Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 Dec 2013 - 26 Sep 2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Test substance administered day 6-15 of gestation, no individual animal data was included in the study report, body weight recorded every 4-5 days, no food consumption recorded, dams were not examined macroscopically

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted Jan 2001
Deviations:
yes
Remarks:
test substance administered day 6-15 of gestation, no individual animal data was included in the study report, body weight recorded every 4-5 days, no food consumption recorded, dams were not examined macroscopically
Qualifier:
according to
Guideline:
other: The Guidelines for the Testing of Chemicals (State Environmental Protection Administration of China) 2004.5
Deviations:
no
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Vital River Laboratory Animal Technology Co. Ltd, China
- Weight at study initiation: 200 - 250 g (males and females)
- Fasting period before study: no
- Housing: pregnant rats were individually housed, no further information available
- Diet: animal feed (HFK BIOSCIENCE Co., Ltd, Beijing, China), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 440 - 70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared at least once per 7 days and each aliquot was stirred prior to dosing.

VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: until successful mating was confirmed
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Day 6 -15 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
From mating to day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 P females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the dose levels were chosen based on the results of an acute toxicity study (not available) in which the LD50 value was > 5000 mg/kg bw. The highest dose level in the main study was the limit dose of 1000 mg/kg bw/day as recommended in the OECD guideline 414.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed daily for mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were observed from gestation day 0 - 6 for clinical signs, including abortion. Females showing symptoms of abortion were sacrificed and subjected to necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: On gestation day 0, 5, 9, 13, 17 and 20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: No data
- Sacrifice on gestation day 20
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: placenta and ovaries were examined (no further information given)
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one third of the pups per litter
- Skeletal examinations: Yes: one third of the pups per litter
- Head examinations: Yes: the same pups that were subjected to soft tissue examination
Statistics:
Continuous data, including body weights, body weight gain, pup body weights, gestation length, mean live litter size were analysed by using a One-Way Analysis of Variance (ANOVA). If significance (p<0.05) was detected, group by group comparisons were performed using Dunnet's Test. Count data were analysed utilising Chi-Square test for copulation and fertility indices, pup sex ratios, number of live and dead pups per group on lactation day 0, and pup survival after lactation day 0. All analyses utilised 2-tailed tests for a minimum significance level of 5% comparing the control to the treated groups.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
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 examined
Changes in number of pregnant:
not examined
Details on maternal toxic effects:
There was no significant difference in gravid uterus weight between the control and treatment groups.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no significant adverse systemic effects were observed up to and including the highest dose level

Maternal abnormalities

Key result
Abnormalities:
no effects observed

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 examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effects were observed on offspring parameters up to and including the highest dose level

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1. Parental female body weight (g)

Dose (mg/kg bw/day)

Control

250

500

1000

No. of pregnant animals

20

20

20

20

Day of gestation

Body weight (g)*

0

250.9 ± 16.4

247.5 ± 18.0

254.2 ± 23.4

247.3 ± 14.8

5

274.0 ± 14.4

273.4 ± 17.5

279.8 ± 21.4

268.9 ± 13.0

9

290.7 ± 15.6

293.2 ± 19.1

299.4 ± 20.1

285.4 ± 15.9

13

315.0 ± 18.8

319.0 ± 22.9

324.2 ± 23.2

312.3 ± 30.2

17

356.3 ± 26.1

355.7 ± 34.4

362.5 ± 29.4

350.0 ± 39.0

20

400.8 ± 37.6

396.4 ± 26.4

412.0 ± 29.9

403.0 ± 55.2

* Mean ± standard deviation

Table 2. Developmental parameters, F1 offspring

Dose (mg/kg bw/day)

0

250

500

1000

Total number of live offspring

268

248

267

275

Live offspring per litter*

13.4 ± 4.5

13.8 ± 3.9

12.4 ± 4.2

13.8 ± 3.3

Number of dead offspring

2

0

1

4

Number of absorbed embryos

5

6

3

3

Foetal body weight (g)*

3.648 ± 0.38

3.638 ± 0.38

3.678 ± 0.46

3.666 ± 0.42

Foetal body length (cm)*

3.679 ± 0.20

3.648 ± 0.23

3.700 ± 0.20

3.710 ± 0.24

* Mean ± standard deviation

 

Applicant's summary and conclusion