2,2',6,6'-tetra-tert-butyl-4,4'-methylenediphenol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 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):

5

Modified dose descriptor starting point:

NOAEC

Value:

4.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

The repeated dose toxicity study showed systemic effects on the liver that can be anticipated to also occur if exposure is via inhalation. No local effects are expected from the available data.

AF for dose response relationship:

1

Justification:

The dose response curve has a normal shape and a NOEL was established that is considered conservative, as an aggravation of effects also occuring as background effects was observed.

AF for differences in duration of exposure:

1

Justification:

2 year study in rats dietary

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling was included in the route to route extrapolation

AF for other interspecies differences:

1

Justification:

No additional factor is applied as 90-day and 2 yr studies in dogs and rats are available that showed the same target organ and similar NOAELs with the rat NOAELs being the lowest one.

AF for intraspecies differences:

5

Justification:

For workers, default of REACH guidance

AF for the quality of the whole database:

1

Justification:

Data base for repeated dose studies covers 90-day and 2 year studies in 2 species, a 3-generation reproductive toxicity study and developmental studies in 2 species.

AF for remaining uncertainties:

1

Justification:

Although the data are relatively old, they are consistent and the effect levels are rather lower than would be expected for recent studies as some background diseased were present in the long term studies.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 592 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):

5

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEC

Value:

864 mg/m³

Explanation for the modification of the dose descriptor starting point:

Based on the NOAEL of the 90-day inhalation study in rats as this seems to be a better starting point for a short term exposure than a 2 year study

AF for dose response relationship:

1

Justification:

NOEC identified, normal dose response curve

AF for interspecies differences (allometric scaling):

1

Justification:

Applied already in the route to route extrapolation

AF for other interspecies differences:

1

Justification:

No additional factor is applied as 90-day and 2 yr studies in dogs and rats are available that showed the same target organ and similar NOAELs with the rat NOAELs being the lowest.

AF for intraspecies differences:

5

Justification:

For workers, default of REACH guidance

AF for the quality of the whole database:

1

Justification:

Data base for repeated dose studies covers 90-day and 2 year studies in 2 species, a 3-generation reproductive toxicity study and developmental studies in 2 species.

AF for remaining uncertainties:

1

Justification:

Although the data are relatively old, they are consistent and the effect levels are rather lower than would be expected for recent studies as some background diseased were present in the long term studies.

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:

0.28 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):

20

Modified dose descriptor starting point:

NOAEL

Value:

4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The repeated dose toxicity study showed systemic effects on the liver that can be anticipated to also occur if exposure is dermal. No local effects are expected from the available data.

AF for dose response relationship:

1

Justification:

The dose response curve has a normal shape and a NOEL was established that is considered conservative as an aggravation of effects also occuring as background effects was observed.

AF for differences in duration of exposure:

1

Justification:

2 year study in rats dietary

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor rat to humans based on metabolic rate seems appropriate

AF for other interspecies differences:

1

Justification:

No additional factor is applied as 90-day and 2 yr studies in dogs and rats are available that showed the same target organ and similar NOAELs with the rat NOAELs being the lowest one.

AF for intraspecies differences:

5

Justification:

For workers default REACH guidance

AF for the quality of the whole database:

1

Justification:

Data base for repeated dose studies covers 90-day and 2 year studies in 2 species, a 3-generation reproductive toxicity study and developmental studies in 2 species.

AF for remaining uncertainties:

1

Justification:

Although the data are relatively old, they are consistent and the effect levels are rather lower than would be expected for recent studies as some background diseased were present in the long term studies.

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

As the substance is not classified, a DNEL derivation is not needed for risk assessment purposes. However, using the existing data base in a conservative approach, based on the avaialble chronic data a DNEL for workers for repeated inhalation and dermal exposure and short term inhalation exposure has been derived as a conservative reference point for the workplace. As the substance is not acutely toxic and does not show any local irritation or sensitizing properties, DNELs for acute dermal toxicity and local effects were not derived. The lowest NOAEL from the 2-year chronic rat dietary study was used for the derivation of the DNEL. The effects observed at the LOAEL were confined to a dose dependent aggravation of liver changes that were also seen at lower incidence and severity in control animals. Very similar findings were also observed in a 2-year study in dogs with a recovery group that demonstrated a tendency of reversibility of the observed liver effect after a 7 months recovery period. No effects were observed in a 3 -generation strudy in rats and in developmental toxicity studies in rats and rabbits at comparable dose levels. The NOAEL in the chronic rat study used as the starting point was 4 mg/kg bw/day, that in the dog study 7 mg/kg bw/day. The NOAEL is considered conservative, as 90-day studies in rats and dogs revealed NOAELs of 700 to 800 mg/kg bw in rats and 810 to 840 mg/kg bw in dogs. A route to route extrapolation is justfied as the effects are of systemic nature and although a first pass metabolism cannot be excluded, it is likely that the substance will also reach the liver after inhalation or dermal exposure. For details on the extrapolation steps see the respective justifications.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 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:

1.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The repeated dose toxicity study showed systemic effects on the liver that can be atnicipated to also occur if exposure is via inhalation. No local effects are expected from the available data.

AF for dose response relationship:

1

Justification:

The dose response curve has a normal shape and a NOEL was established that is considered conservative as an aggravation of effects also occuring as background effects was observed.

AF for differences in duration of exposure:

1

Justification:

2 year study in rats dietary

AF for interspecies differences (allometric scaling):

1

Justification:

allometric scaling was included in the route to route extrapolation

AF for other interspecies differences:

1

Justification:

No additional factor is applied as 90-day and 2 yr studies in dogs and rats are available that showed the same target organ and similar NOAELs with the rat NOAELs being the lowest one.

AF for intraspecies differences:

10

Justification:

Default value of REACH guidance for the general population

AF for the quality of the whole database:

1

Justification:

Data base for repeated dose studies covers 90-day and 2 year studies in 2 species, a 3-generation reproductive toxicity study and developmental studies in 2 species.

AF for remaining uncertainties:

1

Justification:

Although the data are relatively old, they are consistent and the effect levels are rather lower than would be expected for recent studies as some background diseased were present in the long term studies.

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:

0.1 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:

4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The repeated dose toxicity study showed systemic effects on the liver that can be anticipated to also occur if exposure is dermal. No local effects are expected from the available data.

AF for dose response relationship:

1

Justification:

The repeated dose toxicity study showed systemic effects on the liver that can be atnicipated to also occur if exposure is via inhalation. No local effects are expected from the available data.

AF for differences in duration of exposure:

1

Justification:

2 year study in rats dietary

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor rat to humans based on metabolic rate seems appropriate

AF for other interspecies differences:

1

Justification:

No additional factor is applied as 90-day and 2 yr studies in dogs and rats are available that showed the same target organ and similar NOAELs with the rat NOAELs being the lowest one.

AF for intraspecies differences:

10

Justification:

Default value of REACH guidance for the general population

AF for the quality of the whole database:

1

Justification:

Data base for repeated dose studies covers 90-day and 2 year studies in 2 species, a 3-generation reproductive toxicity study and developmental studies in 2 species.

AF for remaining uncertainties:

1

Justification:

Although the data are relatively old, they are consistent and the effect levels are rather lower than would be expected for recent studies as some background diseased were present in the long term studies.

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 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:

4 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The repeated dose toxicity study showed systemic effects on the liver that can be anticipated to also occur if exposure is dermal. No local effects are expected from the available data.

AF for differences in duration of exposure:

1

Justification:

NOEC identified, normal dose response curve

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor rat to humans based on metabolic rate seems appropriate

AF for other interspecies differences:

1

Justification:

No additional factor is applied as 90-day and 2 yr studies in dogs and rats are available that showed the same target organ and similar NOAELs with the rat NOAELs being the lowest one.

AF for intraspecies differences:

10

Justification:

Default value of REACH guidance for the general population

AF for the quality of the whole database:

1

Justification:

Data base for repeated dose studies covers 90-day and 2 year studies in 2 species, a 3-generation reproductive toxicity study and developmental studies in 2 species.

AF for remaining uncertainties:

1

Justification:

Although the data are relatively old, they are consistent and the effect levels are rather lower than would be expected for recent studies as some background diseased were present in the long term studies.

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

As the substance is not classified, a DNEL derivation is not needed for risk assessment purposes. However, using the existing data base in a conservative approach, based on the available chronic data a DNEL for the genral population for repeated inhalation, dermal and oral exposure has been derived as a conservative reference point. As the substance is not acutely toxic and does not show any local irritation or sensitizing properties, DNELs for acute oral, inhalation and dermal toxicity and local effects were not derived. It is furthermore unlikely that the general population would be exposed to high short term concentrations under normal use conditions. The lowest NOAEL from the 2-year chronic rat dietary study was used for the derivation of the DNEL. The effects observed at the LOAEL were confined to a dose dependent aggravation of liver changes that were also seen at lower incidence and severity in control animals. Very similar findings were also observed in a 2-year study in dogs with a recovery group that demonstrated a tendency of reversibility of the observed liver effect after a 7 months recovery period. No effects were observed in a 3 -generation strudy in rats and in developmental toxicity studies in rats and rabbits at comparable dose levels. The NOAEL in the chronic rat study used as the starting point was 4 mg/kg bw/day, that in the dog study 7 mg/kg bw/day. The NOAEL is considered conservative, as 90-day studies in rats and dogs revealed NOAELs of 700 to 800 mg/kg bw in rats and 810 mto 840 mg/kg bw in dogs. A route to route extrapolation is justified as the effects are of systemic nature and although a first pass metabolism cannot be excluded, it is likely that the substance will also reach the liver after inhalation or dermal exposure. For details on the extrapolation steps see the respective justifications.