2-propenoic acid, 2-methyl-, 4-benzoylphenyl ester

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.5 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):

34.3

Dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

523.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction for rat standard breathing volume, 8 hrs = 0.38 m3/kg (ECHA R.8, 2012)

Correction for activity driven differences of respiratory volumes in workers compared to workers = 10 m³/6.7 m³ (ECHA R.8, 2012)

Default AF for oral to inhalation extrapolation = 2 (ECHA R.8, 2012)

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

AF 6 for extrapolation from sub-acute to chronic (ECHA R.8, 2012)

AF for interspecies differences (allometric scaling):

5

Justification:

Default value for workers (ECHA R.8, 2012)

AF for other interspecies differences:

1

Justification:

No other interspecies differences

AF for intraspecies differences:

1

Justification:

No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining differences

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

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):

120

Dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

AF for oral to dermal extrapolation = 1 (ECHA R.8, 2012).

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

AF 6 for extrapolation from sub-acute to chronic (ECHA R.8, 2012)

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans (ECHA R.8, 2012)

AF for other interspecies differences:

1

Justification:

No other interspecies differences.

AF for intraspecies differences:

5

Justification:

Default value for workers (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Sytemic effects, long term

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with BPMA in rats

 

DNEL inhal worker long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:600 mg/kg bw/d	NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage
Step 2) Modification of starting point	0.38 m³/kg   6.7 m^3/10 m^3	Correction for rat standard breathing volume, 8 hrs (ECHA R.8, 2012) -Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m^3/6.7 m^3) is required(ECHA R.8, 2012)
Route-to-Route extrapolation	2	Oral to inhalation extrapolation (ECHA R.8, 2012)
NAEC worker	523.4 mg/m^3
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)
Intraspecies	5	Default value for workers (ECHA R.8, 2012)
Exposure duration	6	The NOAEL is based on a subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining differences
DNEL
Based upon a NOAEL of 600 mg/kg bw/d for male rats, for 50 d by the oral route.	17.5 mg/m^3		Using a total factor (POD modifier and AF) of 34.3 (/ 0.38 x 10/6.7 m³ x 2 x 1 x 5 x 6 x 1 x 1 x 1) a DNELlong-term, inhal, workerof 17.5 mg/m³ is derived.

 

DNEL dermal worker long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:600 mg/kg bw/d	NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage
Step 2) Modification of starting point	1	Oral to dermal extrapolation (ECHA R.8, 2012).
NAEL worker	600 mg/kg bw/d
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans (ECHA R.8, 2012)
Intraspecies	5	Default value for workers (ECHA R.8, 2012)[KK5]
Exposure duration	6	The NOAEL is based on a subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining uncertainties
DNEL
Based upon a NOAEL of 600 mg/kg bw/d for male rats, for 50 d by the oral route.	5.0 mg/kg bw/d		Using a total factor (POD modifier and AF) of 120 (1 x 4 x 5 x 6 x 1 x 1) a DNELlong-term, dermal, workerof 5.0 mg/kg bw/d is derived.

 

ylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of3/5is sufficiently conservative. (ECETOC, 2010)

 [KK5]In Absprache mit Harald 2017-12-06 auf Standardwerte (5/10) gesetzt, da Metabolismusdaten für BPMA fehlen)

Die Begründung für niedrigere ECETOC-Werte wäre gese dann wäre gewesen:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of3/5is sufficiently conservative. (ECETOC, 2010)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.35 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):

138

Dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

199.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction for rat standard breathing volume, 24 hrs = 1.15 m3/kg (ECHA R.8, 2012) 

Default AF for oral to inhalation extrapolation = 2 (ECHA R.8, 2012)

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

AF 6 for extrapolation from sub-acute to chronic (ECHA R.8, 2012)

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)

AF for other interspecies differences:

1

Justification:

No other interspecies differences

AF for intraspecies differences:

10

Justification:

Default value for general poulation (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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):

240

Dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default AF for oral to dermal extrapolation (ECHA R.8, 2012).

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

AF 6 for extrapolation from sub-acute to chronic (ECHA R.8, 2012)

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans (ECHA R.8, 2012)

AF for other interspecies differences:

1

Justification:

No other interspecies differences

AF for intraspecies differences:

10

Justification:

Default value for general population (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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):

240

Dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

600 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:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

6

Justification:

AF 6 for extrapolation from sub-acute to chronic (ECHA R.8, 2012)

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans (ECHA R.8, 2012)

AF for other interspecies differences:

1

Justification:

No other interspecies differences.

AF for intraspecies differences:

10

Justification:

Default value for workers (ECHA R.8, 2012)

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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

Sytemic effects, long term

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with BPMA in rats

DNEL inhal gen pop long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:600 mg/kg bw/d	NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage
Step 2) Modification of starting point	1.15 m³/kg	Correction for rat standard breathing volume, 24 hrs (ECHA R.8, 2012)
Route-to-Route extrapolation	2	Oral to inhalation extrapolation (ECHA R.8, 2012).
NAEC general population	199.8 mg/m^3
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)
Intraspecies	10	Default value for general population (ECHA R.8, 2012)
Exposure duration	6	The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining uncertainties
DNEL
Based upon a NOAEL of 600 mg/kg bw/d for male rats, for 50 d by the oral route.	4.35 mg/m^3		Using a total factor (POD modifier and AF) of 138 (/ 1.15 m³ x 2 x 1 x 10 x 6 x 1 x 1 x 1) a DNELlong-term,inhal, gen. pop.of 4.35 mg/m³ is derived.

 

 

DNEL dermal general population long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:600 mg/kg bw/d	NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage
Step 2) Modification of starting point	1	Oral to dermal extrapolation (ECHA R.8, 2012).
NAEL general population	600 mg/kg bw/d
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans (ECHA R.8, 2012)
Intraspecies	10	Default value for general population (ECHA R.8, 2012)
Exposure duration	6	The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining uncertainties
DNEL
Based upon a NOAEL of 600 mg/kg bw/d for male rats, for 50 d by the oral route.	2.5 mg/kg bw/d		Using a total factor (POD modifier and AF) of 240 (1 x 4 x 10 x 6 x 1 x 1) a DNELlong-term,dermal, gen.pop.of 2.5 mg/kg bw/d is derived.

 

 

DNEL oral general population long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:600 mg/kgbw/d	NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage
Step 2) Modification of starting point	1	No route-to-route extrapolation required.
NAEL general population	600 mg/kg bw/d
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans (ECHA R.8, 2012)
Intraspecies	10	Default value for general population (ECHA R.8, 2012)
Exposure duration	6	The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining uncertainties
DNEL
Based upon a NOAEL of 600 mg/kg bw/d for male rats, for 50 d by the oral route.	2.5 mg/kg bw/d		Using a total factor (POD modifier and AF) of 240 (1 x 4 x 10 x 6 x 1 x 1) a DNELlong-term,oral, gen.pop.of 2.5 mg/kg bw/d is derived.