Tocopherols

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

43.8 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

438 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 an inhalative DNEL.

AF for dose response relationship:

1

Justification:

true NOAEC 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:

already considered in route correction

AF for intraspecies differences:

5

Justification:

ECHA default assessment factor

AF for the quality of the whole database:

1

Justification:

good quality for database

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

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:

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

DNEL acute

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

RRR-(alpha-, beta-, gamma-, delta)-tocopherol does not have to be labelled for acute toxicity and therefore, a derivation of a DNEL_acuteis not necessary.

 

DNEL long-term systemic

RRR-(alpha-, beta-, gamma-, delta)-tocopherol isnot 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, basedon hemorrhagic diathesis in males and females (an increase in APTT, PT and fibrinogen at 2000 mg/kg).

The dermal DNELfor 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 DNELfor 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 m^3/kg bw     x 6.7 m^3/10 m^3         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/m^3
Step 3) Assessment factors
Interspecies	1.0	The allometric scaling is already considered in the starting point correction. 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/m^3/ (1.0 x 5 x 2 x 1 x 1)=44 mg/m^3

 

 

The dermal DNELfor long term exposure - local effects for workers should be established for substances if a local toxicity (leading to C&L) has been identified and a potential for long term risks exists. RRR-(alpha-, beta-, gamma-, delta)-tocopherol does not have to be labelled for local toxicity, including irritation and skin sensitisation and therefore, a derivation of a DNELacute is not necessary.

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:

already considered in rout correction

AF for intraspecies differences:

10

Justification:

default value

AF for the quality of the whole database:

1

Justification:

good quality databse

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:

LOAEL

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 value

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:

no hazard identified

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 rat

AF for intraspecies differences:

10

Justification:

default value

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

ADNEL_acuteshould be established for substances if an acute hazard toxicity (leading to C&L) has been identifiedanda potential for high peak exposures exists. RRR-(alpha-, beta-, gamma-, delta)-tocopherol does not have to be labelled for acute toxicity and therefore, a derivation of a DNEL_acuteis not necessary.

DNEL long-term systemic

RRR-(alpha-, beta-, gamma-, delta)-tocopherol is not classified for systemic target organ toxicitity

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 m^3/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/m^3
Step 3) Assessment factors
Interspecies	1.0	Allometric scaling already considered in starting point correction.
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/m^3/ (1.0 x 10 x 2 x 1 x 1)=10.8 mg/m^3

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 should be established for substances if a local toxicity (leading to C&L) has been identified and a potential for long term risks exists. RRR-(alpha-, beta-, gamma-, delta)-tocopherol does not have to be labelled for local toxicity, including irritation and skin sensitisation and therefore, a derivation of a DNELacute is not necessary.