Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18 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
DNEL value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
441 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral subchronic study has a shown a clear mode of action and a no-effect level has been determined in the study. This endpoint has been used as dose descriptor starting point. The inhalation study shows diffuse symptoms at all concentrations. An assessment factor for differences in absorption of 1 was used because of the high solubility of MMB. Its systemic availability after oral intake is considered to be very high. Calculation of the inhalative NOAEC is done following REACH guidance R.8 as follows: 250 mg/kg/day * 6.7 / 10 / 0.38 = 441 mg/m³.
AF for dose response relationship:
1
Justification:
guidance R.8 default, exceptions do not apply
AF for differences in duration of exposure:
2
Justification:
guidance R.8 default for subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable, see APPENDIX R. 8-2, part 2 example B3
AF for other interspecies differences:
2.5
Justification:
guidance R.8 default
AF for intraspecies differences:
5
Justification:
guidance R.8 default
AF for the quality of the whole database:
1
Justification:
key study was rated Klimisch 1
AF for remaining uncertainties:
1
Justification:
Given that all studies show a similar critical effects, e.g. kidney and liver weight increase and haematological findings, the effects do not require metabolism of the substance. No difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals is to be expected. There is no evidence that individuals may develop different symptoms which may require a safety margin to cover all members of the population.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.25 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
Dose descriptor starting point:
NOAEL
DNEL value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
625 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No dermal endpoint is available; oral subchronic is the most sensitive endpoint. A dermal absorption factor of 0.4 has been considered, see section toxicokinetics. Dermal NOAEL = 250/0.4 = 625

mg/kg bw/day.

AF for dose response relationship:
1
Justification:
guidance R.8 default
AF for differences in duration of exposure:
2
Justification:
guidance R.8 default for subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
guidance R.8 default
AF for other interspecies differences:
2.5
Justification:
guidance R.8 default
AF for intraspecies differences:
5
Justification:
guidance R.8 default
AF for the quality of the whole database:
1
Justification:
key studies were rated Klimisch 1
AF for remaining uncertainties:
1
Justification:
not justified, see above
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:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

The typical pattern of worker and consumer exposure to 3-methoxy-3-methyl-butan-1-ol is low levels of exposure on a repeated basis. Short-term high exposures are considered unlikely given the high levels of control in place at sites formulating and using the substance. DNELs for long-term exposure are therefore adequate to protect against short-term exposures and no separate short-term DNELs are calculated.

The oral subchronic toxicity NOAEL of 250 mg/kg bw/day is selected as critical endpoint on the basis of haematological findings and clinical biochemistry and is used as

point of departure. This endpoint is considered the most sensitive one and representative for adverse effects observed in different species and different studies available.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.4 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
DNEL value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
219 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral subchronic study has a shown a clear mode of action and a no-effect level has been determined in the study. This endpoint has been used as dose descriptor starting point. The inhalation study shows diffuse symptoms at all concentrations. An assessment factor for differences in absorption of 1 was used because of the high solubility of MMB. Its systemic availability after oral intake is considered to be very high. Calculation of the inhalative NOAEC is done following REACH guidance R.8 as follows: 250 mg/kg/day /4 *70 /20= 219 mg/m³.
AF for dose response relationship:
1
Justification:
guidance R.8 default
AF for differences in duration of exposure:
2
Justification:
guidance R.8 default
AF for interspecies differences (allometric scaling):
1
Justification:
included in route to route AF
AF for other interspecies differences:
2.5
Justification:
guidance R.8 default
AF for intraspecies differences:
10
Justification:
guidance R.8 default
AF for the quality of the whole database:
1
Justification:
key studies were rated Klimisch 1
AF for remaining uncertainties:
1
Justification:
Given that all studies show a similar critical effects, e.g. kidney and liver weight increase and haematological findings, the effects do not require metabolism of the substance. No difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals is to be expected. There is no evidence that individuals may develop different symptoms which may require a safety margin to cover all members of the population.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.1 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
DNEL value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
625 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal endpoint is available; oral is the most sensitive endpoint. A dermal absorption factor of 0.4 was applied to the oral NOAEL of 250 mg/kg bw/day, see section toxicokinetics. Dermal NOAEL = 250 /0.4 = 625 mg/kg bw/day.
AF for dose response relationship:
1
Justification:
guidance R.8 default
AF for differences in duration of exposure:
2
Justification:
guidance R.8 default
AF for interspecies differences (allometric scaling):
4
Justification:
guidance R.8 default
AF for other interspecies differences:
2.5
Justification:
guidance R.8 default
AF for intraspecies differences:
10
Justification:
guidance R.8 default
AF for the quality of the whole database:
1
Justification:
key studies were rated Klimisch 1
AF for remaining uncertainties:
1
Justification:
an assessment factor for remaining differences is not justified, see above
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
Most sensitive endpoint:
repeated dose toxicity
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:
2.5 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
DNEL value:
250
Modified dose descriptor starting point:
NOAEL
DNEL value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no differences in oral absorption assumed.

AF for dose response relationship:
1
Justification:
guidance R.8 default
AF for differences in duration of exposure:
2
Justification:
guidance R.8 default
AF for interspecies differences (allometric scaling):
4
Justification:
guidance R.8 default
AF for other interspecies differences:
2.5
Justification:
guidance R.8 default
AF for intraspecies differences:
10
Justification:
guidance R.8 default
AF for the quality of the whole database:
1
Justification:
key studies were rated Klimisch 1
AF for remaining uncertainties:
1
Justification:
an assessment factor for remaining differences is not justified, see above
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population