Ceraphyl 55

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

49 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC (2003; 2010)

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Value:

882 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation performed as described in ECHA (2008)

AF for dose response relationship:

1

Justification:

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

AF for differences in duration of exposure:

6

Justification:

Default AF for sub-acute to chronic extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

Default AF for oral route (allometric scaling, rat)

AF for other interspecies differences:

1

Justification:

Informed AF for worker population: it is unlikely that the toxicokinetics and toxicodymics of Ceraphyl 55 will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). This is consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

AF for intraspecies differences:

3

Justification:

Informed AF for workers: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

AF for the quality of the whole database:

1

Justification:

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC (2003; 2010)

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal and oral absorbtion assumed to be equivalent at 100% in accordance with ECHA guidance

AF for dose response relationship:

1

Justification:

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

AF for differences in duration of exposure:

6

Justification:

Default AF for sub-acute to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for dermal route (allometric scaling, rat)

AF for other interspecies differences:

1

Justification:

Informed AF for worker population: it is unlikely that the toxicokinetics and toxicodymics of Ceraphyl 55 will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). Use of AF=1 is also consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

AF for intraspecies differences:

3

Justification:

Informed AF for workers: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

AF for the quality of the whole database:

1

Justification:

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

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:

other toxicological threshold

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Where relevant data are available, local and systemic DNELs for worker exposure to Ceraphyl 55 have been developed based on results of animal studies obtained for Ceraphyl 55 and assessment factors (AF) recommended by ECHA (2012: Guidance on Information Requirements and Chemical Safety assessment: chapter R.8 – characterisation of dose [concentration] - response for human health. pp 32, ECHA, Helsinki, November 2012 2010), ECETOC (2003: Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, pp 86, ECETOC, Brussels, February 2003) and ECETOC (2010: Guidance on Assessment Factors to Derive a DNEL. Technical Report No. 110, pp 198, ECETOC, Brussels, October 2010).

Acute toxicity

A DNEL for acute toxicity should be derived if a hazard leading to acute toxicity (e. g. C&L) has been identified and there is a potential for high peak exposures. The TGD notes that such peaks are normally associated with inhalation exposure but are less common for skin contact and ingestion (ECHA, Appendix R.8-8). Results for acute oral and acute dermal toxicity both show LD50 values greater than 2000 mg/kg bwt (i. e. no classification required). The derivation of DNELs for acute toxicity is therefore not appropriate or necessary for Ceraphyl 55.

Irritation

Ceraphyl 55 is not classified as an eye or skin irritant. Results are available from four modern, GLP-compliant, guideline studies that have assessed the skin and eye irritation potential of Ceraphyl 55 in the rabbit. Only minimal, transient dermal response observed. Eye irritation studies showed minimal conjunctival redness that resolved rapidly.

Sensitisation

Results are available for 3 well-conducted mouse local lyph node assays. The laboratory eports do not provide EC3 values but based on Stimulation Index (SI) data presented it is estimated that the EC3 value would fall in the range 10-35%. This would suggest a weak to moderate potential for skin sensitization; this is also supported by a negative Buehler sensitization study in guinea pigs.

Skin sensitization is a local effect. Although the effect is exerted through a threshold mode of action, the available data do not allow reliable identification of a threshold or a definitive assessment of potency. Ceraphyl 55 is classified as a Category 1 sensitiser. As derivation of a DNEL is not possible protective measures will be subject to a qualitative assessment.

Long-term systemic effects

The potential to cause long-term systemic effects can judged from results of a repeated dose, 28-day) oral toxicity study in rats with Ceraphyl 55. For Ceraphyl 55, the following NOAELs are presented in the IUCLID dossier:

sub-acute effects: rat oral NOAEL = 1000 mg/kg bw/day

Oral

Dose descriptor

A rat oral sub-acute NOAEL of 1000 mg/kg bw/d will be used with appropriate modification to derive an oral DNEL for Ceraphyl 55. No additional correction of the animal NOAEL is required.

In the absence of information to the contrary it is assumed that oral uptake and dermal uptake are identical (ECHA, Section R.8.4.2, Ad2).

DNELworker-oral = 1000 / 72 = 14 mg/kg bw/d

Dermal

Dose descriptor

A rat oral sub-acute NOAEL of 1000 mg/kg bwt/d will be used with appropriate modification to derive a dermal DNEL for Ceraphyl 55.

Modification of dose descriptor: No additional correction of the animal NOAEL is required.

In the absence of information to the contrary it is assumed that oral uptake and dermal uptake are identical (ECHA, Section R.8.4.2, Ad2).

For workers, no modification of the NOAEL is required.

DNELworker-dermal = 1000 / 72 = 14 mg/kg bw/d

Inhalation

Dose descriptor

A rat oral NOAEL of 1000 mg/kg bwt/d will be used with appropriate modification to derive an inhalation DNEL for Ceraphyl 55

Modification of dose descriptor. No additional correction of the animal NOAEL is required.

In the absence of data to the contrary, it has been assumed that the extent of inhalation uptake Ceraphyl 55 is double that following oral exposure (ECHA, Section R.8.4.2, Ad2).

The corrected inhalatory NOAEC is calculated as follows:

NOAECinhalation = NOAELoral x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 1000 x 1/0.38 x 1/2 x 6.7/10

Corrected inhalation NOAECworker = 882 mg/m3

DNELworker-inhalation = 882 / 18 = 49 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC (2003; 2010)

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Value:

882 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor.In the absence of data to the contrary, it has been assumed that the extent of inhalation uptake Ceraphyl 55 is double that following oral exposure (ECHA, Section R.8.4.2, Ad2).

AF for dose response relationship:

1

Justification:

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

AF for differences in duration of exposure:

6

Justification:

Default AF for sub-acute to chronic extrapolation

AF for interspecies differences (allometric scaling):

5

Justification:

Informed AF for general population: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

AF for other interspecies differences:

1

Justification:

Informed AF for general populationpopulation: it is unlikely that the toxicokinetics and toxicodymics of this substance will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). This is consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

AF for intraspecies differences:

1

Justification:

Default AF for inhalation route (no allometric scaling necessary)

AF for the quality of the whole database:

1

Justification:

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

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:

8.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC (2003; 2010)

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal and oral absorbtion assumed to be equivalent at 100% in accordance with ECHA guidance

AF for dose response relationship:

1

Justification:

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

AF for differences in duration of exposure:

6

Justification:

Default AF for sub-acute to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for dermal route (allometric scaling, rat)

AF for other interspecies differences:

1

Justification:

Informed AF for general population: it is unlikely that the toxicokinetics and toxicodymics of Ceraphyl 55 will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). Use of AF=1 is also consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

AF for intraspecies differences:

5

Justification:

Informed AF for general population: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

AF for the quality of the whole database:

1

Justification:

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

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:

other toxicological threshold

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Dose descriptor starting point:

other: Experimental data insufficient to define potency and/or a reliable dose descriptor

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC (2003; 2010)

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No additional correction of the animal NOAEL is required.

AF for dose response relationship:

1

Justification:

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

AF for differences in duration of exposure:

6

Justification:

Default AF for sub-acute to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for dermal route (allometric scaling, rat)

AF for other interspecies differences:

1

Justification:

Informed AF for general population: it is unlikely that the toxicokinetics and toxicodymics of Ceraphyl 55 will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). Use of AF=1 is also consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

AF for intraspecies differences:

5

Justification:

Informed AF for general population: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

AF for the quality of the whole database:

1

Justification:

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

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

Discussion

Where relevant data are available, local and systemic DNELs for worker exposure to Ceraphyl 55 have been developed based on results of experimental studies with  Ceraphyl 55 and use of assessment factors (AF) recommended by ECHA (2012: Guidance on Information Requirements and Chemical Safety assessment: chapter R.8 – characterisation of dose [concentration] - response for human health. pp 32, ECHA, Helsinki, December 2012), ECETOC (2003: Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, pp 86, ECETOC, Brussels, February 2003) and ECETOC (2010: Guidance on Assessment Factors to Derive a DNEL. Technical Report No. 110, pp 198, ECETOC, Brussels, October 2010).

Acute toxicity

A DNEL for acute toxicity should be derived if a hazard leading to acute toxicity (e. g. hazard classification under CLP) has been identified and there is a potential for high peak exposures. The TGD notes that such peaks are normally associated with inhalation exposure but are less common for skin contact and ingestion (ECHA, Appendix R.8-8). Results for acute oral and acute dermal toxicity both give LD50 values greater than 2000 mg/kg bwt (i. e. no classification required).

The derivation of DNELs for acute toxicity is therefore not appropriate or necessary for Ceraphyl 55.

Irritation

Ceraphyl 55 is not classified as an eye or skin irritant. Results are available from four modern, GLP-compliant, guideline studies that have assessed the skin and eye irritation potential of Ceraphyl 55 in the rabbit.Only minimal, transient dermal response observed. Eye irritation studies showed minimal conjunctival redness that resolved rapidly.

Sensitisation

Results are available for 3 well-conducted mouse local lyph node assays. The laboratory eports do not provide EC3 values but based on Stimulation Index (SI) data presented it is estimated that the EC3 value would fall in the range 10-35%. This would suggest a weak to moderate potential for skin sensitization; this is also supported by a negative Buehler sensitization study in guinea pigs.

Skin sensitization is a local effect. Although the effect is exerted through a threshold mode of action, the available data do not allow reliable identification of a threshold or a definitive assessment of potency. Ceraphyl 55 is classified as a Category 1 sensitiser. As derivation of a DNEL is not possible protective measures will be subject to a qualitative assessment

Long-term systemic effects

The potential to cause long-term systemic effects can judged from results of repeated dose (28-day) oral toxicity study with Ceraphyl 55. For Ceraphyl 55, the following NOAELs are presented in the IUCLID dossier:

sub-acute effects: rat oral NOAEL = 1000 mg/kg bwt/day

Oral

Dose descriptor

A rat oral sub-acute NOAEL of 1000 mg/kg bw/d will be used with appropriate modification to derive an oral dermal DNEL for Ceraphyl 55.

Modification of dose descriptor: No additional correction of the animal NOAEL is required.

For the general population, no modification of the NOAEL is required.

DNELgeneral population-oral = 1000 / 120 = 8.3 mg/kg bwt/d

Dermal

Dose descriptor

A rat oral sub-acute NOAEL of 1000 mg/kg bw/d will be used with appropriate modification to derive a dermal DNEL for Ceraphyl 55.

Modification of dose descriptor: No additional correction of the animal NOAEL is required.

In the absence of information to the contrary it is assumed that oral uptake and dermal uptake are identical (ECHA, Section R.8.4.2, Ad2).

For workers, no modification of the NOAEL is required.

DNELgeneral population-dermal = 1000 / 120 = 8.3 mg/kg bwt/d

Inhalation

Dose descriptor

A rat oral NOAEL of 1000 mg/kg bw/d will be used with appropriate modification to derive an inhalation DNEL for Ceraphyl 55

Modification of dose descriptor.In the absence of data to the contrary, it has been assumed that the extent of inhalation uptake Ceraphyl 55 is double that following oral exposure (ECHA, Section R.8.4.2, Ad2).

The corrected inhalatory NOAEC is calculated as follows:

NOAECinhalation = NOAELoral x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 1000 x 1/0.38 x 1/2 x 6.7/10

Corrected inhalation NOAECworker = 882 mg/m3

DNELgeneral population-inhalation = 882 / 30 = 29 mg/m3