calcium N2,N6-bis(3-carboxypropanoyl)lysine (1:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

88.16 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:

1 250 mg/kg bw/day

Modified dose descriptor starting point:

other: NAEC

Value:

2 204 mg/m³

Explanation for the modification of the dose descriptor starting point:

NAEC worker (8h) = (1250 mg/kg bw/0.38 m³/kg bw) * 6.7 m³/ 10 m³

[where: NAEC is the modified starting point; 1250 mg/kg bw is the NOAEL for the repeated dose toxicity. The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study; 0.38 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity)].

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to Chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Scaling issues already evaluated in modified starting point

AF for other interspecies differences:

2.5

Justification:

For remaining differences

AF for intraspecies differences:

5

Justification:

DNEL derivation for workers

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

Study well conducted. Result supported by a carcinogenicity study NOAEL = 2000 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/kg bw/day

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:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

the dermal route was not considered as a possible exposure due to the physiochemical and toxicological properties of the target substance (Negative logKow, high solubility, very low BCF value, no toxicity by oral route observed and no systemic effects observed during the skin sensitisation in vivo test).

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to Chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling

AF for other interspecies differences:

2.5

Justification:

For remaining differences

AF for intraspecies differences:

5

Justification:

DNEL derivation for workers

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

Study well conducted. Result supported by a carcinogenicity study NOAEL = 2000 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (respiratory tract)

Route of original study:

Dermal

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

INHALATION ROUTE

The Derived No Effect Level for inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the repeated dose toxicity assessment by oral route.

The No Observed Adverse Effect Level (NOAEL) for repeated dose was established as 1250 mg/kg body weight/day. The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study In general, the calculation of DNELs is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

 

Systemic effects long term exposure

NAEC worker (8h) = (1250 mg/kg bw/0.38 m³/kg bw) * 6.7 m³/ 10 m³

[where: NAEC is the modified starting point; 1250 mg/kg bw is the NOAEL for the repeated dose toxicity.

The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study; 0.38 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity)].

 

Thus, the corrected starting point NAEC was estimated to be 2204 mg/m³.

Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 2, because the starting value resulted from a sub-chronic study

- remaining differences 2.5

- intraspecies differences: 5 for workers

 

DERMAL ROUTE

The Derived No Effect Level for dermal systemic long-term exposure is estimated from the No Observed Effect Level obtained from the repeated dose toxicity assessment by oral route.

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21.73 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:

1 250 mg/kg bw/day

Modified dose descriptor starting point:

other: NAEC

Value:

1 086.95 mg/m³

Explanation for the modification of the dose descriptor starting point:

NAEC general population (24h) = (1250 mg/kg bw/1.15 m³/kg bw) [where: NAEC is the modified starting point; 1250 mg/kg bw is the NOAEL for Repeated dose toxicity. The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study ; 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to Chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Scaling issues already evaluated in modified starting point

AF for other interspecies differences:

2.5

Justification:

For remaining differences

AF for intraspecies differences:

10

Justification:

DNEL Derivation for General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

Study well conducted. Result supported by a carcinogenicity study NOAEL = 2000 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

the dermal route was not considered asa possible exposuredue to the physiochemical andtoxicological properties of the target substance (Negative logKow, high solubility, very low BCF value, no toxicity by oral route observed and no systemic effects observed during the skin sensitisationin vivotest).

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to Chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling

AF for other interspecies differences:

2.5

Justification:

For remaining differences

AF for intraspecies differences:

10

Justification:

DNEL Derivation for General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

Study well conducted. Result supported by a carcinogenicity study NOAEL = 2000 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

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:

12.5 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):

100

Dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No default factor should be introduced when performing on the same route; 1250 mg/kg bw/day is the NOAEL for repeated dose toxicity.

The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to Chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Study conducted on rats

AF for other interspecies differences:

2.5

Justification:

For remaining differences

AF for intraspecies differences:

10

Justification:

DNEL Derivation for General Population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

Study well conducted. Result supported by a carcinogenicity study NOAEL = 2000 mg/kg bw/day

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

INHALATION ROUTE

The Derived No Effect Level for inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the repeated dose toxicity assessment by oral route.

The No Observed Adverse Effect Level (NOAEL) for repeated dose was established as 1250 mg/kg body weight/day. The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study In general, the calculation of DNELs is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

 

Systemic effects long term exposure

NAEC general population (24h) = (1250 mg/kg bw/1.15 m³/kg bw) [where: NAEC is the modified starting point; 1250 mg/kg bw is the NOAEL for Repeated dose toxicity.

The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study ; 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]

Thus, the corrected starting point NAEC was estimated to be 1086.95 mg/m³.

Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 2, because the starting value resulted from a sub-chronic study

- remaining differences 2.5

- intraspecies differences: 10 for General Population

 

DERMAL ROUTE

The Derived No Effect Level for dermal systemic long-term exposure is estimated from the No Observed Effect Level obtained from the repeated dose toxicity assessment by oral route.

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

 

ORAL ROUTE

The Derived No Effect Level for oral long-term exposure is estimated from the No Observed Effect Level obtained from the repeated dose toxicity assessment. The No Observed Adverse Effect Level (NOAEL) for reproductive and development was established as 1250 mg/kg body weight/day. The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study In general, the calculation of DNELs is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

 

Systemic effects long term exposure

Starting point for the oral route for general population: NOAEL = 1250 mg/kg bw. The starting point was selected due to the time of exposure, to the tested doses and to the reliability of the study [where: 1250 mg/kg bw is the NOAEL for repeated dose toxicity (oral route)]

 

No default factor should be introduced when performing on the same route.

Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 2, because the starting value resulted from a sub-chronic study

- because the NOAEL was recorded in a study conducted on rats, for interspecies differences the allometric scaling of 4 has been used

- remaining differences 2.5

- intraspecies differences 10, for general population