Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.58 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):

25

Modified dose descriptor starting point:

NOAEC

Value:

264.47 mg/m³

Explanation for the modification of the dose descriptor starting point:

It was assumed that oral absorption rate is 50% of that of inhalation absorption.

AF for dose response relationship:

1

Justification:

based on NOAEC

AF for differences in duration of exposure:

2

Justification:

based n 90 day toxicity (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

reliable data

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21.16 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):

12.5

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEC

Value:

264.47 mg/m³

Explanation for the modification of the dose descriptor starting point:

It was assumed that oral absorption rate is 50% of that of inhalation absorption.

AF for dose response relationship:

1

Justification:

based on NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

reliable data

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 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:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

It is assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:

1

Justification:

based on NOAEL

AF for differences in duration of exposure:

2

Justification:

based n 90 day toxicity (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

reliable data

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6 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):

50

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

It is assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:

1

Justification:

based on NOAEL

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

reliable data

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.67 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

937.5

Dose descriptor starting point:

other: LOAEL

AF for dose response relationship:

3

Justification:

based on LOAEL

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

data reliable

AF for remaining uncertainties:

25

Justification:

vahicle or matrix effect (5) x different exposure conditions (5)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

DNEL - long term, worker

Inhalation systemic long term. Route-to-route extrapolation:

The calculations for the long term DNELs for workers are based on a 90 day oral feeding study performed in Fischer 344 rats. The NOAEL value in this study was found to be 300 mg/kg bw/d. This value was used as basis for DNEL calculation. Route-to-route extrapolation (oral to inhalative) was performed according to the ECHA Guidance Document on information requirements and chemical safety assessment Chapter R.8. It was assumed that oral absorption rate is 50% of that of inhalation absorption.

Starting point (worker, inhalation)= NOAEL oral*(1/sRVrat)*(sRVhuman/wRV)*(ABSoral-rat/ABSinh-human)= 300 mg/kg/d*(1/0.38m3/kg/d)*(6.7m3(8h)/10m3(8h))*0.5=264.47mg/m3

It was assumed that oral and dermal absorption rates are equal.

Starting point (worker,dermal)= 300 mg/kg/d

Assessment factors for DNEL derivations

Inhalation

Overall AF = 25

Dermal

Overall AF = 100

Taken above information

DNEL inhalation, long term, sytemic effects = 264.47/25=10.58 mg/m3

DNEL dermal, long term,systemic effects = 300/100=3 mg/kg bw/d

DNEL - short term, worker

Inhalation systemic effects acute.

DNELacute extrapolated from long term DNEL

Starting point (worker, inhalation, acute)=264.47 mg/m3

Assessment factors for DNEL derivations

Inhalation, worker,acute

Overall AF = 12.5

Dermal systemic effects acute.

DNEL acute extrapolated from long term DNEL

It was assumed that oral and dermal absorption rates are equal.

Starting point (worker,dermal)= 300mg/kg/d

Dermal

Overall AF = 50

Taken above information:

DNEL inhalation, short term, sytemic effects = 264.47/12.5=21.16 mg/m3

DNEL dermal, short term,systemic effects = 300/50=6 mg/kg bw/d

 

Worker DNEL LOCAL short-term dermal route

1.1) DNEL based on local effects (skin sensitisation)

 

The available dose descriptor is LOAEL of 4375μg/cm²obtained from the LLNA.

 

Assessment factors and DNEL calculation for worker-DNEL short-term dermal local effects

 

The relevant assessment factors were chosen in accordance with recommendations of the document Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (May 2008).

 

Uncertainties		AF		Justification
Default AFs
Interspecies differences		2.5		As the DNEL in case of Atlen SK is derived for local effects only, allometric scaling was not applied. For the remaining uncertainties in kinetic and in dynamic interspecies differences in spite of lack of data on the mechanism of toxicity (on the basis of available data it cannot be reliably concluded whether Atlen SK causes skin sensitization through simple destruction of membranes due to its physicochemical properties or through to a mechanism involving local metabolism) the default factor of 2.5 was applied.
Intraspecies differences		5		For intraspecies differences standard approach was taken and default AFs were chosen i.e. in case of workers 5.
Exposure duration		1		As DNEL is derived for acute local effect only, AF of 1 was applied for the effects of exposure duration.
Dose response		3		As the starting point for derivation of DNEL was LOAEL for the dose-response relationship default AF of 3 was applied.
Skin sensitisation specific AFs
Vehicle or matrix effect		5		As exposure of humans to Atlen SK in matrices containing irritants cannot be excluded (taking into account chemicals used in the production process of Atlen SK as well as its use pattern) an AF of 5 was applied for the matrix effect.
Different exposure conditions		5		Taking into account chemicals used in the production process of Atlen SK as well as its use pattern it can be expected that in at least some cases humans (particularly workers) will be exposed not only to Atlen SK but to other chemicals as well. Taking this into consideration an AF of 5 is applied for effects of different exposure conditions.
Overall assessment factor:             937.5
Endpoint specific DNEL:                 4.67 µg/cm²

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.61 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):

50

Modified dose descriptor starting point:

NOAEC

Value:

130.43 mg/m³

Explanation for the modification of the dose descriptor starting point:

It was assumed that oral absorption rate is 50% of that of inhalation absorption.

AF for dose response relationship:

1

Justification:

based on NOAEC

AF for differences in duration of exposure:

2

Justification:

based n 90 day toxicity (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

reliable data

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.22 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):

25

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEC

Value:

130.43 mg/m³

Explanation for the modification of the dose descriptor starting point:

It was assumed that oral absorption rate is 50% of that of inhalation absorption.

AF for dose response relationship:

1

Justification:

based on NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

reliable data

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

It was assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:

1

Justification:

based on NOAEL

AF for differences in duration of exposure:

2

Justification:

based n 90 day toxicity (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

reliable data

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 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

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

It was assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:

1

Justification:

based on NOAEL

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

reliable data

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.33 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 875

Dose descriptor starting point:

other: LOAEL

AF for dose response relationship:

3

Justification:

based on LOAEL

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

data reliable

AF for remaining uncertainties:

25

Justification:

vahicle or matrix effect (5) x different exposure conditions (5)

General Population - Hazard via oral 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

based on NOAEL

AF for differences in duration of exposure:

2

Justification:

based n 90 day toxicity (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

reliable data

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 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

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

based on NOAEL

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

Justification:

differences in metabolic rate

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

reliable data

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

DNEL - long term, general population

Inhalation systemic long term. Route-to-route extrapolation:

The calculations for the long term DNELs for workers are based on a 90 day oral feeding study performed in Fischer 344 rats. The NOAEL value in this study was found to be 1 mg/kg bw/d. This value was used as basis for DNEL calculation. Route-to-route extrapolation (oral to inhalative) was performed according to the ECHA Guidance Document on information requirements and chemical safety assessment Chapter R.8. It was assumed that oral absorption rate is 50% of that of inhalation absorption.

Starting point (general population, inhalation)= NOAEL oral*(1/1.15 m3/kg/d)*(ABSoral-rat/ABSinh-human)= 300mg/kg/d*(1/1.15m3/kg/d)*0.5=130.43 mg/m3

It was assumed that oral and dermal absorption rates are equal.

Starting point (general population,dermal)= 300 mg/kg/d

Assessment factors for DNEL derivations

Inhalation

Overall AF = 50

Dermal

Overall AF = 200

Taken above information

DNEL inhalation, long term, sytemic effects = 130.43/50=2.61 mg/m3

DNEL dermal, long term,systemic effects = 300/200=1.5 mg/kg bw/d

DNEL - short term, general population

Inhalation systemic effects acute.

DNELacute extrapolated from long term DNEL

Starting point (general population, inhalation, acute)=130.43 mg/m3

Assessment factors for DNEL derivations

Inhalation, general population,acute

Overall AF = 25

Dermal systemic effects acute.

DNELacute extrapolated from long term DNEL

It was assumed that oral and dermal absorption rates are equal.

Starting point (general population,dermal)= 300 mg/kg/d

Dermal

Overall AF = 100

Taken above information:

DNEL inhalation, short term, sytemic effects = 130.43/25=5.22 mg/m3

DNEL dermal, short term,systemic effects = 300/100=3 mg/kg bw/d

The DNELoral is the same as the DNEL dermal.

 

General population- Local DNEL short-term dermal route

2.1) DNEL based on local effects (skin sensitisation)

The available dose descriptor is LOAEL of 4375 μg/cm²obtained from the LLNA.

Assessment factors and DNEL calculation for general population-DNEL short-term dermal local effects

 

The relevant assessment factors were chosen in accordance with recommendations of the document Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (May 2008).

 

Uncertainties	AF	Justification
Default AFs
Interspecies differences	2.5	As the DNEL in case of Atlen SK is derived for local effects only, allometric scaling was not applied. For the remaining uncertainties in kinetic and in dynamic interspecies differences in spite of lack of data on the Atlen SK mechanism of toxicity (on the basis of available data it cannot be reliably concluded whether Atlen SK causes skin sensitization through simple destruction of membranes due to its physicochemical properties or through to a mechanism involving local metabolism) the default factor of 2.5 was applied.
Intraspecies differences	10	For intraspecies differences standard approach was taken and default AFs were chosen i.e. 10 in case of general population.
Exposure duration	1	As DNEL is derived for acute local effect only, AF of 1 was applied for the effects of exposure duration.
Dose response	3	As the starting point for derivation of DNEL was LOAEL for the dose-response relationship default AF of 3 was applied.
Skin sensitisation specific AFs
Vehicle or matrix effect	5	As exposure of humans to Atlen SK in matrices containing irritants cannot be excluded (taking into account chemicals used in the production process ofas well as its use pattern) an AF of 5 was applied for the matrix effect.
Different exposure conditions	5	Taking into account chemicals used in the production process of Atlen SK as well as its use pattern it can be expected that in at least some cases humans (particularly workers) will be exposed not only tobut to other chemicals as well. Taking this into consideration an AF of 5 is applied for effects of different exposure conditions
Overall assessment factor:             1875
Endpoint specific DNEL:                 2.33 µg/cm²