Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.88 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
Modified dose descriptor starting point:
NOAEC
Value:
22.04 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic inhalation DNEL has been derived from the oral 90 d Repeated Dose Toxicity Study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
ECHA default - see guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA default - see guidance.
AF for intraspecies differences:
5
Justification:
ECHA default - see guidance.
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
22.04 mg/m³
Explanation for the modification of the dose descriptor starting point:
An acute toxicity hazard leading to a classification according to CLP Regulation (EC) No 1272/2008 acute toxicity Category 4 for the inhalation route has been identified. However, a reliable dose descriptor for acute systemic effects could not be derived from the available inhalation study. Considering high peak exposure the DNEL for acute toxicity was set for a reference period of 15 minutes at twice the value of the long-term DNEL.

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic dermal DNEL has been derived from the oral 90 d Repeated Dose Toxicity Study.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
ECHA default - see guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default - see guidance.
AF for other interspecies differences:
2.5
Justification:
ECHA default - see guidance.
AF for intraspecies differences:
5
Justification:
ECHA default - see guidance.
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
The available studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
An acute toxicity hazard leading to a classification according to CLP Regulation (EC) No1272/2008 acute toxicity Category 3 for the dermal route has been identified. However, a reliable dose descriptor for acute systemic effects could not be derived from the available dermal studies. Considering high peak exposure the DNEL for acute toxicity was set for a reference period of 15 minutes at twice the value of the long-term DNEL.

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General considerations

Short-term data

Data on acute toxicity are available for the oral, inhalation and dermal route. BTMAC is classified for acute oral and dermal toxicity Hazard Category 3 as well as inhalation toxicity Hazard Category 4.

BTMAC is not classified for skin or eye irritation, nor for skin sensitization.

 

Long-term data

Data relevant for long-term toxicity are available from an oral sub-chronic toxicity study and a developmental toxicity study, both in rats.

 

Selection of the relevant dose descriptors:

NOAEL = 25 mg/kg bw/day: 90 d Repeated Dose Toxicity Study, rat, oral (gavage)

NOAEL = 20 mg/kg bw/d: Prenatal Developmental Toxicity Test, rat, oral (gavage)

 

Hazard for the eyes

An additional hazard was listed for acute eye effects, since 3 of 6 animals in the acute eye irritation study died after dosing, even though no eye irritation was observed.

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

No data exist on differences in bioavailability following oral or dermal exposure between experimental animals and humans, and a similar bioavailability is assumed by default.

 

Oral to inhalatory

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

Oral to dermal

For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case value (Guidance on Information Requirements and Chemical Safety Assessment, R8).

 

DERIVATION OF DNELs

DNELs long term systemic effects

 

Uncertainties

 

AF

 

Justification

 

Allometric scaling (inhalation)

 

1

No allometric scaling rat to humans for inhalation - differences in respiratory volume are already included in route-to-route extrapolation (ECHA 2008).

 

Allometric scaling (dermal)

 

4

Allometric scaling rat to humans AF 4 (ECHA 2008).

 

Remaining interspecies differences

 

2.5

Default AF for remaining interspecies differences

 

Intraspecies differences

 

5

Default AF for workers

 

Differences in duration of exposure (90 d repeated dose toxicity study)

 

2

Default assessment factor for extrapolation from subchronic to chronic

 

Differences in duration of exposure (prenatal developmental toxicity study)

1

No time extrapolation is required since the susceptible window is fully covered.

Dose response and endpoint specific/severity

 

1

The NOAELs are reliable. No adjustment is required. 

 

Quality of whole database

 

1

The studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor. 

Remaining uncertainties

 

1

No uncertainties remain.

 

DNELs derived from oral repeated dose toxicity NOAEL (90-d study, rat, OECD Guideline 408) 

Worker-DNEL long-term for dermal route (systemic):  0.25 mg/kg bw/d

Start value: 25 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 25 mg/kg bw/d

Overall AF 4*2.5*5*2*1*1*1 = 100

 

Worker-DNEL long-term for inhalation route (systemic): 0.88 mg/m³

Start value: 25 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 22.04 mg/m³

 

For workers the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                             = 25 x 1/0.38 x 50/100 x 6.7/10

The corrected inhalatory NOAECworker (8h) is therefore:

                                             = 22.04 mg/m³ (8h-TWA)

Overall AF: 1*2.5*5*2*1*1*1 = 25

 

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

 

DNELs derived from oral prenatal developmental toxicity NOAEL (rat, OECD Guideline 414) 

Worker-DNEL long-term for dermal route (systemic):  0.4 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 20 mg/kg bw/d

Overall AF 4*2.5*5*1*1*1*1 = 50

 

Worker-DNEL long-term for inhalation route (systemic): 1.41 mg/m³

Start value: 20 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 17.63 mg/m³

 

For workers the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                             = 20 x 1/0.38 x 50/100 x 6.7/10

The corrected inhalatory NOAECworker (8h) is therefore:

                                             = 17.63 mg/m³ (8h-TWA)

Overall AF: 1*2.5*5*1*1*1*1 = 12.5

 

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

 

The DNELs for developmental toxicity were higher than those for repeated dose toxicity. Thus, the repeated dose toxicity-DNELs are also protective for development. 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

No DNEL derived for general population, as no consumer exposure is anticipated. Substance is used as a catalyst only in industrial settings.