Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic 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
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
starting point is LOAEC instead of NOAEC
AF for differences in duration of exposure:
1
Justification:
no additional factor is required for time duration since the effect observed is not dependent on the time of exposure
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling foreseen
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Justification:
no deficiencies
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no data on the dermal absorption of the members of the amine heads category are available, in a conservative manner it is assumed that dermal absorption does not exceed oral absorption; therefore no correction for absorption has to be made for route-to-route extrapolation
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic; factor of 2 is thought to be sufficiently conservative as the starting NOAEL was obtained in an oral gavage study with DCH, in studies with other category members and other ways of oral application the effect level was at least 4fold higher
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Justification:
no deficiencies
AF for remaining uncertainties:
1
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:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high 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

Worker DNELLong-termfor dermal route, systemic effects

No long-term toxicity study with dermal exposure is available for the members of this category. Therefore the DNEL long-term, dermal exposure, systemic effects is derived by route-to-route extrapolation from a toxicity study with oral exposure. The most sensitive NOAEL for this category was the NOAEL of 150 mg/kg bw/day identified in the Combined repeated dose reproduction and developmental toxicity study (OECD 422) with oral exposure to DCH. In the high dose group (500 mg/kg bw/d) several adverse effects were observed like reduced body weights and body weight gain, haematological and clinical biochemistry findings, macroscopic and microscopic findings in liver, lung and adrenal glands. No mortality was observed during the study (highest dose tested 500 mg/kg bw/day).

 

DNEL derivation:

Basis NOAEL: 150 mg/kg bw/day from combined repeated dose reproduction/developmental screening oral toxicity study (OECD422; males 31 and females approx. 45 days of oral application)

As no specific values on dermal and oral absorption are available-->therefore default assumption for oral absorption: 100 %

Assumption: no data on the dermal absorption of the members of the amine heads category are available, in a conservative manner it is assumed that dermal absorption does not exceed oral absorption; therefore no correction for absorption has to be made for route-to-route extrapolation

Assessment factors:

·        Interspecies differences:                         4 (allometric scaling); 2.5 (remaining differences)

·        Intraspecies differences:                          5

·        Differences in duration of exposure : 2 (sub-chronic to chronic; factor of 2 is thought to be sufficiently conservative as the starting NOAEL was obtained in an oral gavage study with DCH, in studies with other category members and other ways of oral application the effect level was at least 4fold higher)

·        Issues related to dose-response:         1 (none)

·        Quality of whole database:                      1 (no deficiencies)

--> Overall assessment factor: 100

DNEL = 150 mg/kg bw/day/100

DNEL = 1.5 mg/kg bw/day

Worker DNELLong-termfor inhalation route, local effects

In a subacute inhalation toxicity study male rats were exposed for 6 hours per day and overall 10times within two weeks to an aerosol/vapour mixture of the test material (i.e. MPMD). Concentrations used were 0, 9.2, 59 and 250 mg/m³ (analytical). Systemic effects and macroscopic lesions of the lung were obvious in the lung were observed in the high dose group. Microscopically exposure-related lesions were confined to the respiratory tract and were dose related. In the 50 and 250 mg/m3groups, lesions were observed in the nose, trachea, larynx/pharynx, and lung. These lesions were mainly minimal to mild in the 50 mg/m3group and mild to moderate in the 250 mg/m3group. Within the low dose group minimal to mild inflammation of the nasal epithelium was observed. Due to the fact that local effects on the respiratory tract were seen in all concentration groups tested and these effects were clearly concentration related a no observed adverse effect level could not be determined. The LOAEC of this study with MPMD was established to be 9.2 mg/m³. The results of this study where confirmed using another amine of the Amine heads category (i.e. DCH). In a study with the same study design, the local irritating effects on the upper respiratory effect were obvious also at the lowest dose group tested, thus the LOAEC = 10 mg/m³. In a subchronic study with HMD-dihydrochloride (HDDC = salt of HMD, which is another member of the amine heads category; inhalation exposure of rats 6h/day, 5d/week for 13 weeks) also local respiratory effects were critical. Under the test conditions, the NOAEC (HDDC) = 16 mg/m³/day for local respiratory damage (nasal respiratory epithelium degeneration), corresponding to a NOAEC (HMD) = 10 mg/m³/day. In another subchronic inhalation toxicity study with rats, the animals were repeatedly exposed to aqueous Hexamethylene Diamine (HMD) aerosol for six hours per day, five days per week at mean analytical concentrations of 0, 12.8, 51 and 215 mg/m³. Under the test conditions, no systemic effects were observed related to the treatment with HMD. The significant local irritation of respiratory tract, inducing clinical signs, was observed at the two highest concentrations tested. The NOAEC in male and female rats exposed by whole-body inhalation was 12.8 mg HMD/m³.

The NOAEC of the study with HMD-dihydrochloride is not considered adequate as starting point for DNEL derivation as the study was conducted with the less irritating HMD-dihydrochloride instead of the amine. However it can be used as supporting evidence for verifying the local irritating nature of all members of the amine heads category and that the effect is not crucially time dependent either - therefore no assessment factor was used for differences in duration of exposure.

 

DNEL derivation:

Basis LOAEC: 9.2 mg/m³ from 14 days toxicity study after aerosol/vapour exposure

Effects: dose dependent effects seen on the upper respiratory tract (e.g. nasal lesions) which were from minimal to moderate severity and were reversible within the 14-day recovery period

No correction of LOAEC was performed as local irritating effects are concentration dependent and are independent of the absorbed dose.

Assessment factors:

·        Interspecies differences:                         no allometric scaling, 2.5 (remaining differences)

·        Intraspecies differences:                           5

·        Differences in duration of exposure:  1 (no additional factor is required for exposure duration since the effect observed is not dependent on the time of exposure)

·        Issues related to dose-response:         3 (starting point is LOAEC instead of NOAEC)

·        Quality of whole database:                      1 (no deficiencies)

--> Overall assessment factor: 37.5

DNEL = 9.2 mg/m³/37.5

DNEL = 245.3 µg/m³ = 0.245 mg/m³ ~ 0.25 mg/m³

 

Worker DNELacute/short termfor inhalation route, local effects

As an acute toxicity hazard has been identified (leading to C&L) a DNEL for peak exposure has to be derived. Ideally sub-lethal toxicity should be the starting point rather than mortality. In our case from the acute inhalation toxicity studies only information on mortality could be extracted as there were no detailed descriptions on pathological findings included. Therefore repeated-dose data from the sub-acute inhalation studies is thought to better characterize the acute hazard originating from the toxicological profile of the substances building this category.

Effects after repeated application of the submission substance by inhalation to rats were restricted to the respiratory tract. Therefore, an acute DNEL inhalation for local effects was established from the WORKER DNEL LONG-TERM FOR INHALATION ROUTE, LOCAL EFFECTS by using a multiplying factor of 2 considering that the observed adverse effects are mainly driven by the exposure concentration of the submission substance with respect to its corrosive properties.

 

DNEL: 245 µg/m³ *2 = 490 µg/m³ = 0.49 mg/m³ ~ 0.5 mg/m³

General Population - Hazard via inhalation route

Systemic 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
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
starting point is LOAEC instead of NOAEC
AF for differences in duration of exposure:
1
Justification:
no additional factor is required for time duration since the effect observed is not dependent on the time of exposure
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Justification:
no deficiencies
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no data on the dermal absorption of the members of the amine heads category are available, in a conservative manner it is assumed that dermal absorption does not exceed oral absorption; therefore no correction for absorption has to be made for route-to-route extrapolation
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic; factor of 2 is thought to be sufficiently conservative as the starting NOAEL was obtained in an oral gavage study with DCH, in studies with other category members and other ways of oral application the effect level was at least 4fold higher
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Justification:
no deficiencies
AF for remaining uncertainties:
1
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:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high 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:
0.75 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic; factor of 2 is thought to be sufficiently conservative as the starting NOAEL was obtained in an oral gavage study with DCH, in studies with other category members and other ways of oral application the effect level was at least 4fold higher
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Justification:
no deficiencies
AF for remaining uncertainties:
1
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:
high hazard (no threshold derived)

Additional information - General Population

General population DNELLong-termfor dermal route, systemic effects

No long-term toxicity study with dermal exposure is available for the members of this category. Therefore the DNEL long-term, dermal exposure, systemic effects is derived by route-to-route extrapolation from a toxicity study with oral exposure. The most sensitive NOAEL for this category was the NOAEL of 150 mg/kg bw/day identified in the Combined repeated dose reproduction and developmental toxicity study (OECD 422) with oral exposure to DCH. In the high dose group (500 mg/kg bw/d) several adverse effects were observed like reduced body weights and body weight gain, haematological and clinical biochemistry findings, macroscopic and microscopic findings in liver, lung and adrenal glands. No mortality was observed during the study (highest dose tested 500 mg/kg bw/day).

 

DNEL derivation:

Basis NOAEL: 150 mg/kg bw/day from combined repeated dose reproduction/developmental screening oral toxicity study (OECD422; males 31 and females approx. 45 days of oral application)

As no specific values on dermal and oral absorption are availableàtherefore default assumption for oral absorption: 100 %

Assumption: no data on the dermal absorption of the members of the amine heads category are available, in a conservative manner it is assumed that dermal absorption does not exceed oral absorption; therefore no correction for absorption has to be made for route-to-route extrapolation

Assessment factors:

·        Interspecies differences:                         4 (allometric scaling), 2.5 (remaining differences)

·        Intraspecies differences:                           10

·        Differences in duration of exposure:  2 (sub-chronic to chronic)

·        Issues related to dose-response:         1 (none)

·        Quality of whole database:                      1 (no deficiencies)

--> Overall assessment factor: 200

DNEL = 150 mg/kg bw/day / 200

DNEL = 0.75 mg/kg bw/day

General population DNELlong-termfor inhalation route, local effects

In a subacute inhalation toxicity study male rats were exposed for 6 hours per day and overall 10times within two weeks to an aerosol/vapour mixture of the test material (i.e. MPMD). Concentrations used were 0, 9.2, 59 and 250 mg/m³ (analytical). Systemic effects and macroscopic lesions of the lung were obvious in the lung were observed in the high dose group. Microscopically exposure-related lesions were confined to the respiratory tract and were dose related. In the 50 and 250 mg/m3groups, lesions were observed in the nose, trachea, larynx/pharynx, and lung. These lesions were mainly minimal to mild in the 50 mg/m3group and mild to moderate in the 250 mg/m3group. Within the low dose group minimal to mild inflammation of the nasal epithelium was observed. Due to the fact that local effects on the respiratory tract were seen in all concentration groups tested and these effects were clearly concentration related a no observed adverse effect level could not be determined. The LOAEC of this study with MPMD was established to be 9.2 mg/m³. The results of this study where confirmed using another amine of the Amine heads category (i.e. DCH). In a study with the same study design, the local irritating effects on the upper respiratory effect were obvious also at the lowest dose group tested, thus the LOAEC = 10 mg/m³. In a subchronic study with HMD-dihydrochloride (HDDC = salt of HMD, which is another member of the amine heads category; inhalation exposure of rats 6h/day, 5d/week for 13 weeks) also local respiratory effects were critical. Under the test conditions, the NOAEC (HDDC) = 16 mg/m³/day for local respiratory damage (nasal respiratory epithelium degeneration), corresponding to a NOAEC (HMD) = 10 mg/m³/day.

In another subchronic inhalation toxicity study with rats, the animals were repeatedly exposed to aqueous Hexamethylene Diamine (HMD) aerosol for six hours per day, five days per week at mean analytical concentrations of 0, 12.8, 51 and 215 mg/m³. Under the test conditions, no systemic effects were observed related to the treatment with HMD. The significant local irritation of respiratory tract, inducing clinical signs, was observed at the two highest concentrations tested. The NOAEC in male and female rats exposed by whole-body inhalation was 12.8 mg HMD/m³.

The NOAEC of the study with HMD-dihydrochloride is not considered adequate as starting point for DNEL derivation as the study was conducted with the less irritating HMD-dihydrochloride instead of the amine. However it can be used as supporting evidence for verifying the local irritating nature of all members of the amine heads category and that the effect is not crucially time dependent either - therefore no assessment factor was used for differences in duration of exposure.

 

DNEL derivation:

Basis LOAEC: 9.2 mg/m³ from 14 days toxicity study after aerosol/vapour exposure

Effects: dose dependent effects seen on the upper respiratory tract (e.g. nasal lesions) which were from minimal to moderate severity and were fully reversible within the 14-day recovery period

No correction of LOAEC was performed as local irritating effects are concentration dependent and are independent of the absorbed dose.

Assessment factors:

·        Interspecies differences:                         no allometric scaling, 2.5 (remaining differences)

·        Intraspecies differences:                           10

·        Differences in duration of exposure:  1 (no additional factor is required for exposure duration since the effect observed is not dependent on the time of exposure)

·        Issues related to dose-response:         3 (starting point is LOAEC instead of NOAEC)

·        Quality of whole database:                      1 (no deficiencies)

--> Overall assessment factor: 75

DNEL = 9.2 mg/m³/75

DNEL = 123 µg/m³ ~ 125 µg/m³ = 0.125 mg/m³

 

General population DNELacute/short termfor inhalation route, local effects

As an acute toxicity hazard has been identified (leading to C&L) a DNEL for peak exposure has to be derived. Ideally sub-lethal toxicity should be the starting point rather than mortality. In our case from the acute inhalation toxicity studies only information on mortality could be extracted as there were no detailed descriptions on pathological findings included. Therefore repeated-dose data from the sub-acute inhalation studies is thought to better characterize the acute hazard originating from the toxicological profile of the substances building this category.

Effects after repeated application of the submission substance by inhalation to rats were restricted to the respiratory tract. Therefore, an acute DNEL inhalation for local effects was established from the GENERAL POPULATION DNEL LONG-TERM FOR INHALATION ROUTE, LOCAL EFFECTS by using a multiplying factor of 2 considering that the observed adverse effects are mainly driven by the exposure concentration of the submission substance with respect to its corrosive properties.

 

DNEL: 125 µg/m³ *2 = 250 µg/m³ = 0.25 mg/m³

 

General population DNELLong-termfor oral route, systemic effects

The DNEL long-term, oral exposure, systemic effects is derived from a toxicity study with oral exposure. The most sensitive NOAEL for this category was the NOAEL of 150 mg/kg bw/day identified in the Combined repeated dose reproduction and developmental toxicity study (OECD 422) with oral exposure to DCH. In the high dose group (500 mg/kg bw/d) several adverse effects were observed like reduced body weights and body weight gain, haematological and clinical biochemistry findings, macroscopic and microscopic findings in liver, lung and adrenal glands. No mortality was observed during the study (highest dose tested 500 mg/kg bw/day).

 

DNEL derivation:

Basis NOAEL: 150 mg/kg bw/day from combined repeated dose reproduction/developmental screening oral toxicity study (OECD422; males 31 and females approx. 45 days of oral application)

As no specific values on oral absorption are availableàtherefore default assumption for oral absorption: 100 %

Assessment factors:

·        Interspecies differences:                         4 (allometric scaling), 2.5 (remaining differences)

·        Intraspecies differences:                           10

·        Differences in duration of exposure:  2 (sub-chronic to chronic)

·        Issues related to dose-response:         1 (none)

·        Quality of whole database:                      1 (no deficiencies)

-->Overall assessment factor: 200

DNEL = 150 mg/kg bw/day / 200

DNEL = 0.75 mg/kg bw/day