Registration Dossier

Administrative data

Description of key information

Oral (OECD 425): LD50 > 2000 mg/kg bw

Inhalation (similar to OECD 403): LC50 > 5.47 mg/L

Dermal (OECD 402): LD50 > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 Dec 2009 - 09 Feb 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
adopted Oct 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
The Department of Health of the Government of the United Kingdom, UK
Test type:
up-and-down procedure
Limit test:
yes
Species:
rat
Strain:
other: Wistar (HsdRccHan:WIST)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Bicester, UK
- Age at study initiation: 8 - 12 weeks old
- Weight at study initiation: 156 - 205 g
- Fasting period before study: overnight until 3 - 4 hours after dosing
- Housing: animals were individually housed in suspended solid-floor polypropylene cages furnished with woodflakes and with enviromental enrichment items
- Diet: 2014 Teklad Global Rodent diet (Harlan Teklad, Bicester, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 17.5, 55 and 200 mg/mL
- Justification for choice of vehicle: arachis oil BP was used as the test substance did not dissolve in water

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual): the test material was formulated within 2 hours of administration. No analysis was conducted to determine the homogeneity, concentration or stability of the formulation.
Doses:
175, 550 and 2000 mg/kg bw
No. of animals per sex per dose:
5 females per dose group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for mortality and clinical signs 0.5, 1, 2 and 4 hours after dosing, and thereafter once daily for the rest of the observation period; the body weight was recorded on Day 0 (prior to dosing), 7 and 14
- Necropsy of survivors performed: yes
-Other: No information was available regarding the toxicity of the test substance. Therefore, the default values for LD50 and sigma were entered into AOT425 Statistical Program. The program gave a recommended dose progression of 2000, 550, 175, 55, 17.5, 5.5 and 1.75 mg/kg bw. The first animal was dosed with 175 mg/kg bw, the second with 550 mg/kg bw and animal 3 - 5 were dosed with 2000 mg/kg bw. The animals were treated sequentially, with at least 48 hours between each one to confirm the outcome of the previously dosed animal.
Statistics:
The mortality data was used by the statistical program to calculate an oral LD50 (the maximum likelihood method).
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
Hunched posture was observed from 2 hours after dosing on the day of dosing only in 2/3 rats administered 2000 mg/kg bw. No other clinical signs were observed during the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy did not reveal substance-related findings.

Table 1. Mortality and clinical signs

Dose
[mg/kg bw]

Toxicological results*

Duration of clinical signs

Time of death

Mortality (%)

Females

175

0/0/1

---

---

0

550

0/0/1

--

--

0

2000

0/2/3

2 h – Day 1

--

0

LD50 = 2000 mg/kg bw

* first number = number of dead animals

 second number = number of animals with clinical signs

 third number = number of animals used

 

Interpretation of results:
other: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
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 VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
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:
Few details on materials and methods were given, the individual animal data was not reported, no necropsy was performed, the airflow was not monitored, air changes per minute were not reported, the type of inhalation exposure was not specified. The requirements of the listed guideline were not available.
Qualifier:
according to
Guideline:
other: The Guidelines for the Testing of Chemicals (State Environmental Protection Administration of China) 2004.5
Deviations:
no
Qualifier:
according to
Guideline:
other: The Guidelines for the Hazard Evaluation of New Chemical Substances (HJ/T 154-2004)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted Sep 2009
Deviations:
yes
Remarks:
few details on materials and methods were given, individual animal data not reported, no necropsy was performed, air changes per minute not reported, airflow was not monitored, the type of inhalation exposure not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: SPF Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Vital River Laboratory Animal Technology Co. Ltd., Beijing, China
- Weight at study initiation: 252.2 ± 1.9 g (females) and 258.0 ± 4.9 g (males)
- Housing: animals were housed individually
- Diet: rodent 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 (%): 55 ± 15
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: dust
Type of inhalation exposure:
not specified
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Dynamic inhalation control system (HOPE-MED8051C), solid phase dust inhalation chamber (8051) and automatic dust dynamic control system (8051C) (Tianjin HOPE Co., Ltd., Tianjin, China); dust sampler and filter membrane (Yancheng Kebo Electron Instrument Co., Ltd., Jiangsu, China)
- Exposure chamber volume: 300 L
- Source and rate of air: 4.0 m³/h
- System of generating particulates/aerosols: dust of the test substance was generated with the dust generator and entered the inhalation chamber at a rate of 2.8 mL/min.

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric method. Samples of the test substance were collected at 1, 2 and 3 h using a dust sampler equipped with a filter membrane that had been weight prior to sampling. The weight minus filter weight was used as the sample weight.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric method
Duration of exposure:
4 h
Concentrations:
5 mg/L (nominal concentration)
5.47 mg/L (analytical concentration)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed for mortality and clinical signs immediately after exposure, and daily thereafter for the rest of the study period; the body weight was recorded on Day 0 (prior to dosing), 7 and 14
- Necropsy of survivors performed: no
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.47 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred during the study period.
Clinical signs:
other: No clinical signs of toxicity were observed during the 14-day observation period.
Body weight:
The body weight gains were within the normal ranges in males and females during the whole study period.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 470 mg/m³
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 VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06 - 20 Jan 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted Feb 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
The Department of Health of the Government of the United Kingdom, UK
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar HsdRccHan:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Bicester, UK
- Age at study initiation: 8 - 12 weeks old
- Weight at study initiation: 230 - 256 g (males); 200 - 219 g (females)
- Fasting period before study: overnight until 3 - 4 hours after dosing
- Housing: during the 24-hour exposure period, animals were individually housed in suspended solid-floor polypropylene cages furnished with woodflakes and with enviromental enrichment items. For the period before and after exposure, animals were housed in groups of 5 by sex.
- Diet: 2014 Teklad Global Rodent diet (Harlan Teklad, Bicester, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
other: the test substance was moistened with arachis oil BP
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flank of the animal
- % coverage: approximately 10
- Type of wrap if used: a piece of surgical gauze was placed over the treatment area and secured with a semi-occlusive self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, residual test substance was removed using cotton wool moistened with arachis oil
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: no, the test substance was moistened using arachis oil BP
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed for mortality and clinical signs 0.5, 1, 2 and 4 hours after administration, and daily thereafter for the rest of the study period; the body weight was recorded on Day 0 (prior to dosing), 7 and 14; the test site was scored for skin irritation (erythema and edema) daily for the entire observation period
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No treatment-related clinical signs were observed during the 14-day observation period.
Body weight:
4/5 males and 2/5 females showed the expected body weight gain during the observation period. 1/5 males showed a body weight loss (< 10%) during week 2 and 3/5 females had no increase in body weight during either week 1 or week 2.
Gross pathology:
The necropsy and gross pathology examination did not reveal any substance-related findings.
Other findings:
- Other observations: No erythema or edema was noted at the test site in any animal during the observation period.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
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 VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Acute oral toxicity

In an acute oral toxicity study performed according to OECD guideline 425 and under GLP conditions, 175, 550 and 2000 mg/kg bw 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 was administered via gavage to female Wistar rats (Sanders, 2010). In line with the up-and-down procedure, a maximum of 5 animals were administered increasing doses of the test substance at 48-hour intervals, until an LD50 could be derived or calculated. There was no mortality during the 14-day observation period at any dose level. Two of three rats administered 2000 mg/kg bw had a hunched posture on the dosing day from 2 hours after administration. No effect on body weight and body weight gain was observed and no findings were reported from the necropsy. The LD50 oral for female rats is considered to be > 2000 mg/kg bw.

Acute inhalation toxicity

The acute inhalation toxicity of 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 was assessed in a study performed according to the Chinese Guidelines for the Testing of Chemicals (State Environmental Protection Administration of China) 2004.5, using a protocol similar to OECD guideline 403 (Ning, 2015). 5 SPF Wistar rats/sex were administered 5.47 mg/L (analytical concentration) of the test substance (unspecified exposure type) for 4 hours. The rats were exposed to the test substance as a dust in a solid phase dust inhalation chamber (300 L volume). No mortality occurred and no clinical signs were observed during the 14-day observation period. The body weight gain was within the range that is normal for this strain and study type. No macroscopic examination was performed. The LC50 is considered to be > 5.47 mg/L (analytical concentration).

Acute dermal toxicity

An acute dermal toxicity study (limit test) was performed with 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 according to OECD guideline 402 and under GLP conditions (Sanders, 2010). 2000 mg/kg bw of the test substance was moistened with arachis oil BP applied to the skin of 5 Wistar rats/sex/dose under a semi-occlusive dressing for 24 hours. No mortality occurred and no treatment-related clinical signs were noted during the 14-day observation period. The body weight increases were within the range expected for rats used in this type of study for 4/5 males and 2/5 females. 1/5 males showed body weight loss (< 10%) during week 2 and 3/5 females showed no body weight increase during either week 1 or week 2. No treatment-related findings were reported during the gross necropsy. There were no local skin effects at the treatment site. The LD50 dermal is considered to be > 2000 mg/kg bw.

Justification for classification or non-classification

The available data on acute toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.