Leucophor 1111X

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.9 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

other: NAEC worker

Value:

740 mg/m³

Explanation for the modification of the dose descriptor starting point:

NAEC worker (8h) = (300 mg/kg bw/0.38 m³/kg bw) * 6.7 m³/ (10 m³ x 7/5) [where: NAEC is the modified starting point; 300 mg/kg bw is the NOAEL for reproductive toxicity (Turck, 2001); 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). Since worker are exposed 5 days per week and the rats were exposed 7 days per week a factor 7/5 was included]

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Scaling issues just evaluated in modified starting point

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Worker population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

100 % adsorption for inhalation route for animal and human is assumed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

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:

14 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

other: Corrected NOAEL

Value:

4 200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. At least a factor of 0.1 can be applied to extrapolate from oral to dermal toxicity.

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric factor rat to man

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Worker population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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:

no hazard identified

Most sensitive endpoint:

acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The Derived No Effect Level for inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the reproductive toxicity assessment. In fact, relevant systemic effects have been reported only in a Rabbit developmental study (Turk, 2000). The analogous derivative was also tested for the developmental toxicity in New Zealand White rabbits and Sprague-Dawley rats (Turk, 1999).

Rabbits were dosed with 100, 400 and 800 mg/kg bw/day by gavage from gestation days 7 – 28, and rats were dosed with 100, 400 and 1000 mg/kg bw/day by gavage from gestation days 6 – 19. The highest dose administered in the rat study (1000 mg/kg bw/day) did not cause toxicity to maternal animals or the developing foetus. In rabbits, the NOELs for maternal and foetotoxicity were 100 mg/kg bw/day, and the NOAEL for teratogenicity was 400 mg/kg bw/day. Exposure to 400 mg/kg bw/day was associated with early delivery in 2 does, abortion in 1 doe, and soft faeces and discoloured stool in general. Mean body weights of all foetuses and male foetuses from does treated with 400 mg/kg bw/day were significantly lower than control. These changes may have been secondary to the maternal toxicity observed in this study and were not considered to be an indication of developmental toxicity (Turk, 2000).

In the two generation study performed on rat dosed with analogous substance 03 a NOAEL of 300 was set for parental toxicity (Turk A.P., 2000).

Based on the parental toxicity in the rat two generation study, the NOAEL of 300 mg/Kg bw/day has been considered as representative, for hazard assessment.

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.

INHALATION ROUTE - Systemic effects long term exposure

Corrected starting point for the inhalation route for workers: NAEC worker (8h) = (300 mg/kg bw/0.38 m³/kg bw) * 6.7 m³/ 10 m³ x (7 d/5 d)

[where: NAEC is the modified starting point; 300 mg/kg bw is the NOAEL for reproductive toxicity(Turck, 2001); 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). Since worker are exposed 5 days per week and the rats were exposed 7 days per week a factor 7/5 was included]

Thus, the corrected starting point NAEC was estimated to be 740 mg/m³.

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

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- remaining differences 2.5

- intraspecies differences 5, for worker population

DERMAL ROUTE - Systemic effects long term exposure

Corrected starting point for the dermal route for workers: = NOEL*10*(7/5) = 4200 mg/kg bw/day.

Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. At least a factor of 0.1 can be applied to extrapolate from oral to dermal toxicity. Since worker are exposed 5 days per week and the rats were exposed 7 days per week a factor 7/5 was included.

Thus, the corrected starting point for the dermal route for workers was estimated to be 4200 mg/kg bw/day

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

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- allometric factor rat to man 4

- remaining differences 2.5

- intraspecies differences 5, for worker population

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

other: NAEC general population

Value:

261 mg/m³

Explanation for the modification of the dose descriptor starting point:

NAEC general population (24h) = 300 mg/kg bw/1.15 m³/kg bw [where: NAEC is the modified starting point; 300 mg/kg bw is the NOAEL for reproductive toxicity (Turck, 2001); 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:

6

Justification:

Subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Scaling issues just evaluated in modified starting point

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

100 % adsorption for inhalation route for animal and human is assumed

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:

5 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

other: Corrected NOAEL

Value:

3 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. At least a factor of 0.1 can be applied to extrapolate from oral to dermal toxicity.

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric factor rat to man

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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:

no hazard identified

Most sensitive endpoint:

acute toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

300 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; 300 mg/kg bw is the NOAEL for reproductive toxicity (Turck, 2001).

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric factor rat to man

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

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

The Derived No Effect Level for inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the reproductive toxicity assessment. In fact, relevant systemic effects have been reported only in a Rabbit developmental study (Turk, 2000). The analogous derivative was also tested for the developmental toxicity in New Zealand White rabbits and Sprague-Dawley rats (Turk, 1999).

Rabbits were dosed with 100, 400 and 800 mg/kg bw/day by gavage from gestation days 7 – 28, and rats were dosed with 100, 400 and 1000 mg/kg bw/day by gavage from gestation days 6 – 19. The highest dose administered in the rat study (1000 mg/kg bw/day) did not cause toxicity to maternal animals or the developing foetus. In rabbits, the NOELs for maternal and foetotoxicity were 100 mg/kg bw/day, and the NOAEL for teratogenicity was 400 mg/kg bw/day. Exposure to 400 mg/kg bw/day was associated with early delivery in 2 does, abortion in 1 doe, and soft faeces and discoloured stool in general. Mean body weights of all foetuses and male foetuses from does treated with 400 mg/kg bw/day were significantly lower than control. These changes may have been secondary to the maternal toxicity observed in this study and were not considered to be an indication of developmental toxicity (Turk, 2000).

In the two generation study performed on rat dosed with analogous substance 03 a NOAEL of 300 was set for parental toxicity (Turk A.P., 2000).

Based on the parental toxicity in the rat two generation study, the NOAEL of 300 mg/Kg bw/day has been considered as representative, for hazard assessment.

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.

INHALATION ROUTE -Systemic effects long term exposure

Corrected starting point for the inhalation route for general population: NAEC general population (24h) = (300 mg/kg bw/1.15 m³/kg bw)

[where: NAEC is the modified starting point; 300 mg/kg bw is the NOAEL for reproductive toxicity (Turck, 2001); 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 261 mg/m³.

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

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- remaining differences 2.5

- intraspecies differences 10, for general population

DERMAL ROUTE -Systemic effects long term exposure

Corrected starting point for the dermal route for general population: = NOEL*10 = 3000 mg/kg bw/day.

Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. At least a factor of 0.1 can be applied to extrapolate from oral to dermal toxicity.

Thus, the corrected starting point for the dermal route for workers was estimated to be 3000 mg/kg bw/day

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

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- allometric factor rat to man 4

- remaining differences 2.5

- intraspecies differences 10, for general population

ORAL ROUTE -Systemic effects long term exposure

Starting point for the oral route for general population: NOAEL = 300 mg/kg bw

[where: 300 mg/kg bw is the NOAEL for reproductive toxicity (oral route) (Turk, 2000)]

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 6, because the starting value resulted from a subacute 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