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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:
3.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
18
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
Most sensitive endpoint:
repeated dose toxicity
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:
7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
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

Acute toxicity

The substance is classified for acute oral toxicity. However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure therefore does not occur.Furthermore, the substance does not have to be classified based on the acute dermal toxicity data. Therefore, no acute DNEL is needed.

Eye irritation

Regarding eye irritation, classification is needed under EU-CLP (not under DSD). The available data do not permit a DNEL derivation. Therefore, a qualitative approach will be applied for eye irritation.

 

 

Skin sensitisation

The substance is not classified for skin sensitisation. Therefore, no DNEL has to be derived.

 

 

Repeated dose toxicity

 

a.      Worker-DNEL long-term dermal, systemic

 

The NOAEL of 40 mg/kg bw/day from the 28-day repeat dose oral study in the rat was taken as dose descriptor. The available dermal data (calculation according to model by Magnusson at al. (2004)) suggest a dermal absorption figure of 8%.

 

The corrected human dermal NAEL = oral NOAEL (rat) x (oral rat absorption/dermal human absorption) = 40 x (1/0.08) = 500 mg/kg bw/day.

 

The DNEL long-term dermal, systemic is calculated by applying assessment factors to the NOAEL. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 72 was calculated using the ECETOC document (2003):

-       Inter-species differences = 4

-       Intra-species differences = 3

-       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

 

Worker-DNEL long-term, dermal, systemic = 500/72 = 7 mg/kg bw/day

 

 

b.     Worker-DNEL long-term inhalation, systemic

 

The NOAEL of 40 mg/kg bw/day from the 28-day repeat dose oral study in the rat was taken as dose descriptor. The NAEC worker (8h) was calculated as prescribed by the guidance:

Corrected inhalatory NAEC = rat oral NOAEL x (1/sRVrat) x (ABSoral rat/human inhal) x (sRVhuman/wRV)

 

-       NAEC = 40 x (1/0.38) x 1 x (6.7/10)

-       NAEC = 40 x 2.63 x 0.67 = 71 mg/m³.

 

The DNEL long-term inhalation, systemic is calculated by applying assessment factors to the NAEC. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 18 was calculated using the ECETOC document (2003):

-       Inter-species differences = 1

-       Intra-species differences = 3

-       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

 

Worker-DNEL long-term inhalation, systemic = 71 mg/m³/18 = 3.9 mg/m³

 

 

Mutagenicity and carcinogenicity

 

The substance is not considered mutagenic. Based on the toxicological profile of the substance, carcinogenicity is not expected.

 

 

Reproduction toxicity

 

The NOAEL for reproduction toxicity was concluded to be 160 mg/kg bw/day (highest dose tested in OECD 421 study). As no adverse reproduction toxic effects were observed at the highest dose tested, a DNEL for reproduction toxicity is not quantifiable.

Nevertheless in case the highest dose of 160 mg/kg bw/day will be used for a DNEL derivation this will not result in a more critical DNEL compared to the DNEL for repeated dose toxicity. Firstly, the NOAEL for reproduction is far above the one for repeated dose toxicity. Secondly, when deriving a DNEL for reproduction from an OECD 421 assay an additional assessment factor of 2 to 5 should be applied. However, as the assessment factor of 6 for exposure duration (conversion from a sub-acute study to a chronic study) is not applicable for deriving a DNEL for reproduction, the extra assessment factor of 2 to 5 for lower sensitivity of the OECD 421 study does not result in a higher overall assessment factor for reproduction toxicity compared to repeated dose toxicity.

 

 

Reference

 

ECETOC (2003).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
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:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
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

Acute toxicity

The substance is classified for acute oral toxicity. However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure therefore does not occur. Furthermore, the substance does not have to be classified based on the acute dermal toxicity data. Therefore, no acute DNEL is needed.

Eye irritation

Regarding eye irritation, classification is needed under EU-CLP (not under DSD). The available data do not permit a DNEL derivation. Therefore, a qualitative approach will be applied for eye irritation.

 

 

Skin sensitisation

The substance is not classified for skin sensitisation. Therefore, no DNEL has to be derived.

 

 

Repeated dose toxicity

 

a.      General population-DNEL long-term oral, systemic

The NOAEL of 40 mg/kg bw/day from the 28-day repeat dose oral study in the rat was taken as dose descriptor.

 

The DNEL (oral) is calculated by applying assessment factors to the NOAEL. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 120 was calculated using the ECETOC document (2003):

-       Inter-species differences = 4

-       Intra-species differences = 5

-       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

 

General population-DNEL long-term, oral, systemic = 40/120 = 0.33 mg/kg bw/day

 

 

b.     General population-DNEL long-term dermal, systemic

The NOAEL of 40 mg/kg bw/day from the 28-day repeat dose oral study in the rat was taken as dose descriptor. The available dermal data (calculation according to model by Magnusson at al. (2004)) suggest a dermal absorption figure of 8%.

 

The corrected human dermal NAEL = oral NOAEL (rat) x (oral rat absorption/dermal human absorption) = 40 x (1/0.08) = 500 mg/kg bw/day.

 

The DNEL (dermal) is calculated by applying assessment factors to the NAEL. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 120 was calculated using the ECETOC document (2003):

-       Inter-species differences = 4

-       Intra-species differences = 5

-       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

 

General population-DNEL long-term, dermal, systemic = 500/120 = 4.2 mg/kg bw/day

 

 

c.      General population-DNEL long-term, inhalation

 

The NOAEL of 40 mg/kg bw/day from the 28-day repeat dose oral study in the rat was taken as dose descriptor. The NAEC general population (24 h) was calculated as prescribed by the guidance:

Corrected inhalatory NAEC = rat oral NOAEL x (1/sRVrat) x (ABS oral rat/inhal human)

 

-       NAEC = 40 x (1/1.15) x 1

-       NAEC = 40 x 0.87 = 35 mg/m³

 

The DNEL (inhalation) is calculated by applying assessment factors to the NAEC. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 30 was calculated using the ECETOC document (2003):

-       Inter-species differences = 1

-       Intra-species differences = 5

-       Exposure duration: Conversion from a sub-acute study to a chronic study = 6

 

General population-DNEL long-term inhalation, systemic = 35 mg/m³/30 = 1.2 mg/m³

 

 

Mutagenicity and carcinogenicity

 

The substance is not considered mutagenic. Based on the toxicological profile of the substance, carcinogenicity is not expected.

 

 

Reproduction toxicity

 

The NOAEL for reproduction toxicity was concluded to be 160 mg/kg bw/day (highest dose tested in OECD 421 study). As no adverse reproduction toxic effects were observed at the highest dose tested, a DNEL for reproduction toxicity is not quantifiable.

Nevertheless in case the highest dose of 160 mg/kg bw/day will be used for a DNEL derivation this will not result in a more critical DNEL compared to the DNEL for repeated dose toxicity. Firstly, the NOAEL for reproduction is far above the one for repeated dose toxicity. Secondly, when deriving a DNEL for reproduction from an OECD 421 assay an additional assessment factor of 2 to 5 should be applied. However, as the assessment factor of 6 for exposure duration (conversion from a sub-acute study to a chronic study) is not applicable for deriving a DNEL for reproduction, the extra assessment factor of 2 to 5 for lower sensitivity of the OECD 421 study does not result in a higher overall assessment factor for reproduction toxicity compared to repeated dose toxicity.

 

 

Reference

 

ECETOC (2003).