Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
52.9 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):
10
Modified dose descriptor starting point:
NOAEC
Value:
529 mg/m³
Explanation for the modification of the dose descriptor starting point:

Refer to discussion

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic (90-day repeated dose toxicity study) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not necessary for the inhalation route
AF for other interspecies differences:
1
Justification:
The substance is not metabolised in vivo
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
The available information is of adequate and reliable quality
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.38 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):
32
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Refer to discussion

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic (90-day repeated dose toxicity study) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human allometric scaling
AF for other interspecies differences:
1
Justification:
The substance is not metabolised in vivo
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
The available information is of adequate and reliable quality
AF for remaining uncertainties:
0.8
Justification:
80% dermal absorption
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

No DNELs have been derived for the short-term dermal and inhalation exposure of 2-dimethylamino-2-methyl-1-propanol (DMAMP) for workers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of DMAMP. Therefore, an absolute value for the local effects has been determined. The most sensitive local endpoint is eye corrosion (Parekh, 1982). The long-term worker DNEL for dermal systemic effects is based on the 90-day repeated dose toxicity study (Wasil, 2012), which was performed according to OECD 408 in rats. In this study, no clinical signs with toxicological relevance were observed and there were no treatment-related effects on body weight, body weight gain and food consumption. The results of the opthalmological and neurobehavioural examinations were comparable between the control and treatment groups. In the highest dose group, the alkaline phosphatase levels were increased by around 30% in males (significantly) and females (not significantly). The absolute and relative liver weight, and relative kidney weight was significantly increased at the highest dose level in both males and females. The histopathology results showed treatment-related, and possibly toxicologically relevant, effects in the liver in females, and in the kidneys in males administered the highest dose. Based on the effects observed in the target organs (liver in females, kidneys in males), the NOAEL is set at 300 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 (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2, December 2010). For DMAMP, a dermal absorption of 80% was calculated using QSAR and the available physico-chemical properties.

The long-term worker DNEL for inhalation systemic effects is based on the 90 -day repeated dose toxicity study (Wasil, 2012), which was performed according to OECD 408 in rats. This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose 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, December 2010), the oral NOAEL should be converted into an inhalatory NAEC: 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). Considering these differences, the correct starting point is a NAEC of 529.0 mg/m³. The absorption via the inhalative route is considered to be in the same order as via the oral route.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, Version 2, December 2010) were used when applicable to derive the DNELs. One AF for which there is additional information was refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 1, as the toxicokinetic data indicates that DMAMP will not be metabolised. Due to its polarity and size, DMAMP will mainly be excreted unmetabolised via the urine (see toxicokinetics).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.04 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):
20
Modified dose descriptor starting point:
NOAEC
Value:
260.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

Refer to discussion

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic (90-day repeated dose toxicity study) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not necessary for the inhalation route
AF for other interspecies differences:
1
Justification:
The substance is not metabolised in vivo
AF for intraspecies differences:
10
Justification:
Default value for the general population
AF for the quality of the whole database:
1
Justification:
The available information is of adequate and reliable quality
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.69 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):
64
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

refer to discussion

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic (90-day repeated dose toxicity study) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human allometric scaling
AF for other interspecies differences:
1
Justification:
The substance is not metabolised in vivo
AF for intraspecies differences:
10
Justification:
Default value for the general population
AF for the quality of the whole database:
1
Justification:
The available information is of adequate and reliable quality
AF for remaining uncertainties:
0.8
Justification:
80% dermal absorption
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.75 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):
80
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic (90-day repeated dose toxicity study) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human allometric scaling
AF for other interspecies differences:
1
Justification:
The substance is not metabolised in vivo
AF for intraspecies differences:
10
Justification:
Default value for the general population
AF for the quality of the whole database:
1
Justification:
The available information is of adequate and reliable quality
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

No DNELs have been derived for the short-term dermal, inhalation and oral exposure of DMAMP for the general population, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of DMAMP. Therefore, an absolute value for the local effects has been determined. The most sensitive local endpoint is eye corrosion (Parekh, 1982). The long-term DNEL for the general population, dermal systemic effects is based on the 90-day repeated dose toxicity study (Wasil, 2012), which was performed according to OECD 408 in rats. In this study, no clinical signs with toxicological relevance were observed and there were no treatment-related effects on body weight, body weight gain and food consumption. The results of the opthalmological and neurobehavioural examinations were comparable between the control and treatment groups. In the highest dose group, the alkaline phosphatase levels were increased by around 30% in males (significantly) and females (not significantly). The absolute and relative liver weight, and relative kidney weight was significantly increased at the highest dose level in both males and females. The histopathology results showed treatment-related, and possibly toxicologically relevant, effects in the liver in females, and in the kidneys in males administered the highest dose. Based on the effects observed in the target organs (liver in females, kidneys in males), the NOAEL is set at 300 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 (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2, December 2010). For DMAMP, a dermal absorption of 80% was calculated using QSAR and the available physico-chemical properties.

The long-term DNEL for the general population, inhalation systemic effects is based on the 90-day repeated dose toxicity study that was performed according to OECD 408 in rats (Wasil, 2012). This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose 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, December 2010), the oral NOAEL should be converted into an inhalatory NAEC: 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). Therefore, the corrected starting point is a NAEC of 260.9 mg/m³. The absorption via the inhalative route is considered to be in the same order of magnitude as via the oral route.

The long-term DNEL for the general population, oral systemic effects is based on the 90-day repeated dose toxicity study that was performed according to OECD 408 in rats (Wasil, 2012). In this study, treatment-related effects were observed in the liver (in females) and kidneys (in males) at the highest dose level of 1000 mg/kg bw/day, leading to a NOAEL of 300 mg/kg bw/day. The study was performed via the oral route and the value can be used directly to derive the oral DNEL.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, Version 2, December 2010) were used when applicable to derive the DNELs. One AF for which there is additional information was refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 1, as the toxicokinetic data indicates that DMAMP will not be metabolised. Due to its polarity and size, DMAMP will mainly be excreted unmetabolised via the urine (see toxicokinetics).