Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
44 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):
10
Modified dose descriptor starting point:
NOAEC
Value:
440 mg/m³
Explanation for the modification of the dose descriptor starting point:
As no inhalation study is available an reliable subchronic oral study is considered appropriate for the estimation of a inhalative DNEL.
AF for dose response relationship:
1
Justification:
true NOAEL applied
AF for differences in duration of exposure:
2
Justification:
correction for duration from sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route extrapolation
AF for intraspecies differences:
5
Justification:
ECHA default assessment factor
AF for the quality of the whole database:
1
Justification:
good quality of database
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:
125 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):
40
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal route is typically covered by oral route information in the absence of data for this administration route.
AF for dose response relationship:
1
Justification:
true NOAEL used
AF for differences in duration of exposure:
2
Justification:
correction for duration from sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
allometric scaling rat to human
AF for intraspecies differences:
5
Justification:
default factor
AF for the quality of the whole database:
1
Justification:
good quality database
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
185 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
10
Dose descriptor:
other: EC3
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

DNEL acute

A DNELacuteshould be established for substances if an acute hazard toxicity (leading to C&L) has been identified and a potential for high peak exposures exists.

D,L-alpha-tocopherol does not have to be labelled for acute toxicity and therefore, a derivation of a DNELacute is not necessary.

DNEL long-term systemic

D,L-alpha-tocopherol is not classified for any endpoint related to systemic toxicity.

For the DNEL-derivation a NOAEL of 500 mg/kg bw was used derived from the 90-day repeated dose oral, based on hemorrhagic diathesis in males and females (an increase in APTT, PT and fibrinogen at 2000 mg/kg).

The dermal DNEL for long-term exposure - systemic effects for workers is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 500 mg/kg bw/day

Based on hemorrhagic diathesis in males and females

Step 2) Modification of starting point

 

x 50/5

 

 

50% for oral absorption, and 5% absorption is assumed for dermal absorption

Modified dose-descriptor

500 mg/kg bw/d x 50/5 = 5000 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

 

Allometric scaling for the rat, the additional factor of 2.5 is omitted.

Intraspecies

5

Default assessment factor

Exposure duration

2

A correction for duration from sub-chronic to chronic is required

Dose response

1

 NOAEL used

Quality of database

1

 good quality database

DNEL

Value

 5000 mg/kg bw/d/ (4 x 5 x 2 x 1 x 1)= 125 mg/kg bw/d

The inhalative DNEL for long-term exposure - systemic effects for workers is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 500 mg/kg bw/d

Based on hemorrhagic diathesis in males and females

Step 2) Modification of starting point

/0.38 m3/kg bw

  

 x 6.7 m3/10 m3

 

 

 

 

x50/100

 

8 h respiratory volume for rat.

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.

 

 

Default 50% for oral absorption, and 100% absorption is assumed for inhalation.

Modified dose-descriptor

500 x 0.67 x 0.5 / 0.38 = 440 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1.0

 

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation. The additional factor of 2.5 is omitted.

Intraspecies

5

Default assessment factor

Exposure duration

2

A correction for duration from sub-chronic to chronic is required

Dose response

1

 NOAEL used

Quality of database

1

 good quality database

DNEL

Value

 

 440 mg/m3 / (1.0 x 5 x 2 x 1 x 1)= 44 mg/m3

The dermal DNEL for long term exposure - local effects for workers is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOEL: 7.4% (w/v)

EC3 = NOEL in human sensitization test

Step 2) Modification of starting point

1 cm2 / ear = 2 cm2

25 µl / ear = 50 µl

Area treated ( 1 cm2 per mouse ear (ECHA Guidance Appendix R8.20 Skin sensitization)

Amount applied

 

Modified dose descriptor

 7.4 % (w/v= mg/0.1 ml) x 0.05 ml/2 cm2 = 1.85 mg/cm2 = 1850 µg/cm2

Step 3) Assessment factors

 

 

Vehicle or matrix effect

Exposure conditions

1

1

Uncertainty factor for matrix effects is considered to be included in the exposure estimation and, therefore disregarded

Uncertainty factor for differences in exposure conditions between animal experiment and human exposure situation is considered to be included in the exposure estimation and therefore disregarded.

Interspecies

Intraspecies

1

10

EC3 = NOEL in human sensitization tests

Combined influence of genetic effects, sensitive subpopulations, inherent barrier function, age, gender, ethnicity

Exposure duration

1

A correction for duration from sub-chronic to chronic is not required

Dose response

1

 

Quality of database

1

 

DNEL

Value

1850 µg/cm2 / (1 x 1 x 1 x 10 x 1 x 1 x 1)= 185 µg/cm2

Justification:

An induction-specific DNEL was derived for skin sensitization according to Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008) based on the EC3 value from an LLNA study (CTL, 2001). The EC3 value for 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl) -2H-benzopyran-6-ol (CAS no. 10191-41-0) was

reported to be 7.4 % (w/v) = 1850 µg/cm2, indicative of a sensitizer of weak potency (ECETOC 2003). Interspecies: There are different views on the threshold derived from local lymph node data (EC3, EC1.5). Whereas the ECHA guidance considers it to be the LOAEL for induction (ECHA guidance R.8, 2008), a number of other organizations were able to empirically show that the EC3 closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3 or EC1.5, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.

Intraspecies:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term ‘sensitive subpopulations’ refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor and a factor of 10 is thought to adequately address the combined influence of these effects.

 

Reference:

· Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

· Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients.Reg Toxicol Pharmacol52: 3-23.

· ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.for fragrance ingredients.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.8 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):
20
Modified dose descriptor starting point:
NOAEC
Value:
217 mg/m³
Explanation for the modification of the dose descriptor starting point:
As no inhalation study is available an reliable subchronic oral study is considered appropriate for the estimation of a inhalative DNEL.
AF for dose response relationship:
1
Justification:
true NOAEL used
AF for differences in duration of exposure:
2
Justification:
correction fro duration from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
no allomtric scaling in case of oral to inhalation route extrapolation
AF for intraspecies differences:
10
Justification:
default factor
AF for the quality of the whole database:
1
Justification:
good quality database
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:
DNEL (Derived No Effect Level)
Value:
62.5 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):
40
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal route is typically covered by oral route information in the absence of data for this administration route.
AF for dose response relationship:
1
Justification:
true NOAEL used
AF for differences in duration of exposure:
2
Justification:
correction factor for duration from sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
allometric scaling for the rat
AF for intraspecies differences:
10
Justification:
default factor
AF for the quality of the whole database:
1
Justification:
good quality database
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
185 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
10
Dose descriptor:
other: EC3
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:
6.25 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):
80
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not necessary as key study uses oral administration
AF for dose response relationship:
1
Justification:
true NOAEL used
AF for differences in duration of exposure:
2
Justification:
correction factor for duration from sub-chronic to chronic is required
AF for interspecies differences (allometric scaling):
4
Justification:
allometric scaling for the rat
AF for intraspecies differences:
10
Justification:
default assessment factor
AF for the quality of the whole database:
1
Justification:
good quality database
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

DNEL acute

A DNELacuteshould be established for substances if an acute hazard toxicity (leading to C&L) has been identified and a potential for high peak exposures exists. D,L-alpha-tocopherol does not have to be labelled for acute toxicity and therefore, a derivation of a DNELacuteis not necessary.

DNEL long-term systemic

D,L-alpha-tocopherol

is not classified for systemic target organ toxicity

For the DNEL-derivation a NOAEL of 500 mg/kg bw/d was used derived from the 90 -day repeated dose oral, based on hemorrhagic diathesis in males and females (an increase in APTT, PT and fibrinogen at 2000 mg/kg).

The dermal DNEL for long-term exposure - systemic effects for general population is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 500 mg/kg bw/d

Based on hemorrhagic diathesis

Step 2) Modification of starting point

 

x 50/5

 

 

50% for oral absorption and 5% absorption is assumed for dermal absorption.

Modified dose-descriptor

500 mg/kg bw/d x 50/5 = 5000 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

 

Allometric scaling for the rat

Intraspecies

10

Default assessment factor

Exposure duration

2

A correction for duration from sub-chronic to chronic is required

Dose response

1

 

Quality of database

1

 good quality database

DNEL

Value

5000 mg/kg bw/d/ (4 x 10 x 2 x 1 x 1)= 62.5 mg/kg bw/d

The inhalation DNEL for long-term exposure - systemic effects for general population is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 500 mg/kg bw/d

Based on hemorrhagic diathesis

Step 2) Modification of starting point

/ 1.15 m3/kg bw

 

 

x 50/100

 

24 h respiratory volume for rats.

 

 

50% for oral absorption and 100% absorption is assumed for inhalation.

Modified dose-descriptor

500 / 1.15 x 0.5 = 217 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1.0

 

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor

Exposure duration

2

A correction for duration from sub-chronic to chronic is required.

Dose response

1

 

Quality of database

1

 

DNEL

Value

*DNEL using ECETOC AF

217 mg/m3/ (1.0 x 10 x 2 x 1 x 1)= 10.8 mg/m3

The oral DNEL for long-term exposure - systemic effects for general public is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 500 mg/kg bw/d

Based on hemorrhagic diathesis

Step 2) Modification of starting point

Not required

 

 

 

 

 

Step 3) Assessment factors

 

 

Interspecies

4

 

Allometric scaling for the rat.

Intraspecies

10

Default assessment factor

Exposure duration

2

A correction for duration from sub-chronic to chronic is required

Dose response

1

 

Quality of database

1

 

DNEL

Value

500 mg/kg bw/d/ (4 x 10 x 2 x 1 x 1)= 6.25 mg/kg bw/d

The dermal DNEL for long-term local effects (based on LLNA test) for the general population is derived as follows:

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOEL: 7.4% (w/v)

EC3 = NOEL in human sensitization test

Step 2) Modification of starting point

1 cm2 / ear = 2 cm2

25 µl / ear = 50 µl

Area treated ( 1 cm2 per mouse ear (ECHA Guidance Appendix R8.20 Skin sensitization)

Amount applied

 

Modified dose descriptor

 7.4 % (w/v= mg/0.1 ml) x 0.05 ml/2 cm2 = 1.85 mg/cm2 = 1850 µg/cm2

Step 3) Assessment factors

 

 

Vehicle or matrix effect

Exposure conditions

1

1

Uncertainty factor for matrix effects is considered to be included in the exposure estimation and, therefore disregarded

Uncertainty factor for differences in exposure conditions between animal experiment and human exposure situation is considered to be included in the exposure estimation and therefore disregarded.

Interspecies

Intraspecies

1

10

EC3 = NOEL in human sensitization tests

Combined influence of genetic effects, sensitive subpopulations, inherent barrier function, age, gender, ethnicity

Exposure duration

1

not required

Dose response

1

 

Quality of database

1

 

DNEL

Value

1850 µg/cm2 / (1 x 1 x 1 x 10 x 1 x 1 x 1)= 185 µg/cm2

Justification:

An induction-specific DNEL was derived for skin sensitization according to Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008) based on the EC3 value from an LLNA study (CTL, 2001). The EC3 value for 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl) -2H-benzopyran-6-ol (CAS no. 10191-41-0) was

reported to be 7.4 % (w/v) = 1850 µg/cm2, indicative of a sensitizer of weak potency (ECETOC 2003). Interspecies: There are different views on the threshold derived from local lymph node data (EC3, EC1.5). Whereas the ECHA guidance considers it to be the LOAEL for induction (ECHA guidance R.8, 2008), a number of other organizations were able to empirically show that the EC3 closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3 or EC1.5, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.

Intraspecies:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term ‘sensitive subpopulations’ refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor and a factor of 10 is thought to adequately address the combined influence of these effects.

 

Reference:

· Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

· Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients.Reg Toxicol Pharmacol52: 3-23.

· ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.for fragrance ingredients.