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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
246 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: SCOEL derived an OEL
Overall assessment factor (AF):
4
Modified dose descriptor starting point:
NOAEC
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:
DNEL (Derived No Effect Level)
Value:
492 mg/m³
DNEL related information
DNEL derivation method:
other: SCOEL derived a STEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
140.17 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The study used as starting point was an inhalation study. It was the most recent study available (105 weeks). This study is regarded as the key study related to repeated dose toxicity. Furhter justification is provided in the discussion section.The start value was a NOAEL of 483,35 mg/m3. To derive a suitable starting poing point an AF of 0,29 was applied to correct for the respiratory volume (default factor R.8.4.2: sRV Table R. 8-2 (p 20)). Furthermore it is assumed that there is no difference between the absorption via the inhalation and dermal route of exposure (AF = 1) which is a conservative estimate. Furthermore it is assumed that there is no difference in absorption between rats and human.
AF for dose response relationship:
1
Justification:
starting point is a NOAEL, no additional AF is deemed necessary.
AF for differences in duration of exposure:
1
Justification:
the starting point of the DNEL derivation is a chronic study (105 weeks), no additional AF is deemed necessary.
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to human.
AF for other interspecies differences:
2.5
Justification:
other remaining interspecies differences (default value).
AF for intraspecies differences:
5
Justification:
default intraspecies assessment factor according to ECHA guideline R.8.4.3.1 for workers.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.105 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor:
other: LOAEL
AF for dose response relationship:
2
Justification:
the starting point in this case is a LOAEL. As this differs from the default situation where a NOAEL is used, an AF is to be applied. This is typically 3, however as the EC3 is 46%, but the 25% solution was clearly below the EC3 (and thus considered the "assigned" NOAEL), an AF of 2 is deemed to be sufficient.
AF for other interspecies differences:
10
Justification:
default factor value according to ECHA guideline R.8.Appendix 8-10. There is no specific evidence available of good correlation between the EC3 and human NOAEL/LOAEL.
AF for intraspecies differences:
5
Justification:
default factor value according to ECHA guideline R.8.4.3.1 for worker
AF for remaining uncertainties:
1
Justification:
assessment factor related to skin sensisitation specific regarding (1) uncertainties of the matrix: the matrix in which the substance will be used in practice will normally be different from the vehicle used for testing. Nevertheless, there are no indications that the matrix composition would have a negative effect on the sensitisation potential of the substance ==> AF of 1 and (2) the uncertainties of the conditions of exposure: this substance is only to be used in an industrial or professional setting, consumer exposure is not relevant. The experimental setup indeed differs from the actual human exposure situation as for industrial and professional workers, the most likely parts of the body that can be exposed are the hands. However, in comparison to the ear of the mouse, the skin of the hands is not to be considered more sensitive. Therefore, based on this argument and based on the fact that the substance is only classified as a WEAK sensitizer according to the ECETOC criteria (WEAK means EC3 is between 10 and 100%; and the EC3 for AMS is 50%) an additional assessment factor is not deemed necessary ==> AF:1.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

In function of the dermal DNEL for workers - systemic, long term effects a long-term repeated dose inhalation study was used as start point. This is approach was followed for the following reasons:

1) The inhalation study is the most recent, good quality, repeated dose study available.

2) Absorption: In comparison to the GI tract and the lungs, the surface of the skin that is exposed is relatively small considering the fact of clothing. In comparison GI tract, the lungs have a large alveolar region. When considering the parts of the skin being exposed, it can be stated that there are various layers in the skin that need to be penetrated by passive diffusion in order to reach the circulation which is dependent on the solubility of the substance. In the lungs and the GI tract, substances will penetrate more easy. In addition, the blood flow in the skin is rather low, while in the lungs this is high. Once a substance penetrates the skin it can be stated that it will reach the systemic circulation immediately, however, this is not different from the other routes. In fact the extrapolation could be an overestimation as the pulmonary absorption is likely to be greater than the absorption through the skin. However, as unknown toxic compound could (however unlikely) be formed via interactions with the skin, the systemic toxicity by both routes is considered to be equal.

3) Toxicokinetics: The information on toxicokinetics for this substance indicates that there are no clear differences in how the substance will metabolised depending on the route. The information coming from an oral, inhalation and intraveneus studies was taken together. AMS is readily metabolised, breakdown products are mainly excreted via the urine (90% in 72h). There is little accumulation seen and thus bio-accumulation can be excluded. There is no ‘first-pass’ metabolism following inhalation exposure (Reference: IGHRC Guidelines, April 2006). The metabolic pathway is determined and considered the same for all routes as this occurs after systemic uptake of the substance. Because the mode of action of the substance can be considered to be systemic and the toxicokinetic data was taken into account, therefore this route-to-route extrapolation is feasible (Reference: IGHRC Guidelines, April 2006). Moreover, the critical toxic effects are rather systemic than local.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.83 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEC
Value:
483.35 mg/m³
Explanation for the modification of the dose descriptor starting point:
Not applicable as starting point is an inhalation study.
AF for dose response relationship:
1
AF for differences in duration of exposure:
4
Justification:
the starting point of the DNEL derivation is a chronic study (105 weeks), consequently no additional AF is deemed necessary for the exposure duration of the study itself. However, as the exposure duration was only 6hr, a correction is required for 24hr of exposure. This leads to an AF of 4.
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable
AF for other interspecies differences:
2.5
Justification:
differences not related to calorimetric differences
AF for intraspecies differences:
10
Justification:
default intraspecies assessment factor according to ECHA guideline R.8.4.3.1 for general population.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
1.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Modified dose descriptor starting point:
NOAEL
Value:
140.17 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The study used as starting point was an inhalation study. It was the most recent study available (105 weeks). This study is regarded as the key study related to repeated dose toxicity. Further justification is provided in the discussion section.The start value was a NOAEL of 483,35 mg/m3. To derive a suitable starting poing point an AF of 0,29 was applied to correct for the respiratory volume (default factor R.8.4.2: sRV Table R. 8-2 (p 20)). Furthermore it is assumed that there is no difference between the absorption via the inhalation and dermal route of exposure (AF = 1) which is a conservative estimate. Furthermore it is assumed that there is no difference in absorption between rats and human.
AF for dose response relationship:
1
Justification:
starting point is a NOAEL, no additional AF is deemed necessary.
AF for differences in duration of exposure:
1
Justification:
the starting point of the DNEL derivation is a chronic study (105 weeks), no additional AF is deemed necessary.
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to human.
AF for other interspecies differences:
2.5
Justification:
other remaining interspecies differences (default value).
AF for intraspecies differences:
10
Justification:
default intraspecies assessment factor according to ECHA guideline R.8.4.3.1 for general population.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.052 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor:
other: LOAEL
AF for dose response relationship:
2
Justification:
the starting point in this case is a LOAEL. As this differs from the default situation where a NOAEL is used, an AF is to be applied. This is typically 3, however as the EC3 is 46%, but the 25% solution was clearly below the EC3 (and thus considered the "assigned" NOAEL), an AF of 2 is deemed to be sufficient.
AF for other interspecies differences:
10
Justification:
default factor value according to ECHA guideline R.8.Appendix 8-10. There is no specific evidence available of good correlation between the EC3 and human NOAEL/LOAEL.
AF for intraspecies differences:
10
Justification:
default assessment factor value according to ECHA guideline R.8.4.3.1 for the general population
AF for remaining uncertainties:
1
Justification:
Assessment factor related to skin sensisitation specific regarding (1) uncertainties of the matrix: the matrix in which the substance will be used in practice will normally be different from the vehicle used for testing. Nevertheless, there are no indications that the matrix composition would have a negative effect on the sensitisation potential of the substance ==> AF of 1 and (2) the uncertainties of the conditions of exposure: this substance is only to be used in an industrial or professional setting, consumer exposure is not relevant. The experimental setup indeed differs from the actual human exposure situation as for industrial and professional workers, the most likely parts of the body that can be exposed are the hands. However, in comparison to the ear of the mouse, the skin of the hands is not to be considered more sensitive. Therefore, based on this argument and based on the fact that the substance is only classified as a WEAK sensitizer according to the ECETOC criteria (WEAK means EC3 is between 10 and 100%; and the EC3 for AMS is 50%) an additional assessment factor is not deemed necessary ==> AF:1.
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):
400
Modified dose descriptor starting point:
NOAEL
Value:
40 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not applicable as there is no route to route extrapolation required.
AF for dose response relationship:
1
Justification:
starting point is a NOAEL, no additional AF is deemed necessary.
AF for differences in duration of exposure:
4
Justification:
1) the dosing period is longer than sub-acute (AF = 6), but not sub-chronic (AF = 2), 2) the metabolism and bio-elimination of the substance is indeed rapid. 3) Limited increased effect after longer dosing.
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to human.
AF for other interspecies differences:
2.5
Justification:
other remaining interspecies differences (default value).
AF for intraspecies differences:
10
Justification:
default intraspecies assessment factor according to ECHA guideline R.8.4.3.1 for the general population.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

In function of the dermal DNEL for general population - systemic, long term effects a long-term repeated dose inhalation study was used as start point. This is approach was followed for the following reasons:

1) The inhalation study is the most recent, good quality, repeated dose study available.

2) Absorption: In comparison to the GI tract and the lungs, the surface of the skin that is exposed is relatively small considering the fact of clothing. In comparison GI tract, the lungs have a large alveolar region. When considering the parts of the skin being exposed, it can be stated that there are various layers in the skin that need to be penetrated by passive diffusion in order to reach the circulation which is dependent on the solubility of the substance. In the lungs and the GI tract, substances will penetrate more easy. In addition, the blood flow in the skin is rather low, while in the lungs this is high. Once a substance penetrates the skin it can be stated that it will reach the systemic circulation immediately, however, this is not different from the other routes. In fact the extrapolation could be an overestimation as the pulmonary absorption is likely to be greater than the absorption through the skin. However, as unknown toxic compound could (however unlikely) be formed via interactions with the skin, the systemic toxicity by both routes is considered to be equal.

3) Toxicokinetics: The information on toxicokinetics for this substance indicates that there are no clear differences in how the substance will metabolised depending on the route. The information coming from an oral, inhalation and intraveneus studies was taken together. AMS is readily metabolised, breakdown products are mainly excreted via the urine (90% in 72h). There is little accumulation seen and thus bio-accumulation can be excluded. There is no ‘first-pass’ metabolism following inhalation exposure (Reference: IGHRC Guidelines, April 2006). The metabolic pathway is determined and considered the same for all routes as this occurs after systemic uptake of the substance. Because the mode of action of the substance can be considered to be systemic and the toxicokinetic data was taken into account, therefore this route-to-route extrapolation is feasible (Reference: IGHRC Guidelines, April 2006). Moreover, the critical toxic effects are rather systemic than local.