Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene

Developmental toxicity / teratogenicity

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 guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

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

Test guideline 2

Qualifier:

according to guideline

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

Test material information

Constituent 1

Reference substance name:

1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene]

EC Number:

306-832-3

EC Name:

1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene]

Cas Number:

97416-84-7

Molecular formula:

C23H24Br8O2

IUPAC Name:

1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene]

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Doses / concentrations 3

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