Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 763.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

The long-term worker DNEL for inhalation systemic effects is based on the 90-day repeated dose toxicity study 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 408 (Zhang, 2014). 10 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. A control and 1000 mg/kg bw/day satellite group was included and observed for 14 days after treatment ended to assess the reversibility of any treatment-related effects. No animals died and no effects with toxicological relevance were observed on body weights, organ weights, haematologic parameters, clinical chemistry parameters and urinary parameters in the study. The gross and histopathologic examinations did not show treatment-related effects. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose toxicity study. According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2.1, November 2012), the oral NOAEL should be converted into an inhalatory NOAEC, whereby the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 h exposure). Additionally, it should be taken into account that during 8 hours light activity at work the respiratory rate becomes higher (10 m³/person) than standard (6.7 m³/person). The NOAECcorr is calculated below. In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (for details please refer to section 7.1 Toxicokinetics, metabolism and distribution).

 

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)) = 1000 mg/kg bw/day*(1/0.38 m³/kg bw/day)*0.67*(1/1) = 1763.2 mg/m³. ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default AF.
AF for intraspecies differences:
5
Justification:
Default AF for workers.
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
100 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The long-term worker DNEL for dermal systemic effects is based on the 90-day repeated dose toxicity study 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 408 (Zhang, 2014). 10 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. A control and 1000 mg/kg bw/day satellite group was included and observed for 14 days after treatment ended to assess the reversibility of any treatment-related effects. No animals died and no effects with toxicological relevance were observed on body weights, organ weights, haematologic parameters, clinical chemistry parameters and urinary parameters in the study. The gross and histopathologic examinations did not show treatment-related effects. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. This study was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study. To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. For the test substance the oral bioavailability was predicted to be moderate (see section 7.1 Toxicokinetics), so the default factor (AF) of 1 is used for oral absorption. The toxicokinetic data (log Pow <-1 or > 4 and MW > 500) indicate that the dermal bioavailability is very low. In line with the ECHA CSA Guidance Chapter R.7c (November 2014) and Figure R.7.12-5 of the above-mentioned Guidance, the absorption rate is considered to be 10%, leading to a factor of 0.1.

NOAELcorr = NOAELoral*(ABSoral-rat/ABSdermal-human) = (1000 mg/kg bw/day)*(1/0.1) = 10 000 mg/kg bw/day. ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats.
AF for other interspecies differences:
2.5
Justification:
Default AF.
AF for intraspecies differences:
5
Justification:
Default AF for workers.
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
869.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

The long-term general population DNEL for inhalation systemic effects is based on the 90-day repeated dose toxicity study 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 408 (Zhang, 2014). 10 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. A control and 1000 mg/kg bw/day satellite group was included and observed for 14 days after treatment ended to assess the reversibility of any treatment-related effects. No animals died and no effects with toxicological relevance were observed on body weights, organ weights, haematologic parameters, clinical chemistry parameters and urinary parameters in the study. The gross and histopathologic examinations did not show treatment-related effects. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose toxicity study.

According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2.1, November 2012), the oral NOAEL should be converted into an inhalatory NOAEC, whereby the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 h exposure). The NOAECcorr is calculated below. . In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (for details please refer to section 7.1 Toxicokinetics, metabolism and distribution).

NOAECcorr = NOAELoral*(1/1.15 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)) = 1000 mg/kg bw/day*(1/1.15 m³/kg bw/day)*(1/1) = 869.6 mg/m³. ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default AF.
AF for intraspecies differences:
10
Justification:
Default AF for general population.
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The long-term general population DNEL for dermal systemic effects is based on the 90-day repeated dose toxicity study 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 408 (Zhang, 2014). 10 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. A control and 1000 mg/kg bw/day satellite group was included and observed for 14 days after treatment ended to assess the reversibility of any treatment-related effects. No animals died and no effects with toxicological relevance were observed on body weights, organ weights, haematologic parameters, clinical chemistry parameters and urinary parameters in the study. The gross and histopathologic examinations did not show treatment-related effects. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. This study was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study. To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. For the test substance the oral bioavailability was predicted to be moderate (see section 7.1 Toxicokinetics), so the default factor of 1 is used for oral absorption. The toxicokinetic data indicate that the dermal bioavailability is very low. In line with the ECHA CSA Guidance Chapter R.7c (November 2014) and Figure R.7.12-5 of the above-mentioned Guidance, the absorption rate is considered to be 10%, leading to a factor of 0.1.

 

NOAELcorr = NOAELoral*(ABSoral-rat/ABSdermal-human) = (1000 mg/kg bw/day)*(1/0.1) = 10 000 mg/kg bw/day.

ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats.
AF for other interspecies differences:
2.5
Justification:
Default AF.
AF for intraspecies differences:
10
Justification:
Default AF for general population.
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remianing uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
The DNEL is based on a subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats.
AF for other interspecies differences:
2.5
Justification:
Default AF.
AF for intraspecies differences:
10
Justification:
Default AF for general population.
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population