Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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):
75
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
37 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
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:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
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:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 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):
300
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
42 mg/kg bw/day
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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
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 quality of the whole data base is considered to be sufficient and uncritical.
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:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

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 CeTePox® 0214 H is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with the target substance CeTePox® 0214 H is available. Under the conditions of this study, CeTePox® 0214 H caused reduced body weight and body weight gain, reduced food consumption in parental male and female Han:WIST rats at 100 mg/kg bw/day administered by oral gavage. In male animals at 100 mg/kg bw/day, test item influence on hepatic function was detected in clinical chemistry parameters, in necropsy findings and histopathological findings (centrilobular vacuolation in the hepatocytes). At 100 mg/kg bw/day, the delivery data of dams (mean number of implantation sites and lower mean birth (total birth, live born and viable pups per litter) was slightly depressed. There were no test item related changes in male or female animals at 10 or 30 mg/kg bw/day. The development of the F1 offspring was not impaired at any dose level from birth to post-natal day 13 after repeated oral administration of dams. Based on these observations the NOAEL were determined as follows: NOAEL for systemic toxicity of male/female rats: 30 mg/kg bw/day, NOAEL for reproductive performance of male rats: 100 mg/kg bw/day, NOAEL for reproductive performance of female rats: 30 mg/kg bw/day, NOAEL for F1 Offspring: 100 mg/kg bw/day

The NOAEL for systemic toxicity of 30 mg/kg bw/day is used as PoD for DNEL derivation.

Step 1:PoD: NOAEL = 30 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:

= 30 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 37 mg/m3

Step 3: Overall AF= 75

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 6

The exposure duration of the OECD TG 422 study performed with the test item was 50-67 days for females and 49 days for males.

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 = 0.5 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

No data on inhalation are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to mucosal tissue may occur by inhalative exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016).

For risk assessment it is assumed that the local effect (corrosion) is predominating over possible systemic effects. Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

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

No data on inhalation are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to mucosal tissue may occur by inhalative exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016). Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

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

Step 1:PoD: NOAEL = 30 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:

= 30 mg/kg bw/day x 1.4

= 42 mg/kg bw/day

Step 3:Overall AF= 300

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: 6

In conclusion, long term systemic dermal DNEL, workers = 0.14 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

No dermal experimental data are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to the skin may occur by dermal exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016).

 

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

No dermal experimental data are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to the skin may occur by dermal exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016). For risk assessment it is assumed that the local effect (corrosion) is predominating over possible systemic effects. Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

Hazard to the eye-local effects (worker)

The test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016). Since no threshold limit values can be defined for the local effect, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

 

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:
0.08 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):
150
Dose descriptor starting point:
NOAEL
Value:
30 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
13 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
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 more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
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:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 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):
600
Dose descriptor starting point:
NOAEL
Value:
30 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
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 more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
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:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
0.05 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):
600
Dose descriptor starting point:
NOAEL
Value:
30 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
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 more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
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:
DNEL (Derived No Effect Level)
Value:
0.15 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.33
DNEL extrapolated from long term DNEL

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)

Using a conservative approach, a DNEL (long-term inhalation exposure) is calculated. This 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 CeTePox® 0214 H is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with the target substance CeTePox® 0214 H is available. Under the conditions of this study, CeTePox® 0214 H caused reduced body weight and body weight gain, reduced food consumption in parental male and female Han:WIST rats at 100 mg/kg bw/day administered by oral gavage. In male animals at 100 mg/kg bw/day, test item influence on hepatic function was detected in clinical chemistry parameters, in necropsy findings and histopathological findings (centrilobular vacuolation in the hepatocytes). At 100 mg/kg bw/day, the delivery data of dams (mean number of implantation sites and lower mean birth (total birth, live born and viable pups per litter) was slightly depressed. There were no test item related changes in male or female animals at 10 or 30 mg/kg bw/day. The development of the F1 offspring was not impaired at any dose level from birth to post-natal day 13 after repeated oral administration of dams. Based on these observations the NOAEL were determined as follows: NOAEL for systemic toxicity of male/female rats: 30 mg/kg bw/day, NOAEL for reproductive performance of male rats: 100 mg/kg bw/day, NOAEL for reproductive performance of female rats: 30 mg/kg bw/day, NOAEL for F1 Offspring: 100 mg/kg bw/day

The NOAEL for systemic toxicity of 30 mg/kg bw/day is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 30 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:

= 30 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 13 mg/m3

Step 3: Overall AF= 150

Intraspecies AF (General population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 6

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 = 0.08 mg/m3

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

No data on inhalation are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to mucosal tissue may occur by inhalative exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016).

For risk assessment it is assumed that the local effect (corrosion) is predominating over possible systemic effects. Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

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

No data on inhalation are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to mucosal tissue may occur by inhalative exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016). Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

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

Step 1:PoD: NOAEL= 30 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= 600

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: 6

In conclusion, long term systemic dermal DNEL, general population = 0.05 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

No dermal experimental data are available. However, the test substance is classified for skin corrosion (UN GHS Category 1B, H314) according to Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to the skin may occur by dermal exposure. Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016).

For risk assessment it is assumed that the local effect (corrosion) is predominating over possible systemic effects. Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

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

The test item is classified for skin corrosion (UN GHS Category 1B) according to Regulation (EC) No 1272/2008 (CLP). According to the Guidance on IR + CSA, Part E (ECHA, 2016) the test substance is characterized with a moderate hazard. Since no threshold limit values can be defined for this kind of local effect, no DNEL derivation was performed. Instead a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

Oral

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

A NOAEL of 30 mg/kg bw/day for systemic toxicity derived from an OECD TG 422 study performed with the target was used as the PoD.

Step 1: PoD: NOAEL = 30 mg/kg bw/day

Step 2: Overall AF= 600

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: 6.

In conclusion, long term systemic oral DNEL, general population= 0.05 mg/kg bw/day

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

Due to the acute oral toxicity observed for the test item, the substance is considered to be classified for acute oral toxicity Cat.4 under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776. In the ECHA Guidance it is stated that “[..], the acute DNEL can by default be set as 1-5 times the long-term DNEL”. Therefore, the DNEL for acute systemic oral, worker was extrapolated according to the ECHA Guidance by applying the AF of 0.33.

 

DNEL, long-term systemic dermal (0.05 mg/kg bw/day)/ AF (0.33)

 

DNEL, short-term systemic oral = 0.15 mg/kg bw/day

 

Hazard to the eye-local effects (general population)

The test item is classified for skin corrosion (UN GHS Category 1B) according to Regulation (EC) No 1272/2008 (CLP). Therefore, a hazard for the eyes cannot be excluded. According to the Guidance on IR + CSA, Part E (ECHA, 2016) the test substance is characterized with a moderate hazard. Since no threshold limit values can be defined for this kind of local effect, no DNEL derivation was performed. Instead a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

 

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