Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.6 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):
25
Dose descriptor starting point:
NOAEL
Value:
540 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
666.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

Modification of PoD into a correct starting point:  

 

Relevant dose descriptor (NOAEL): 540 mg/kg bw/day

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

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

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

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

Corrected NOAEC (inhalation) for workers:

= 540 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 666.6 mg/m³

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:
Extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
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 OECD TG 408 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.
AF for remaining uncertainties:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The vapour pressure of the test substance is low (5.9 hPa at 20°C) and exposure via inhalation is unlikely to occur. Furthermore, 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”. Therefore, no DNEL for acute systemic effects is derived as acute inhalation toxicity is expected to be low and does not require classification based on data on acute oral and dermal toxicity.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
7.6 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):
100
Dose descriptor starting point:
NOAEL
Value:
540 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
756 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification of the PoD into a correct starting point:

Relevant dose descriptor (NOAEL): 540 mg/kg bw/day

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

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

 

Corrected NOAEL (dermal) for workers:

= 540 mg/kg bw/day x 1 x 1.4

= 756 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:
2
Justification:
Extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
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 OECD TG 408 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.
AF for remaining uncertainties:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived.

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

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 derived. 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 studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it will be necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation. Human data are not available.

 

Step 1:PoD and most sensitive endpoint: repeated dose toxicity (oral)

 

A 90-day oral toxicity study according OECD TG 408 was performed with the test substance in male and female Wistar rats (BASF, 2019). The no observed adverse effect level (NOAEL) for was set to 540 mg/kg bw/d. This systemic NOAEL is used for risk assessment purposes.

 

Step 2:Modification of PoD into a correct starting point:  

 

Relevant dose descriptor (NOAEL): 540 mg/kg bw/day

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

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

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

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

Corrected NOAEC (inhalation) for workers:

= 540 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 666.6 mg/m³

 

Step 3: Overall AF= 25

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (oral)-to route (inhalation) is applied.

Interspecies AF, remaining differences: no evidence for species differences in the general mode of

action

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

Whole database AF: 1

The repeated dose oral toxicity study was conducted according to modern 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 = 26.6 mg/m3

 

Acute, systemic DNEL- exposure via inhalation (workers)

The vapour pressure of the test substance is low (5.9 hPa at 20°C) and exposure via inhalation is unlikely to occur. Furthermore, 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”. Therefore, no DNEL for acute systemic effects is derived as acute inhalation toxicity is expected to be low and does not require classification based on data on acute oral and dermal toxicity.

 

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

A DNEL for local effect via inhalation is not established because the substance is not classified for skin/eye irritation/corrosion and skin sensitization according to Regulation (EC) No 1272/2008.

 

 

Dermal

 

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

No studies have been undertaken by the dermal route to characterize the dose-response relationship for systemic effects therefore it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

 

Step 1:PoD and most sensitive endpoint: repeated dose toxicity (oral)

A 90-day oral toxicity study according OECD TG 408 was performed with the test substance in male and female Wistar rats (BASF, 2019). The no observed adverse effect level (NOAEL) for was set to 540 mg/kg bw/d. This systemic NOAEL is used for risk assessment purposes.

 

Step 2:Modification of the PoD into a correct starting point:

Relevant dose descriptor (NOAEL): 540 mg/kg bw/day

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

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

 

Corrected NOAEL (dermal) for workers:

= 540 mg/kg bw/day x 1 x 1.4

= 756 mg/kg bw/day

 

Step 3:Overall AF= 100

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 (subchronic to chronic): 2

 

In conclusion, long term systemic dermal DNEL, workers = 7.56 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, DNEL was derived.

 

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

A DNEL for local effects on the skin is not established because the substance is not classified for skin/eye irritation/corrosion and skin sensitization according to Regulation (EC) No 1272/2008.

 

Hazard to the eye- local effects (worker)

The substance is not classified for eye irritation under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776. No hazard assessment it required.

 

 

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:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

No DNELs for general population are derived since exposure to the registered substance can be excluded.