Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 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):
50
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
123.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to "Additional Information".

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
4
Justification:
The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to routeextrapolation.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The study according OECD TG 422 was conducted according to 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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
140 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

See "Additional Information" for details.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
4
Justification:
The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The study according OECD TG 422 was conducted according to 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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation:

In a study according to OECD TG 422 the target substance was administered daily as an aqueous preparation to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 100, 300 and 1000 mg/kg bw/day. The NOAEL for reproductive performance and fertility of the F0 parental rats and developmental toxicity in the offspring was 1000 mg/kg bw/day, the highest dose tested. The NOAEL for general, systemic toxicity of the test item was 100 mg/kg bw/day based on the findings in the target organ kidney. This NOAEL systemic is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 100 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 hours: 6.7 m3

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 100 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 123.4 mg/m3

Step 3: Overall AF= 50

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.

Whole database AF: 1

The OECD TG 422 toxicity study was conducted according to 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.

In conclusion, long term systemic inhalation DNEL, workers = 2.5 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

Due to the extremely low vapor pressure (< 1 Pa) of the substance, inhalation exposure is not considered as relevant. Furthermore, no acute oral or dermal toxicity was reported for the substance. Therefore, no DNEL was derived for acute inhalation exposure. The long-term systemic inhalation DNEL will be protective also for acute inhalation exposure.

 

Long term & acute, local DNEL- exposure via inhalation (workers)

The substance is classified for serious eye irritation and in conclusion local mucosal membrane damage of the respiratory membranes might be possible (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). Furthermore, the substance is classified for skin sensitization and therefore respiration sensitization might be possible. However, due to the extremely low vapor pressure (calculation with EPI Suite 1.57xE-7 Pa) of the substance, inhalation exposure is not considered as relevant and the potential for local respiratory irritation or sensitization is expected to be low. Therefore, no DNEL was derived.

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 100 mg/kg bw/day derived from an OECD TG 422 study performed with the target was used as the PoD.

Step 1: PoD: NOAEL = 100 mg/kg bw/day

Step 2: Modification into a correct starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

= 100 mg/kg bw/day x 1.4

= 140 mg/kg bw/day

Step 3: Overall AF= 200

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.

In conclusion, long term systemic dermal DNEL, workers = 0.7 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required. The long-term dermal DNEL will be protective also for acute dermal exposure.

 

Long term & acute, local DNEL- dermal exposure (workers)

A qualitative approach has to be implemented to deal with the serious eye damage as well as skin sensitization properties of the substance. As a result, a high hazard is derived.

Hazard to the eye-local effects (worker)

The test item is classified for serious eye damage Cat 1 (H318: "Causes serious eye damage") under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776. Thus, a qualitative risk assessment is done and the substance is assigned to the medium hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.435 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):
100
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to "Additional Information".

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
4
Justification:
The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The study according OECD TG 422 was conducted according to 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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
400
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

See "Additional Information" for details.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
4
Justification:
The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The OECD TG 422 toxicity study performed with the test item was conducted according to 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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
400
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
4
Justification:
The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The study according OECD TG 422 was conducted according to 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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (general population)

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation:

In a study according to OECD TG 422 the target substance was administered daily as an aqueous preparation to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 100, 300 and 1000 mg/kg bw/day. The NOAEL for reproductive performance and fertility of the F0 parental rats and developmental toxicity in the offspring was 1000 mg/kg bw/day, the highest dose tested. The NOAEL for general, systemic toxicity of the test item was 100 mg/kg bw/day based on the findings in the target organ kidney. This NOAEL systemic is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 100 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

Corrected NOAEC (inhalation) for general population:

= 100 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 43.5 mg/m3

Step 3: Overall AF= 100

Intraspecies AF (General population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.

Whole database AF: 1

The OECD TG 422 toxicity study was conducted according to 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.

In conclusion, long term systemic inhalation DNEL, general population = 0.435 mg/m3

Acute, systemic DNEL- exposure via inhalation (general population)

Due to the extremely low vapor pressure (< 1 Pa) of the substance, inhalation exposure is not considered as relevant. Furthermore, no acute oral or dermal toxicity was reported for the substance. Therefore, no DNEL was derived for acute inhalation exposure. The long-term systemic inhalation DNEL will be protective also for acute inhalation exposure.

 

Long term, local DNEL- exposure via inhalation (general population)

The substance is classified for serious eye irritation and in conclusion local mucosal membrane damage of the respiratory membranes might be possible (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). Furthermore, the substance is classified for skin sensitization and therefore respiration sensitization might be possible. However, due to the extremely low vapor pressure (calculation with EPI Suite 1.57xE-7 Pa) of the substance, inhalation exposure is not considered as relevant and the potential for local respiratory irritation or sensitization is expected to be low. Therefore, no DNEL was derived.

Dermal

Long term, systemic DNEL- exposure via dermal route (general population)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 100 mg/kg bw/day derived from an OECD TG 422 study performed with the target was used as the PoD.

Step 1:PoD: NOAEL= 100 mg/kg bw/day

Oral absorption of the rat/dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d, 24 h rat/7 d, 24 h general population

Step 2:Overall AF= 400

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.

In conclusion,long term systemic dermal DNEL, general population = 0.25 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required. The long-term dermal DNEL will be protective also for acute dermal exposure.

 

Long term & acute, local DNEL- dermal exposure (general population)

A qualitative approach has to be implemented to deal with the serious eye damage as well as skin sensitisation properties of the substance. As a result, a high hazard is derived.

Oral

Long term, systemic DNEL- exposure by oral route (general population)

In a study according to OECD TG 422 the target substance was administered daily as an aqueous preparation to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 100, 300 and 1000 mg/kg bw/day. The NOAEL for reproductive performance and fertility of the F0 parental rats and developmental toxicity in the offspring was 1000 mg/kg bw/day, the highest dose tested. The NOAEL for general, systemic toxicity of the test item was 100 mg/kg bw/day based on the findings in the target organ kidney. This NOAELsystemicis used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 100 mg/kg bw/day

Step 2: Overall AF= 400

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric

scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 4

 

The exposure duration of the OECD TG 422 study performed with the test item was 65 days for females and 34 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (65 days) for females an Assessment factor of 4 is justified.

In conclusion, long term systemic oral DNEL, general population= 0.25 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute oral toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required. The long-term oral DNEL will be protective also for acute oral exposure.

 

Hazard to the eye-local effects (general population)

The test item is classified for serious eye damage Cat 1 (H318: "Causes serious eye damage") under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.Thus, a qualitative risk assessment is done and the substance is assigned to the medium hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016