Asparagine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

81.4 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

Dose descriptor starting point:

NOAEL

Value:

1 650 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2 035.23 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the oral subchronic repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.

AF for dose response relationship:

1

Justification:

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default assessment factor for intraspecies differences

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

Based on reliable and relevant data for the test item no remaining uncertainties are expected.

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

80.61 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

Dose descriptor starting point:

NOAEL

Value:

1 650 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 015.23 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long term studies with dermal exposure are not available. The long term systemic DNEL for dermal exposure has been derived from the oral subchronic repeated dose toxicity study.

AF for dose response relationship:

1

Justification:

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2008).

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

Based on reliable and relevant data for the test item no remaining uncertainties are expected.

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

Selection of the relevant dose descriptors:

Oral:

NOAEL =1650 mg/kg bw/day: subchronic repeated dose toxicity study, rat, oral (gavage)

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

The physicochemical properties of L-asparagine (log Kow = -3.82) and the molecular weight of 132.1179 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (molecular weight < 200 g/mol, log Kow between < -1).

For chemical safety assessment an oral absorption rate of 50 % is assumed as a worst case default value in the absence of other data

 

Dermal absorption

In the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur.

For chemical safety assessment a dermal absorption rate of 50 % is assumed as a worst case default value.

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value due to lack of reliable data. Thus, twice as high absorption is assumed compared to oral absorption (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DERIVATION OF DNELs

DNELs derived from subchronic repeated dose toxicity NOAEL (OECD guideline 408)

 

Worker-DNEL long-term for inhalation route (systemic): 80.61 mg/m³

Start value: 1650 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 2015.23 mg/m³

 

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV

                                             = 1650 x 1/0.384 x 50/100 x 6.7/10

In order to implement a correction for the differences between human and experimental exposure conditions as recommended by ECHA Guidance R.8 (version 2.1, November 2012), the NOEC was corrected for by a factor of 1.4 for the workers population:

Experimental exposure conditions:

From oral studies: 7 days/week

Human exposure conditions (workers):

Exposure via oral route: 5 days /week

7days/5 days = 1.4

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 2015.23 mg/m³ (8h-TWA)

Overall AF: 1*2*1*2.5*5*1 = 25

 

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

 

Worker-DNEL long-term for dermal route (systemic):  23.10 mg/kg bw/d

Start value: 1650 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 2310 mg/kg bw/d

Overall AF: 1*2*4*2.5*5*1 = 100

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.2 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

Dose descriptor starting point:

NOAEL

Value:

1 650 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

611.11 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the oral subchronic repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Based on reliable and relevant data for the test item no remaining uncertainties are expected.

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:

8.25 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 650 mg/kg bw/day

Value:

1 650 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long term studies with dermal exposure are not available. The long term systemic DNEL for dermal exposure has been derived from the oral subchronic repeated dose toxicity study.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Based on reliable and relevant data for the test item no remaining uncertainties are expected.

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:

8.25 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 650 mg/kg bw/day

Value:

1 650 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The long term systemic DNEL for oral exposure has been derived from the oral subchronic repeated dose toxicity study.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

Based on reliable and relevant data for the test item no remaining uncertainties are expected.

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

Selection of the relevant dose descriptors:

Oral:

NOAEL =1650 mg/kg bw/day: subchronic repeated dose toxicity study, rat, oral (gavage); OECD 408

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

The physicochemical properties of L-asparagine (log Kow = -3.82) and the molecular weight of 132.1179 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (molecular weight < 200 g/mol, log Kow between < -1).

For chemical safety assessment an oral absorption rate of 50% is assumed as a worst case default value in the absence of other data.

 

Dermal absorption

In the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur.

For chemical safety assessment a dermal absorption rate of 50% is assumed as a worst case default value.

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value due to lack of reliable data.Thus, twice as high absorption is assumed compared to oral absorption (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DERIVATION OF DNELs

DNELs derived from subchronic repeated dose toxicity NOAEL (OECD guideline 408)

 

General population-DNEL long-term for inhalation route (systemic): 12.2 mg/m³

Start value: 1650 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 611.11 mg/m³

 

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human

                                             = 1650 x 1/1.152 x 50/100

 In order to implement human body weight scaling as recommended by ECHA Guidance R.8 (version 2.1, November 2012), the respiratory volume was corrected for 60 kg body weight:

sRV (human, 8h) = 6.7 m³/kg bw/60 kg = 0.1117 m³/kg bw/8h

plus the allometric scaling from rat:

sRV(rat, 8h) = sRV (human, 8h) x allometric scaling factor = 0.1117 x 4 = 0.45 m³/kg bw/8h

and for the exposure time of 24h:

sRV(rat, 24h) = sRV(rat, 8h) x 24/8 =1.35m³/kg bw/24h.

Under consideration of body weight scaling the corrected NOEC was calculated as follows:

                                               = 1650 x 1/1.35 x 50/100

The corrected inhalation NOAECgeneral population (24 h) is therefore:

                                             = 611.11 mg/m³ (24 h)

Overall AF: 1*2*1*2.5*10*1 = 50

 

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

 

general population-DNEL long-term for dermal route (systemic):  8.25 mg/kg bw/d

Start value: 1650 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1650 mg/kg bw/d

Overall AF: 1*2*4*2.5*10*1 = 200

 

general population-DNEL long-term for oral route (systemic):  8.25 mg/kg bw/d

Start value: 1650 mg/kg bw/d

Route of original study: oral

Overall AF: 1*2*4*2.5*10*1 = 200