reaction products of diglycidyl ether bisphenol F (DGEBF) and oligomeric phenol diglycidyl ethers with acrylic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.88 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):

225

Modified dose descriptor starting point:

NOAEC

Value:

872.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for the inhalation route has been derived from the oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans for inhalation - differences in respiratory volume are already included in route-to-route extrapolation (ECHA 2008).

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 limit 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.

AF for remaining uncertainties:

3

Justification:

An additional AF of 3 has been applied to account for remaining uncertainties due to incomplete reversibility of the observed effects

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:

1.11 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):

900

Modified dose descriptor starting point:

NOAEL

Value:

1 000 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 DNEL for the dermal route has been derived from the oral repeated dose toxicity study.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

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

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 limit 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.

AF for remaining uncertainties:

3

Justification:

An additional AF of 3 has been applied to account for remaining uncertainties due to incomplete reversibility of the observed effects

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Selection of the relevant dose descriptors:

Oral:

NOAEL 1000 mg/kg bw/day: Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, rat, oral (gavage)

 

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 inhalatory

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

Oral to dermal

The physicochemical properties of Epoxy half acrylate (log Kow in the range of 2.90 – 3.06) and the molecular weight of 312.36 -384.42 g/mol are in a range suggestive of absorption via the dermal route.

The substance is a skin irritant; damage to the skin surface may enhance penetration. As the substance has been identified as a skin sensitizer, some uptake must have occurred although it may only have been a small fraction of the applied dose.

Thus, in the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur. For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value based on the physicochemical properties and toxicological data.

For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value in the absence of experimental toxicokinetic data. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no AF (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation. (Guidance on Information Requirements and Chemical Safety Assessment, R8).

 

 

DERIVATION OF DNELs

DNELs long term systemic effects

Uncertainties	AF	Justification
Allometric scaling (inhalation)	1	No allometric scaling rat to humans for inhalation - differences in respiratory volume are already included in route-to-route extrapolation (ECHA 2008).
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	6	Default assessment factor for extrapolation from subacute to chronic
Dose response and endpoint specific/severity	1	In a reliable, adequate and relevant subacute study in rats there were no toxicological effects relevant to humans up to and including the limit 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 limit 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	3	The effects observed in the OECD TG 422 study were reversible, or at least a clear tendency towards reversibility was observed. Thus, the effects were considered not to be adverse. However, to account for remaining uncertainties due to only partial reversibility, an additional AF of 3 has been applied.

 

 

Worker-DNEL long-term for dermal route (systemic):  1.11 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*2.5*5*6*1*1*3 = 900

 

Worker-DNEL long-term for inhalation route (systemic): 3.88 mg/m³

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 872.40 mg/m³

 

For workers the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

                                             = 1000 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalatory NOAEC_worker(8h) is therefore:

                                             = 872.40 mg/m³ (8h-TWA)

Overall AF: 1*2.5*5*6*1*1*3 = 225

 

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 NO(A)EL(developmental toxicity/effects on fertility) derived from the same study was 1000 mg/kg bw/d. As no higher assessment factors need to be applied for reproductive and developmental effects, the DNELs for those endpoints would also be higher. Thus, the repeated dose toxicity-DNELs are also protective for fertility as well as for development.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.965 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

450

Modified dose descriptor starting point:

NOAEC

Value:

434.03 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for the inhalation route has been derived from the oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans for inhalation - differences in respiratory volume are already included in route-to-route extrapolation (ECHA 2008).

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 limit 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.

AF for remaining uncertainties:

3

Justification:

An additional AF of 3 has been applied to account for remaining uncertainties due to incomplete reversibility of the observed effects

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:

hazard unknown (no further information necessary)

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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.56 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):

1 800

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:

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

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

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

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 limit 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.

AF for remaining uncertainties:

3

Justification:

An additional AF of 3 has been applied to account for remaining uncertainties due to incomplete reversibility of the observed effects

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

DNELs for general population (for the oral and inhalative routes) were only derived for assessment of risk related to exposure to man via the environment. No REACH-relevant consumer use has been identified.

Selection of the relevant dose descriptors:

Oral:

NOAEL 1000 mg/kg bw/day: Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, rat, oral (gavage)

 

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 inhalatory

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DERIVATION OF DNELs

DNELs long term systemic effects

Uncertainties	AF	Justification
Allometric scaling (inhalation)	1	No allometric scaling rat to humans for inhalation - differences in respiratory volume are already included in route-to-route extrapolation (ECHA 2008).
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	6	Default assessment factor for extrapolation from subacute to chronic
Dose response and endpoint specific/severity	1	In a reliable, adequate and relevant subacute study in rats there were no toxicological effects relevant to humans up to and including the limit 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 limit 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	3	The effects observed in the OECD TG 422 study were reversible, or at least a clear tendency towards reversibility was observed. Thus, the effects were considered not to be adverse. However, to account for remaining uncertainties due to only partial reversibility, an additional AF of 3 has been applied.

 

  

General population-DNEL long-term for oral route (systemic): 0.56 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Overall AF 4*2.5*10*6*1*1*3 = 1800

 

General population -DNEL long-term for inhalation route (systemic): 0.965 mg/m³

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 434.03 mg/m³

 

For general population the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-human

                                             = 1000 x 1/1.152 x 50/100

The corrected inhalatory NOAEC_{general population}(24 h) is therefore:

                                             = 1434.03 mg/m³ (24 h)

Overall AF: 1*2.5*10*6*1*1*3 = 450

 

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 NO(A)EL(developmental toxicity/effects on fertility) derived from the same study was 1000 mg/kg bw/d. As no higher assessment factors need to be applied for reproductive and developmental effects, the DNELs for those endpoints would also be higher. Thus, the repeated dose toxicity-DNELs are also protective for fertility as well as for development.