Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.73 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6

Modified dose descriptor starting point:

NOAEC

Value:

4.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to discussion.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (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:

1

Justification:

Substance specific AF (please refer to "Discussion")

AF for intraspecies differences:

3

Justification:

Substance specific AF (please refer to "Discussion")

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.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.42 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by dermal route. For details on calculations please refer to discussion.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (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:

1

Justification:

Substance specific AF (please refer to "Discussion")

AF for intraspecies differences:

3

Justification:

Substance specific AF (please refer to "Discussion")

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.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

no hazard identified

WORKER

General

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Substance specific assessment factor for remaining differences

Although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (Calabrese and Gilbert, 1993).

Furthermore, within the ERASM project, it was suggested that a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batkeet al, 2010; Bitsch et al, 2006). The comparison of rats and mice indicated an interspecies difference of 1.4 for these two species. This corresponds closely to an interspecies AF solely explained by allometry (7:4 = 1.75) without an additional factor of 2.5 for putative toxicodynamic differences.

Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:

In a subchronic gavage study in rats (acc. to OECD TG 415) adverse effects have been observed consisting of decreased foodconsumption and decreased body weight gain. No other adverse test substance-related effects on clinical examinations, clinical pathology and pathology were detected. Reproductive parameters and organs were not affected in the modified one-generation study. Slightly decreased pre-weaning pup body weights/pup weight gain were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects do not occur in the absence of parental toxicity. No toxicologically relevant effects on viability, litter size or sex ratio were noted.

In the key study given above, the nature of effects observed are based on unspecific systemic adverse effects such as reduced food consumption and body weight changes. In order to add sufficient conservatism into the DNEL derivation, namely to cover for the uncertainty of an putative systemically toxic parent compound/metabolite being excreted dependent on the caloric demand, an AF of 4 for allometric scaling is included for oral/ dermal systemic long term DNELs.

No additional AFs covering toxicodynamic differences between rats and humans are considered necessary. In fact, an underestimation of interspecies differences between rats and humans beyond allometric scaling is unlikely due to the favorable toxicological profile of the registered substance.

It needs further to be pointed out, that the multiplicatory principle of different AFs used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a only a classification as skin irritant Cat 2 according to regulation (EU) 1272/2008.

Substance specific assessment factor for intraspecies extrapolation

Studies on the distribution of human data for various toxicokinetic and toxicodynamic parameters were taken into account, including ‘healthy adults’ of both sexes, young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. (Hattis 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998). Using the 95th percentile of the combined distribution of the toxicokinetic and -dynamic variability of datasets is a statistical approach to account for intraspecies variability based on toxicological datasets. On the basis of the above mentioned assessments and statistical approach, an AF of 5 for the general population and AF factor of 3 for the more homogenous worker population can be estimated to account for intraspecies variability.

It needs further to be pointed out, that the multiplicatory principle of AF used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a non-classification according to 67/548/EEC and regulation (EU) 1272/2008.

Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:

In a subchronic gavage study in rats (acc. to OECD TG 415) adverse effects have been observed consisting of decreased foodconsumption and decreased body weight gain. No other adverse test substance-related effects on clinical examinations, clinical pathology and pathology were detected. Reproductive parameters and organs were not affected in the modified one-generation study. Slightly decreased pre-weaning pup body weights/pup weight gain were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects do not occur in the absence of parental toxicity. No toxicologically relevant effects on viability, litter size or sex ratio were noted.

In the key study given above, the nature of effects observed are based on unspecific systemic adverse effects such as reduced food consumption and body weight changes. No human relevant organ specific toxicity is identified for the registered substance, which would justify a conservative default assessment factor for intraspecies variations in toxicokinetics or toxicodynamics. However, an AF of 3 or 5 has been included to cover for remaining uncertainties within a controlled subpopulation, i.e. healthy workers or the general population, respectively.

Workers – Hazard via inhalation route

Long term systemic inhalation DNEL, worker

The DNEL long-term, systemic (inhalation) is derived by route-to route.

Step 1: Selection of the relevant dose descriptor (starting point):

The toxicity to reproduction study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 5 mg/kg bw/day.

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.

Relevant dose descriptor (NOAEL): 5 mg/kg bw/day

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

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

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

Corrected inhalatory NOAEC for workers

= 5 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³)

= 4.4 mg/m³

Step 3: Use of assessment factors: 6

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 1

Intraspecies AF (worker): 3

Exposure duration AF: 2

Remaining uncertainties AF: 1

In conclusion, long-term systemic inhalation DNEL, workers = 0.73 mg/m3

Short term systemic inhalation DNEL, worker

The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Acute/longterm, local effects, inhalation worker

No data on long-term local toxicity after inhalation is available. Data on acute local toxicity after inhalation is available and showed no specific local effects. The substance is not classified for acute inhalation, therefore no adverse effects on the respiratory system are expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL local, long-term and acute (inhalation) is required. In addition DNEL for local effects does also not need to be derived as no eye irritation (leading to classification) and in conclusion no indication of local mucosal membrane damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8).

Workers – Hazard via dermal route

Long term systemic dermal DNEL, worker

The DNEL long-term, systemic (dermal) is derived by route-to route extrapolation.

Step 1: Selection of the relevant dose descriptor (starting point):

The toxicity to reproduction study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 5 mg/kg bw/day.

Step 2: Modification of the starting point:

The logPow of the test substance was determined to be in the range of 4.0 to 4.3. Therefore the dermal uptake is considered to be 50% of the oral uptake. Dermal NOAEL= 50% oral NOAEL = 10 mg/kg bw/day

Step 3: Use of assessment factors: 24

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

Interspecies AF, remaining differences: 1

Intraspecies AF (worker): 3

Exposure duration AF: 2

Remaining uncertainties AF: 1

In conclusion, long term systemic dermal DNEL, workers = 0.42 mg/kg bw/day

Short-term systemic dermal DNEL, worker

The test material is not classified and labelled for acute systemic toxicity (dermal), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Local effects, long and short term dermal exposure, worker

The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E).

Worker – Hazard for the eyes

The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required.

References

(not included as endpoint study record)

- 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 (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2014.

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.22 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

2.17 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to discussion.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

AF for other interspecies differences:

1

Justification:

Substance specific AF (please refer to "Discussion")

AF for intraspecies differences:

5

Justification:

Substance specific AF (please refer to "Discussion")

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.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

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 derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by dermal route. For details on calculations please refer to discussion.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (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:

1

Justification:

Substance specific AF (please refer to "Discussion")

AF for intraspecies differences:

5

Justification:

Substance specific AF (please refer to "Discussion")

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.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation was used as one repeated oral exposure study was available. For details on calculations please refer to discussion.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (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:

1

Justification:

Substance specific AF (please refer to "Discussion")

AF for intraspecies differences:

5

Justification:

Substance specific AF (please refer to "Discussion")

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.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

General Population