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:
56.25 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
400
Modified dose descriptor starting point:
NOAEL
Value:
22 500 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 91 day repeated dose toxicity study. Based on toxicokinetic data, an assessment factor for the route to route extrapolation (oral to dermal) of 45 has been applied (for details see section "Additional information").

AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default allometric scaling factor for rat to humans
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF 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. The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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:
4
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. A further factor of 2 has been applied for read-across: no RDT/reprotox studies are available for the registered substance.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Selection of the relevant dose descriptors:

Oral:

NOAEL 500 mg/kg bw/day: 90-day study, rat, oral (gavage); highest dose tested, read-across from MDEA-Esterquat C16 -18 and C18 unsatd.

NOAEL 1000 mg/kg bw/day: Developmental toxicity study, rat, oral (gavage); highest dose tested, read-across from MDEA-Esterquat C16 -18 and C18 unsatd.

 

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 dermal

For systemic effects available toxicokinetic data will be taken into account for the route to route extrapolation.

Absorption after oral application: 48 ± 4 % (read-across from MDEA-Esterquat C16 -18 and C18 unsatd.)

Absorption after dermal application: 0.3 % (2 ± 0.8 µg/cm²) for paste formulation (101 g/L); 0.9 % (0.03 ± 0.02 µg/cm²) for aqueous dilution (0.311 g/L)

Proposed assessment factor for the route to route extrapolation (oral to dermal): 45

A factor of 48 would have suggested a higher accuracy than the data actually provide; the use of a factor of 40 would result in an overly conservative DNEL, especially as already very conservative assessment factors are used. Thus, a factor of 45 is considered appropriate for route to route extrapolation oral to dermal.

 

DERIVATION OF DNELs

DNELs long term systemic effects (including effects on fertility)

Uncertainties

AF

 

Justification

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

2

Default assessment factor for extrapolation from subchronic to chronic

Dose response and endpoint specific/severity

 

1

In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.

 

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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

4

To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. A further factor of 2 has been applied for read-across: no repeated dose toxicity studies/reproductive toxicity studies are available for the registered substance.

No DNEL for the inhalation route was derived as inhalation is not a relevant route of exposure to MDIPA-Esterquat C16-18 and C18 unsatd. due to the physicochemical properties of the substance and the nature of its uses.MDIPA-Esterquat C16-18 and C18 unsatd. is a waxy solid paste. Generation of inhalable particles such as dust or aerosols is therefore not to be expected. Vaporization needs not to be considered due to the substance’s very low vapour pressure of < 8.4E-07 Pa at 20°C. The generation of dusts and aerosols is prevented by appropriate RMMs, and the substance is not used in spray applications.

 

Worker-DNEL long-term for dermal route (systemic): 56.25 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 22500 mg/kg bw/d

Overall AF 4*2.5*5*2*1*1*4 = 400

 

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.

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral developmental toxicity study, OECD 414):

Uncertainties

AF

 

Justification

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

1

No assessment factor for time extrapolation is applied as the susceptible window is fully covered

Dose response and endpoint specific/severity

 

1

In a reliable, adequate and relevant OECD 414 study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 1000 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.

 

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included thehighest administereddose of 1000 mg/kg bw/day. 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

2

A factor of 2 has been applied for read-across: no repeated dose toxicity studies/reproductive toxicity studies are available for the registered substance.

 

Worker-DNEL long-term for dermal route (systemic): 450 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: 45000 mg/kg bw/d

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

 

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 are higher than those for fertility.Thus, the fertility-DNELs are also protective for development.

 

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:
28.13 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
800
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
22 500 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 91 day repeated dose toxicity study. Based on toxicokinetic data, an assessment factor for the route to route extrapolation (oral to dermal) of 45 has been applied (for details see section "Additional information"

AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default allometric scaling factor for rat to humans
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for 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.
The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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:
4
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. A further factor of 2 has been applied for read-across: no RDT/reprotox studies are available for the registered substance.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low 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:
0.63 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
800
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default allometric scaling factor for rat to humans
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for 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. The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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:
4
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. A further factor of 2 has been applied for read-across: no RDT/reprotox studies are available for the registered substance.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Selection of the relevant dose descriptors:

Oral:

NOAEL 500 mg/kg bw/day: 90-day gavage study rat; highest dose tested

NOAEL 1000 mg/kg bw/day: Developmental toxicity study rat gavage

 

Modificationof 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 dermal

For systemic effects available toxicokinetic data will be taken into account for the route to route extrapolation.

Absorption after oral application: 48 ± 4 % (read-across from MDEA-Esterquat C16 -18 and C18 unsatd.)

Absorption after dermal application: 0.3 % (2 ± 0.8μg/cm²) for paste formulation (101 g/L); 0.9 % (0.03 ± 0.02μg/cm²) for aqueous dilution (0.311 g/L)

 

Proposed assessment factor for the route to route extrapolation (oral to dermal): 45

 

A factor of 48 would have suggested a higher accuracy than the data actually provide; the use of a factor of 40 would result in an overly conservative DNEL, especially as already very conservative assessment factors are used. Thus, a factor of 45 is considered appropriate for route to route extrapolation oral to dermal.

 

DERIVATION OF DNELs

DNELs long term systemic effects (including effects on fertility)

 

Uncertainties

AF

Justification

Allometric scaling (dermal, oral)

 

4

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

Remaining interspecies differences

 

2.5

Default AF for remaining interspecies differences

 

Intraspecies differences

 

10

Default AF for general population

 

Differences in duration of exposure

 

2

Default assessment factor for extrapolation from subchronic to chronic

 

Dose response and endpoint specific/severity

 

1

In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 500 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.

 

Quality of whole database

 

1

The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 500 mg/kg bw/day. 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

 

4

To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied. A further factor of 2 has been applied for read-across: no repeated dose toxicity studies/reproductive toxicity studies are available for the registered substance.

 

 

 

General population-DNEL long-term for dermal route (systemic): 28.13 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 22500 mg/kg bw/d

Overall AF 4*2.5*10*2*1*1*4 = 800

 

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.

 

General population-DNEL long-term for oral route (systemic): 0.63 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Overall AF 4*2.5*10*2*1*1*4 = 800

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral developmental toxicity study, OECD 414):

Uncertainties

AF

Justification

Allometric scaling (dermal, oral)

 

4

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

Remaining interspecies differences

 

2.5

Default AF for remaining interspecies differences

 

Intraspecies differences

 

10

Default AF for general population

 

Differences in duration of exposure

 

1

No assessment factor for time extrapolation is applied as the susceptible window is fully covered

Dose response and endpoint specific/severity

 

1

In a reliable, adequate and relevant OECD 414 study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 1000 mg/kg bw/d. The NOAEL is reliable. No adjustment is required. 

Quality of whole database

 

1

The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 1000 mg/kg bw/day. 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 remaining

 

 

General population-DNEL long-term for dermal route (systemic): 450 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: 45000 mg/kg bw/d

Overall AF 4*2.5*10*1*1*1*1 = 100

 

General population-DNEL long-term for oral route (systemic): 10 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Overall AF 4*2.5*10*1*1*1*1 = 100

 

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

 

The critical long term DNELs for general population are:

DNELgeneral population fertility for dermal route systemic of 28.13 mg/kg bw/day

DNELgeneral population fertility for oral route systemic of 0.63 mg/kg bw/day