4-(4-isopropoxyphenylsulfonyl)phenol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.47 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:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

61.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

For more information please refer to "Additional information".

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 (endpoint).

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:

2.5

Justification:

The default value for interspecies differences is used.

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 repeated dose 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 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:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

70 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see "Additional Information"

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 (endpoint).

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:

2.5

Justification:

The default value for interspecies differences is used.

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 repeated dose 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

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).

1.    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 D-8 in male and female CRL:(WI) BR Wistar rats.D-8 caused no mortality at up to and including 50 mg/kg bw/day in CRL:(WI)BR rats. There were no test-item related clinical signs following administration of D-8 by oral gavage, daily for 90 days. The behaviour and the general condition of the test animals were normal during the study. There was no treatment-related effect on motor activity or in the functional observation battery tests across groups of treated male or female animals and no findings indicative for neurotoxicity were observed. No effects were noted during the ophthalmoscopy evaluation performed on completion of treatment. There were no toxicologically significant changes in body weight, body weight gain or animal feed intake between the control and test item treated groups. Differences were noted in the test item treated groups compared to controls in a few clinical pathology parameters evaluated prior to necropsy (haematology, coagulation, clinical chemistry and/or urinalysis). Although occasionally these changes were statistically significant, no dose related response was observed, the differences were minor and/or there was no consistent reaction in the male and female groups. These changes were not considered toxicologically significant, nor indicated a test item related etiology. There were no macroscopic or microscopic adverse findings, no statistically or toxicologically significant changes in organ weight values or any pathology changes that could be ascribed to test item administration. In conclusion, D-8 administered daily by oral gavage for 90 days in Wistar rats did not lead to any toxicologically adverse effects at dose levels of 5, 10 or 50 mg/kg bw/day. Under the conditions of this study, the no observed effect level (NOEL) for D-8 is 50 mg/kg bw/day. This systemic NOEL of 50 mg/kg bw/day was used for risk assessment purposes (= used as NOAEL).

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 50 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=1.4

Corrected NOAEC (inhalation) for workers:

= 50 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 61.7 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 = 2.47 mg/m³

Acute, systemic DNEL- exposure via inhalation (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 inhalation toxicity. Therefore, a DNEL is not required.

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

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

2.    Dermal

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.

 

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

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

A 90-day oral toxicity study according OECD TG 408 was performed with D-8 in male and female CRL:(WI) BR Wistar rats.

Step 2: Modification into a correct starting point:

Relevant dose descriptor (NOAEL): 50 mg/kg bw/day

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker = 1.4

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

Corrected NOAEL (dermal) for workers:

= 50 mg/kg bw/day x 1 x 1.4

= 70 mg/kg bw/day

Step 3: Overall AF= 100

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

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric

scaling

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF (subchromic to chronic): 2

In conclusion, long term systemic dermal DNEL, workers = 0.7 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, the DNEL is not required.

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

A DNEL long term/acute - local effects is not established because the substance is not classified dangerous 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.

 

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:

DNEL (Derived No Effect Level)

Value:

0.37 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):

50

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

18.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

see "Additional Information"

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 (endpoint).

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:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for "general population" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

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 related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see "Additional Information"

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 (endpoint).

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:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for "general population" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

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 related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

50 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:

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

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:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for "general population" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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

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).

1. Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

Using a conservative approach, a DNEL (long-term inhalation exposure) is derived. This long-term DNEL for the general population is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

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

A 90-day oral toxicity study according OECD TG 408 was performed with D-8 in male and female CRL:(WI) BR Wistar rats. D-8 caused no mortality at up to and including 50 mg/kg bw/day in CRL:(WI)BR rats. There were no test-item related clinical signs following administration of D-8 by oral gavage, daily for 90 days. The behaviour and the general condition of the test animals were normal during the study. There was no treatment-related effect on motor activity or in the functional observation battery tests across groups of treated male or female animals and no findings indicative for neurotoxicity were observed. No effects were noted during the ophthalmoscopy evaluation performed on completion of treatment. There were no toxicologically significant changes in body weight, body weight gain or animal feed intake between the control and test item treated groups. Differences were noted in the test item treated groups compared to controls in a few clinical pathology parameters evaluated prior to necropsy (haematology, coagulation, clinical chemistry and/or urinalysis). Although occasionally these changes were statistically significant, no dose related response was observed, the differences were minor and/or there was no consistent reaction in the male and female groups. These changes were not considered toxicologically significant, nor indicated a test item related etiology. There were no macroscopic or microscopic adverse findings, no statistically or toxicologically significant changes in organ weight values or any pathology changes that could be ascribed to test item administration. In conclusion, D-8 administered daily by oral gavage for 90 days in Wistar rats did not lead to any toxicologically adverse effects at dose levels of 5, 10 or 50 mg/kg bw/day. Under the conditions of this study, the no observed effect level (NOEL) for D-8 is 50 mg/kg bw/day. This systemic NOEL of 50 mg/kg bw/day was used for risk assessment purposes (= used as NOAEL).

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 50 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw

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

Differences experimental/human exposure conditions: 7d/24h rat vs.7d/24h (general population)

Corrected NOAEC (inhalation) for general population:

= 50 mg/kg bw/day× 0.5 × (1 / 1.35 m³/kg bw/24h) x 1

= 18.5 mg/m³

Step 3: Overall AF= 50

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 (general population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

In conclusion, long term systemic inhalation DNEL, general population= 0.37 mg/m³

Acute, systemic DNEL- exposure via inhalation (general population)

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 inhalation toxicity with the LC50 >5000 mg/m³. Therefore, a DNEL is not required.

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

A DNEL acute/long term - local effect is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation (EC) No 1272/2008.

2. Dermal

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

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

A 90-day oral toxicity study according OECD TG 408 was performed with D-8 in male and female CRL:(WI) BR Wistar rats.

Step 2: Modification into a correct starting point:

Relevant dose descriptor (NOAEL): 50 mg/kg bw/day

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

Correction for difference between human and experimental exposure conditions: 7d animal/7d general population

Corrected NOAEL (dermal) for general population:

= 50 mg/kg bw/day

Step 3: Overall AF= 200

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

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

In conclusion, long term systemic dermal DNEL, general population = 0.25 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

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 bw. Therefore, the DNEL is not required.

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

A DNEL acute/long term - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation (EC) No 1272/2008.

Long term, systemic DNEL – exposure by oral route (general population)

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

A 90-day oral toxicity study according OECD TG 408 was performed with D-8 in male and female CRL:(WI) BR Wistar rats.

Step 2: Relevant dose descriptor (NOAEL): 50 mg/kg bw/day

Step 3: Overall AF= 200

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

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

In conclusion, long term systemic oral DNEL, general population= 0.25 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

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 oral toxicity with the LD50 >5000 mg/kg bw. Therefore, a DNEL is not required.

Hazard to the eye-local effects (general population)

The substance is not classified for eye irritation under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) No 2019/521.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization 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 Characterization, Version 3.0, May 2016