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
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:
13.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA 2008 and ECETOC
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no dermal repeated dose toxicity study is available
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a sub-acute study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was 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.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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:
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

Route-to-route extrapolation:

Oral to inhalatory

Based on the very low vapour pressure (the estimated vapour pressure of MAPTAC is 2.52E-07 Pa at 25°C) inhalation is no relevant route of exposure. Thus, no DNEL for the inhalation route is required.

 

Oral to dermal

Only oral studies are available. In the absence of data on dermal uptake, 100% dermal absorption is assumed.

Extrapolation oral to dermal: AF 1

DNEL derivation is based on an OECD422 guideline study (dose levels: 100, 300 and 1000 mg/kg bw/d).

 

Bile acids showed a 7-fold increase in males of the 1000 mg/kg bw/d dose group; however, only 2 animals had high values, and no other relevant findings were noted, this was considered to be of no toxicological relevance;

Reduction in motor activity and reduced grip strength (first trial only) in males treated at 1000 mg/kg bw/d were noted; considering that no differences were noted in other correlated neuromotory tests (second trial of grip strength, landing footsplay and rearing measurements in the open arena) this finding was considered incidental.

 

-> NOAEL (repeated dose, reproduction, neurotoxicity) = 1000 mg/kg bw/d

 

DNEL worker, chronic dermal systemic: 13.9 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1000 mg/kg bw/d

Overall AF: 4*1*3*6*1*1 = 72

 

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
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:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA 2008 and ECETOC
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no dermal repeated dose toxicity study is available
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a sub-acute study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was 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.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA 2008 and ECETOC
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation required
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a sub-acute study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was 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.
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

Route-to-route extrapolation:

Oral to inhalatory

Based on the very low vapour pressure (the estimated vapour pressure of MAPTAC is 2.52E-07 Pa at 25°C) inhalation is no relevant route of exposure. Thus, no DNEL for the inhalation route is required.

 

Oral to dermal

Only oral studies are available. In the absence of data on dermal uptake, 100% dermal absorption is assumed.

Extrapolation oral to dermal: AF 1

DNEL derivation is based on an OECD422 guideline study (dose levels: 100, 300 and 1000 mg/kg bw/d).

 

Bile acids showed a 7fold increase in males of the 1000 mg/kg bw/d dose group; however, only 2 animals had high values, and no other relevant findings were noted, this was considered to be of no toxicological relevance;

Reduction in motor activity and reduced grip strength (first trial only) in males treated at 1000 mg/kg bw/d were noted; considering that no differences were noted in other correlated neuromotory tests (second trial of grip strength, landing footsplay and rearing measurements in the open arena) this finding was considered incidental

 

-> NOAEL (repeated dose, reproduction, neurotoxicity) = 1000 mg/kg bw/d

DNEL general population, chronic dermal systemic: 8.33 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1000 mg/kg bw/d

Overall AF: 4*1*5*6*1*1 = 120

 

DNEL general population, chronic oral systemic: 8.33 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point: 1000 mg/kg bw/d

Overall AF: 4*1*5*6*1*1 = 120