Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.042 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
150
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:
0.24 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
2.5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
2.5

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

No acute – systemic or local dermal effects DNELs were calculated based on a lack of observed effects. A DNEL was not derived for acute – systemic inhalation effects based on a lack of observed effects. A DNEL was not derived for long-term local dermal effects based on a lack of observed effects.

 

Inhalation local effects –inhalation DNELs are needed due to the effects of respirable particulate observed in acute and repeated-dose inhalation studies where the test material is aerosolized. In certain use scenarios, workers in particular have the potential to be exposed to respirable particulate. In an acute 4-hr inhalation study on male and female rats, the NOAEC for histopathological effects in the respiratory tract (lesions of the larynx) was 1.0 mg/m3 for the actual test substance. In a 14-day repeated-exposure study the NOAEC for very similar effects was 1.2 mg a.i./m3 (total solids) for male and female rats based on the minimal inflammation and minimal to mild mineralization of the U-shaped cartilage in the animals exposed to 5.2 mg/m3 (total solids). Two sets of calculations are needed for acute and chronic local inhalation effects.

 

In an oral 90-day subchronic study in rats a NOAEL not determined for Zonyl (see attached ARF document for justification of read-across) in male rats due to observations of liver necrosis at all doses (10, 60, and 300 mg/kg BW/day). The NOAEL for female rats was 60 mg/kg bw/day based on liver enzyme elevations and thyroid hypertrophy. Only minimal focal hepatocellular necrosis was observed in male rats administered 10 and 60 mg/kg/day after 90 days of exposure and in male rats given 60 mg/kg/day after three months recovery. Minimal focal hepatocellular necrosis is considered a very light lesion and not indicative of compromised liver function or overt toxicity. Accordingly, the LOAEL (NAEL approach used) of 10 mg/kg bw/day was used as the basis for derivation of the inhalation long-term - systemic endpoint DNEL. Since the test material was 35.5% solids the adjusted departure point is therefore 3.6 a.i. mg/kg bw/day.

 

In a 28-day dermal toxicity study in male rats, a NOAEL of 1000 mg/kg bw/day was observed based on only mild liver effects (increased ALT, AST, and Alk Phos), which were not statistically significant at this dose. The NOAEL 1000 mg/kg bw/day was used in the derivation of the dermal long-term systemic DNEL. Since the test material was 35.5% solids the adjusted departure point is therefore 357 mg a.i./kg bw/day.

 

 

The DNEL for acute local effects inhalation exposure was derived as follows.

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: NOAEC (corrected): 0.67 mg/m m3

Remark: The NOAEC in a 4-hour inhalation study in rats of 1.0 mg/m3was based on histopathologic findings (ulceration of the larynx). The NOEAC was corrected for respiratory volume (resting to active) (6.7 m3/10m3= 0.67). The corrected dose descriptor is 0.67 mg/m m3.

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 1

Remark: This is an inhalation-to-inhalation DNEL. A default factor of 1 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 1

Remark: No allometric scaling per REACH Guidance R.8.4.3.1.

 

Step 4)

Description: Assessment factor ─ Other Interspecies Differences

Value: 1

Remark: A default assessment factor of 1 is to be used, based on simple local destruction of membranes seen in the in the acute inhalation study in rats. A default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 2.5

Remark: An assessment factor of 2.5 is to be used, based on local destruction of membranes with little variability in sensitivity among human workers for respiratory effects. A factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 1

Remark: No exposure duration extrapolation is appropriate (acute to acute).

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 1

Remark: When the starting point for the DNEL calculation is a NOAEC, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: The quality database for this substance demonstrates a consistent target organ and dose range across several studies.

 

Description: DNEL acute - local inhalation exposure

Value: 0.3 mg/m³

Remark: 0.67 mg/m³ ÷ (1 × 1 × 1 × 2.5 × 1 × 1 × 1) = 0.3 mg/m³

 

 

The DNEL for long-term – systemic effects dermal exposure was derived as follows.

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: NOAEL (corrected): 357 mg a.i./kg bw/day.

Remark: The NOAEL 1000 mg/kg bw/day from a 28-day dermal toxicity study in male rats was used in the derivation of the dermal long-term systemic DNEL. Since the test material was 35.5% solids the adjusted departure point is therefore 357 mg a.i./kg bw/day.

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 1

Remark: This is dermal-to-dermal DNEL. A default factor of 1 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 4

Remark: Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 4)

Description: Assessment factor ─ Other Interspecies Differences

Value: 2.5

Remark: The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences.A default factor of 2.5 is appropriate based on no mechanistic data to indicate a relationship between metabolism and liver injury for rat to human extrapolation.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 5

Remark: For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill. A default factor of 5 is appropriate per REACH Guidance R.8.4.3.3.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 6

Remark: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The NOAEL (357 mg a.i./kg bw/day) is based on a 28-day rat study (sub-acute) and a default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 1

Remark: When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: Surrogate data is used, but the test substance is 50% of actual notified substance with remainder higher chain length distribution. Therefore, an assessment factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Description: DNEL long-term - systemic effects dermal exposure

Value: 1.2 mg/kg/day

Remark: 357 mg/kg/day ÷ (1 × 4 × 2.5 × 5 × 6 × 1× 1) = 1.2 mg/kg/day

 

 

The DNEL for long-term – systemic effects inhalation exposure was derived as follows.

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: LOAEL (corrected): 6.347 mg/ m3

Remark: The LOAEL of 10 mg/kg bw/day from a 90-day subchronic oral study in rats with Zonyl was used as the basis for derivation of the inhalation long-term - systemic endpoint DNEL. Since the test material was 35.5% solids the value is therefore 3.6 a.i. mg/kg bw/day.

Inhalation corrections:

3.6 mg/kg bw/day ÷ 0.38 m3/kg bw = 9.47 mg/ m3

9.47 mg/ m38 h * 0.67 m3= 6.347 mg/ m3

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 2

Remark: According to REACH Guidance (R.8.4.2), in the case of oral-to-inhalation extrapolation, and in the absence of route-specific information on the starting route, a default factor of 2 should be included (i.e. the absorption percentage for the starting route is half that of the end route). The inclusion of factor of 2 means that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. A default factor of 2 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 1

Remark: Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. Modification of the starting point (oral NOAEL to an inhalation equivalent) has already accounted for allometric scaling (animal to human). Therefore, a factor of 1 is appropriate.

 

Step 4)

Description: Assessment factor ─ Other Interspecies Differences

Value: 2.5

Remark: The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences.A default factor of 2.5 is appropriate based on no mechanistic data to indicate a relationship between metabolism and liver injury for rat to human extrapolation.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 5

Remark: For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill. A default factor of 5 is appropriate per REACH Guidance R.8.4.3.3.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 2

Remark: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The LOAEL is based on a 90-day subchronic oral study in rats and a default factor of 2 (subchronic to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 3

Remark: : The LOAEL (corrected) of 6.347 mg/ m3was extrapolated from the LOAEL of 10 mg/kg bw/day (liver necrosis) in a 90-day subchronic oral study in rats. A default factor of 3 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: Surrogate data is used, but the test substance is 50% of actual notified substance with remainder higher chain length distribution. Therefore, an assessment factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Description: DNEL long-term - systemic effects inhalation exposure

Value: 0.042 mg/m3day

Remark: 6.347 mg/ m3/day ÷ (2 × 1 × 2.5 × 5 × 2 × 3× 1) = 0.042 mg/m3/day

 

 

The DNEL for long-term local effects inhalation exposure was derived as follows.

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: NOAEC (corrected): 0.6 mg/m3

Remark: The NOAEC in a 14-day inhalation study in rats of 1.2 mg/m3was based on histopathologic findings (minimal inflammation and minimal to mild ulceration of the U-shaped cartilage). The NOEAC was corrected for respiratory volume (resting to active) (6.7 m3/10m3= 0.67) and for 6 hour rat exposure vs 8 hour work exposure = 0.75 = 0.5 correction factor. The corrected dose descriptor = 1.2 mg/ m3÷ 2 (correction factor) = 0.6 mg/m3.

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 1

Remark: This is an inhalation-to-inhalation DNEL. A default factor of 1 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 1

Remark: No allometric scaling per REACH Guidance R.8.4.3.1.

 

Step 4)

Description: Assessment factor ─ Other Interspecies Differences

Value: 1

Remark: A default assessment factor of 1 is to be used, based on simple local destruction of membranes seen in the in the 14-day inhalation study in rats. A default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 2.5

Remark: An assessment factor of 2.5 is to be used, based on local destruction of membranes with little variability in sensitivity among human workers for respiratory effects. A factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 1

Remark: An assessment factor of 1 was selected based on the rationale that since the experimental NOAEC did not decrease with increasing exposure times for the local effect of simple destruction of membranes, a more conservative AF was not appropriate in this case. The NOAEC is based on a 14-day rat study (subacute) and a default factor of a 1 (subacute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 1

Remark: When the starting point for the DNEL calculation is a NOAEC, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: The quality database for this substance demonstrates a consistent target organ and dose range across several studies.

 

Description: DNEL long-term - locals effects inhalation

Value: 0.24 mg/m³

Remark: 0.6 mg/m³ ÷ (1 × 1 × 1 × 2.5 × 1 × 1 × 1) = 0.24 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
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:
0.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
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:
0.006 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

No acute – systemic or local effects DNELs were calculated based on a lack of observed effects. No long-term local effects dermal DNEL was calculated as no local effects were observed in any study. No long-term local effects inhalation DNEL was calculated as no exposure scenario was indicated for this risk assessment which required it.

 

In a 28-day dermal toxicity study in male rats, a NOAEL of 1000 mg/kg BW/day was observed based on only mild liver effects (increased ALT, AST, and Alk Phos), which were not statistically significant at this dose. The NOAEL 1000 mg/kg BW/day was used in the derivation of the dermal long-term systemic DNEL. Since the test material was 35.5% solids the adjusted departure point is therefore 357 mg a.i./kg BW/day.

 

In an oral 90-day subchronic study in rats a NOAEL not determined for Zonyl (see attached ARF document for justification of read-across) in male rats due to observations of liver necrosis at all doses (0, 10, 60, and 300 mg/kg bw/day). The NOAEL for female rats was 60 mg/kg BW/day based on liver enzyme elevations and thyroid hypertrophy. Only minimal focal hepatocellular necrosis was observed in male rats administered 10 and 60 mg/kg/day after 90 days of exposure and in male rats given 60 mg/kg/day after three months recovery. Minimal focal hepatocellular necrosis is considered a very light lesion and not indicative of compromised liver function. Accordingly, the LOAEL of 10 mg/kg bw/day was used as the basis for derivation of the oral systemic endpoints DNELs. Since the test material was 35.5% solids the adjusted departure point is therefore 3.6 a.i. mg/kg bw/day for assessment of this endpoint for the general public/consumers.

 

 

The DNEL for long-term – systemic effects dermal exposure was derived as follows

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: NOAEL (corrected): 357 mg a.i./kg bw/day.

Remark: The NOAEL 1000 mg/kg bw/day from a 28-day dermal toxicity study in male rats was used in the derivation of the dermal long-term systemic DNEL. Since the test material was 35.5% solids the adjusted departure point is therefore 357 mg a.i./kg bw/day.

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 1

Remark: This is dermal-to-dermal DNEL. A default factor of 1 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 4

Remark: Allomethric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 4)

Description: Assessment factor ─ Other Interspecies Differences

Value: 2.5

Remark: The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences.A default factor of 2.5 is appropriate based on no mechanistic data to indicate a relationship between metabolism and liver injury for rat to human extrapolation.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 10

Remark: A default assessment factor of 10 is sufficient to protect the larger part of the population, including children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 6

Remark: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The NOAEL (357 mg a.i./kg bw/day) is based on a 28-day rat study (sub-acute) and a default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 1

Remark: When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: Surrogate data is used, but the test substance is 50% of actual notified substance with remainder higher chain length distribution. Therefore, an assessment factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Description: DNEL long-term - systemic effects dermal exposure

Value: 0.6 mg/kg/day

Remark: 357 mg/kg/day ÷ (1 × 4 × 2.5 × 10 × 6 × 1× 1) = 0.6 mg/kg/day

 

 

The DNEL for long-term – systemic effects inhalation exposure was derived as follows.

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: LOAEL (corrected): 3.130 mg/ m3

Remark: The LOAEL of 10 mg/kg bw/day from a 90-day subchronic oral study in rats with Zonyl was used as the basis for derivation of the inhalation long-term - systemic endpoint DNEL. Since the test material was 35.5% solids the value is therefore 3.6 a.i. mg/kg bw/day.

Inhalation corrections:

3.6 mg/kg bw/day ÷ 1.15 m3/kg bw = 3.130 mg/ m3

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 2

Remark: According to REACH Guidance (R.8.4.2), in the case of oral-to-inhalation extrapolation, and in the absence of route-specific information on the starting route, a default factor of 2 should be included (i.e. the absorption percentage for the starting route is half that of the end route). The inclusion of factor of 2 means that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. A default factor of 2 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 1

Remark: Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. Modification of the starting point (oral NOAEL to an inhalation equivalent) has already accounted for allometric scaling (animal to human). Therefore, a factor of 1 is appropriate.

 

Step 4)

Description: Assessment factor ─ Other Interspecies Differences

Value: 2.5

Remark: The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences.A default factor of 2.5 is appropriate based on no mechanistic data to indicate a relationship between metabolism and liver injury for rat to human extrapolation.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 10

Remark: A default assessment factor of 10 is sufficient to protect the larger part of the population, including children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 2

Remark: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The LOAEL is based on a 90-day subchronic oral study in rats and a default factor of 2 (subchronic to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 3

Remark: : The LOAEL (corrected) of 6.347 mg/ m3was extrapolated from the LOAEL of 10 mg/kg bw/day (liver necrosis) in a 90-day subchronic oral study in rats. A default factor of 3 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: Surrogate data is used, but the test substance is 50% of actual notified substance with remainder higher chain length distribution. Therefore, an assessment factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Description: DNEL long-term - systemic effects inhalation exposure

Value: 0.0104 mg/m3day

Remark: 3.130 mg/ m3/day ÷ (2 × 1 × 2.5 × 10 × 2 × 3× 1) = 0.01 mg/m3/day

 

 

The DNEL for long-term – systemic effects oral exposure was derived as follows.

 

Step 1)

Description: Relevant dose-descriptor, modification of the starting point.

Value: LOAEL (corrected): 3.6 a.i. mg/kg bw/day

Remark: The LOAEL of 10 mg/kg bw/day from a 90-day subchronic oral study in rats with Zonyl was used as the basis for derivation of the inhalation long-term - systemic endpoint DNEL. Since the test material was 35.5% solids the value is therefore 3.6 a.i. mg/kg bw/day.

 

Step 2)

Description: Assessment factor ─ Route to Route Extrapolation

Value: 1

Remark: This is an oral-to-oral DNEL. A default factor of 1 is appropriate per REACH Guidance R.8.4.2.

 

Step 3)

Description: Assessment factor ─ Allometric Scaling Factor – Animal to Human

Value: 4

Remark: Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 4)

Description: Assessment factor – Intraspecies Differences

Value: 2.5

Remark: A default assessment factor of 2.5 is to be used, based on local destruction of membranes with little variability in sensitivity among consumers for respiratory effects. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 5)

Description: Assessment factor – Intraspecies Variability

Value: 10

Remark: A default assessment factor of 10 is sufficient to protect the larger part of the population, including children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 6)

Description: Assessment factor ─ Duration Extrapolation

Value: 2

Remark: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The LOAEL is based on a 90-day subchronic oral study in rats and a default factor of 2 (subchronic to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.

 

Step 7)

Description: Assessment factor ─ Dose Response

Value: 3

Remark: The LOAEL (corrected) 3.6 a.i. mg/kg bw/day was extrapolated from the LOAEL of 10 mg/kg bw/day (liver necrosis) in a 90-day subchronic oral study in rats. A default factor of 3 is appropriate per REACH Guidance R.8.4.3.1.

 

Step 8)

Description: Assessment factor ─ Quality Database

Value: 1

Remark: Surrogate data is used, but the test substance is 50% of actual notified substance with remainder higher chain length distribution. Therefore, an assessment factor of 1 is appropriate per REACH Guidance R.8.4.3.1.

 

Description: DNEL for long-term – systemic effects oral exposure

Value: 0.006 mgkg bw/day

Remark: 3.6 mg/kg/day ÷ (1 × 4 × 2.5 × 10 × 2 × 3 × 1) = 0.006 mg/kg bw/day