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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral: OECD 421, rat, NOAEL fertility ≥1000 mg/kg bw/day

Oral: OECD 421, rat, NOAEL systemic  ≥ 1000 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

screening for reproductive / 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:

The age of the animals was not reported; no data on individual animals was given; the body weight of females was not recorded during the mating period; the time of onset, duration, number affected and severity of the clinical signs was not reported; the number of implantation sites was not recorded.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

adopted Jul 1995

Deviations:

yes

Remarks:

animal age not reported; no data on individual animals given; time of onset, duration, number affected and severity of the clinical signs not reported; number implantation sites not given

Qualifier:

according to guideline

Guideline:

other: The Guidelines for the Testing of Chemicals (State Environmental Protection Administration of China) 2004.5

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Vital River Laboratory Animal Technology Co., Ltd., Beijing, China
- Weight at study initiation: (P) Males: 225 - 305 g; Females: 205 -267 g
- Fasting period before study: no
- Housing: the animals were housed individually, except during the mating period
- Diet: reproductive diet (Certificate No. SCXK(JING) 2009-0008, HFK BIOSCIENCE Co., Ltd., Tianjin, China), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared at least once every 7 days. Each aliquot was stirred prior to dosing.

VEHICLE
- Concentration in vehicle: 50, 100 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/ kg bw

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: up to 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility for a maximum of 5 days
- After successful mating each pregnant female was caged: individually

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

(P) males: 42 days (from 14 days prior to mating, during mating until Day 43)
(P) females: up to 54 days (from 14 days prior to mating, up to 14 days during mating, up to 22 days during gestation, 4 days during lactation; for non-pregnant females, until 25 days after vaginal plug was observed)

Frequency of treatment:

daily, 7 days/week

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:

15

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: the dose levels were based on the results of the acute oral toxicity study (study report not available), in which the LD50 was > 5000 mg/kg bw.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: females: week 1 and 2 (prior to mating), gestation day 0, 7 and 14, and lactation day 0 and 4; males: week 1, 2 (prior to mating), 3, 4 and 5

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, food consumption was measured in females during week 1 and 2 (prior to mating), and gestation week 1 and 2; and in males during the whole treatment period (week 1 - 6).
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

Sperm parameters (parental animals):

Parameters examined in all male parental generations:
testis weight, epididymis weight

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on Day 43
- Maternal animals: All surviving animals on lactation day 4; non-pregnant females were sacrificed on the same day

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations for abnormalities

HISTOPATHOLOGY / ORGAN WEIGHTS
The following organs/tissues were prepared for microscopic examination and weighed, respectively: testes, epididymes, ovaries and uterus. Any organs with lesions were prepared and subjected to a histopathological examination.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age
- These animals were subjected to postmortem examinations (macroscopic examination) as follows: all pups were examined for external and visceral abnormalities

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations for abnormalities

HISTOPATHOLOGY / ORGAN WEIGTHS
No histopathological examinations were performed.

Statistics:

Continuous data, including body weight, body weight gain, feed consumption, organ weight, pup body weight, gestation length and mean live litter size were analysed using a one-way analysis of variance (ANOVA). If significance (p < 0.05) was noted, group by group comparisons were performed using Dunnet's test. Count data were analysed using chi-square test for copulation and fertility indices, pup sex ratio, number of live and dead pups per group on lactation day 0, and pup survival after lactation day 0. All anaylses used two-tailed tests for a minimum significance level of 5% comparing the control to the treated groups. A p value of less than 0.5% was judged a significant difference.

Reproductive indices:

Mating index (%): (numbers of pairs with successful mating/ number of pairs) x 100
Fertility index (%): (Number of pregnant females/ number of pairs with successful mating) x 100

Offspring viability indices:

Live birth index (%): (Number of live pups born/ number of pups born) x 100
Viability index (%): (Number of live pups on lacation day 4/ number of live pups born) x 100

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Decreased activity, disorientation and unkempt fur was observed in most males of the high-dose group. These transient effects are not considered to be toxicologically relevant.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The body weight and body weight gain was comparable between the treatment and control groups in males and females. The body weight increase in females of the high-dose group observed on Day 14 of gestation only, is considered to be an incidental effect.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The food consumption was significantly reduced in males of the low- and mid-dose group in week 6, and in males of the high-dose group in week 4, 5 and 6 (see Table 1 and 2 under ' Any other information on results incl. tables'). The reduced food intake did not affect the body weight, therefore, the reduced food consumption is not considered to be toxicologically relevant. The test substance intake was adjusted weekly based on the body weight and was considered by the study report authors to be close to the reported dose levels.

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

The testis and epididymes weights were comparable between the treatment and control groups in males.

Reproductive performance:

effects observed, non-treatment-related

Description (incidence and severity):

There were no significant differences in fertility index and dams with live young born between the control and treatment groups. The mating index was slightly, but not significantly reduced in the 500 and 1000 mg/kg bw/day groups (see Table 3 under ' Any other information on results incl. tables'). Two of nine dams in the high-dose group cannibalised their entire litter post-partum, with the study authors indicating the reason was 'abnormal maternal behaviour'. This information was not included in the English translation of the study report (only in the Chinese version) and no additional information was available. Due to the limited information given in the study report and the lack of individual animal data the possibility that this effect is treatment-related cannot be excluded. However, no toxicological relevance was evident in the general health and reproductive health of the dams and cannibalisation is known to occur in rats.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No toxicologically relevant effects were observed up to and including the highest dose level

Key result

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive function (sperm measures)

reproductive performance

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

The survival rate (as viability index) of pups in the high-dose group was significantly reduced, compared with the control group (see Table 3 under 'Any other information on results incl. tables'). Two of nine dams cannibalised their entire litter post-partum, which is likely to have caused the reduction in viability.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The body weight of pups in the high-dose group was significantly reduced on lactation day 0, compared with the control group. The difference was approximately 5%; indicating that the variation in body weight is incidental and not treatment-related. Furthermore, the mean weight for the control and treatment groups fell within the historical data range given for rat pups on lactation day 0 (Lang, P.L. Historical control data for development and reproductive toxicity studies using the Crl:CD BR rat. Charles River Laboratories, September 1993. www.criver.com) No significant difference was noted between the control and treatment groups on lactation day 4.

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

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

no effects observed

Description (incidence and severity):

The tail length of the pups in the high-dose group was significantly shorter than that of the control group. However, this is not a standard parameter and is unlikely to affect the survival and development of the pups. Therefore it is not considered to be a toxicologically relevant effect. A significant increase in pup length in the mid-dose group is considered to be incidental.

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEL

Remarks:

development

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment-related adverse effects were observed up to and including the highest dose level

Key result

Critical effects observed:

no

Reproductive effects observed:

no

Table 1: body weight in males

Body weight, g (mean ± SD)
	Dose group (mg/kg bw/day)
	Control (vehicle)	250	500	1000
Day 0	269.3 ± 17.0	268.5 ± 18.3	267.3 ± 19.4	271.7 ± 13.2
Week 1	318.1 ± 17.5	323.2 ± 14.6	320.5 ± 13.7	319.7 ± 16.2
Week 2	357.3 ± 23.5	366.0 ± 14.6	366.9 ± 17.2	357.9 ± 16.4
Week 3	416.9 ± 31.7	423.6 ± 21.6	426.3 ± 26.0	411.7 ± 21.0
Week 4	437.0 ± 33.6	443.4 ± 25.4	445.5 ± 26.5	429.3 ± 22.2
Week 5	460.7 ± 37.1	471.9 ± 28.9	474.6 ± 28.8	454.3 ± 23.5
Week 6	487.7 ± 43.0	492.5 ± 31.5	493.6 ± 32.1	475.4 ± 24.9

Table 2: food consumption in males

Food consumption, g (mean ± SD)
	Dose group (mg/kg bw/day)
	Control (vehicle)	250	500	1000
Week 1	176.6 ± 11.8	180.9 ± 6.5	180.9 ± 14.0	174.8 ± 9.1
Week 2	189.3 ± 20.9	187.7 ± 11.4	188.5 ± 8.2	179.7 ± 11.1
Week 4	195.4 ± 17.9	193.7 ± 20.9	188.1 ± 14.4	177 ± 14.6*
Week 5	183.6 ± 19.3	179.3 ± 20.4	174.9 ± 11.8	166 ± 17.2*
Week 6	200.0 ± 20.3	180.7 ± 18.0*	181.5 ± 11.0*	173.2 ± 15.2*

* p < 0.05

 

Table 3: reproductive performance and development data

	Dose group (mg/kg bw/day)
	Control (vehicle)	250	500	1000
Females showing evidence of mating (N)	15	14	10	12
Mating index (%)	100	93	67	80
Females achieving pregnancy (N)	11	11	10	9
Fertility index (%)	73	79	100	75
Dams with live young born (N)	11	11	10	9
Pups born (N)	159	154	144	137
Live pups born (N)	159	151	142	135
Live birth index (%)	100	98	99	99
Live pups on day 4 (N)	156	148	137	117
Viability index (%)	98	98	96	87*
Sex ratio (male/female)	84/74	74/77	69/73	71/64
Pup weight on day 0 (g)	6.51 ± 0.63	6.54 ± 0.77	6.67 ± 0.68	6.21 ± 0.85*
Pup weight on day 4 (g)	11.14 ± 1.80	11.43 ± 2.03	11.13 ± 1.43	11.04 ± 1.05
Pup length on day 0 (cm)	4.54 ± 0.23	4.61 ± 0.32	4.63 ± 0.26*	4.50 ± 0.30
Pup tail length on day 0 (cm)	1.74 ± 0.16	1.69 ± 0.21	1.77 ± 0.20	1.68 ± 0.16*

* p < 0.05

 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A reproduction/developmental toxicity screening study was performed according to the Chinese Guidelines for the Testing of Chemicals (State Environment Protection Administration of China) 2004.5, using a protocol similar to OECD guideline 421 (Guan, 2014). No individual animal data was included in the study report. 15 rats/sex/dose were administered 250, 500 and 1000 mg/kg bw/day 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 once daily, via gavage. Males were exposed for 42 days, from two weeks before mating on test day 1. Females were exposed for up to 54 days (during 2 weeks prior to mating, during mating, during gestation, and during 3 days of lactation). There was no mortality among the P animals during the study period.

Decreased activity, disorientation and unkempt fur was observed in most males of the high-dose group. These effects were considered to be transient and not toxicologically relevant.

No treatment-related effects were seen in the parental (P) animals on body weight and body weight gain, while the food consumption was significantly reduced in males of the low- and mid-dose group in week 6 (approximately 11%), and in males of the high-dose group in week 4, 5 and 6 (approximately 10 – 15%). The reduced food intake was 15% or less and did not affect the body weight. No treatment-related effects were noted during necropsy.

The NOAEL for parental systemic toxicity was considered to be ≥ 1000 mg/kg bw/day (males, females).

 

In parental animals, no effects on reproductive function (testis and epididymis weight) or performance (male and female mating and fertility indices, number of dams with live born young) were observed, compared with the control animals. The weight and appearance of the testis, epididymis, uterus and ovaries was comparable between the control and treatment groups. The histopathological examination of the reproductive organs of males and females did not show any treatment-related effect. There were no significant differences in mating index, fertility index and dams with live young born between the control and treatment groups. Two of nine dams in the high-dose group cannibalised their entire litter post-partum, with the study authors indicating the reason was 'abnormal maternal behaviour'. This information was not included in the English translation of the study report (only in the Chinese version) and no additional information was available. Due to the limited information given in the study report and the lack of individual animal data the possibility that this effect is treatment-related cannot be excluded. However, no toxicological relevance was evident in the general health and reproductive health of the dams and cannibalisation is known to occur in rats. The body weight of pups in the high-dose group was significantly reduced on day 0, compared with the control group. The difference was approximately 5%; indicating that the variation in body weight is incidental and not treatment-related. No significant difference was noted between the control and treatment groups on day 4. The tail length of the pups in the high-dose group was significantly shorter than that of the control group. However, this is not a standard parameter and is unlikely to affect the survival and development of the pups. Therefore it is not considered to be a toxicologically relevant effect. The gross pathological examinations did not reveal any treatment-related effects. The results of the offspring born, live birth index, sex ratio, pup length on post-partum day 0 and body weight on post-partum day 4 were comparable between the control and treatment groups. The survival rate (as viability index) of pups in the high-dose group was significantly reduced, compared with the control group. Two of nine dams cannibalised their entire litter post-partum, which is likely to have caused the reduction in viability and therefore is related to maternal behaviour rather than the health conditions of the pups.

A NOAEL for parental fertility of ≥ 1000 mg/kg bw/day was derived for male and female rats.

Effects on developmental toxicity

Description of key information

Oral: OECD 414, rat, NOAEL development ≥1000 mg/kg bw/day

Oral: OECD 414, rat, NOAEL systemic ≥1000 mg/kg bw/day

Link to relevant study records

Reference

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

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

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

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

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

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.

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.

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

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.

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

Key result

Abnormalities:

no effects observed

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

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

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

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

 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A developmental toxicity/teratogenicity study was performed according to the Chinese Guidelines for the Testing of Chemicals (State Environment Protection Administration of China) 2004.5, using a protocol similar to OECD guideline 414 (He, 2015). No individual animal data was included in the study report. 20 female rats/dose were administered 250, 500 and 1000 mg/kg bw/day 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] once daily, via gavage, during gestation day 6 – 15. On gestation day 20 the animals were euthanized and examined for maternal and fetal parameters. There was no mortality during the study period. The body weight (gain), and prevalence and duration of clinical signs did not vary significantly between the control and treatment groups. The gravid uterus weight, number of corpora lutea, number of implantations, number of early and late resorptions, and appearance of placenta and ovaries was comparable between the control and treatment groups. The NOAEL for maternal toxicity was found to be ≥ 1000 mg/kg bw/day.

In the offspring, the viability (number of live and dead foetuses), foetal body weight and length, litter size, and prevalence of external malformations, skeletal malformations and visceral malformations, was comparable between the offspring of the control and treatment groups. There were no indications of teratogenic effects. The NOAEL for developmental toxicity/teratogenicity was considered to be ≥ 1000 mg/kg bw/day.

Justification for classification or non-classification

The available data on toxicity to reproduction and development does not meet the classification criteria according to Regulation (EC) 1272/2008 and is therefore conclusive but not sufficient for classification.