated with test material orally.