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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
176 mg/m³
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:
10 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
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

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, 4,4'-sulphonyldiphenol displays low acute toxicity as evidenced by an LD50 value of 2830 mg/kg bw determined in rats for the oral route. A weight of evidence for the dermal route of exposure is indicating a similar low acute toxicity with a LD50 value well above 2000 mg/kg bw. No experimental data for the inhalation route is available.

Therefore, 4,4'-sulphonyldiphenol is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation No 1272/2008, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

 

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, 4,4'-sulphonyldiphenol is not subject to classification for skin, eye and/or respiratory irritation and no worker DNEL for local effects following acute/short-term or long-term exposure is derived. In addition no skin sensitizing properties were observed.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health".

 

Long-term exposure - systemic effects

All three available oral repeated dose toxicity studies with rats well reflect common features of toxicity (see repeated dose toxicity: oral). Effect levels (LOAELs) were consistently at or above 200 mg/kg bw. The study with the longest exposure (sub-chronic, 90 day) is regarded as the most relevant study to derive a point of departure (NOAEL) for human health risk assessment.

In this study 4,4´-sulphonyldiphenol was administered by gavage to groups of 10 male and 10 female Wistar rats at dose levels of 0, 100, 300 and 1000 mg/kg bw/d (BASF SE, 2014). Due to a severely impaired body weight development in male animals of the high dose group, i.e. -20% on study day 63, the male animals were treated at a dose level of 600 mg/kg bw/d from study day 70 onwards. Female animals were continuously treated at the limit dose. 100mg/kg bw was identified as an overall NOAEL based on an adverse decrease in male body weights and histopathological lesions in the mammary gland observed in male animals of the mid dose group (300 mg/kg bw).

 

Adaptation of the starting point - inhalation:

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)

with:

oral NO(A)EL: 100 mg/kg bw/day (from subchronic study, see above)

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human], high rates of bioavailability via the lung can e.g occur for substances which can penetrate into the lower/alveolar region and well solubilize in the bonchioalveolar fluid. 4,4´-sulphonyldiphenol is a solid granula with a rather low solubility and only a minor share of the particles is in the respirable range (e.g. <4µm). Larger particles deposit in the upper/thoracic region of the respiratory tract in which an effective retrograde mucocilliary transport exists (see toxicokinetics). This is justifying a very conservative deviation from the ECHA guidance factor of 0.5 by anticipating an equal bioavailability in the respiratory- in comparison to the gastrointestinal- tract.

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

 

Accordingly, the oral NO(A)EL of 100 mg/kg bw/day is transformed in an inhalation NO(A)EC of 176 mg/m³.

                     

The following assessment factors are used for the derivation the worker DNEL for inhalation exposure to 4,4'-Sulfonyldiphenol:

Interspecies factor (rat to human): 1 (external concentration)

Remaining differences: 2.5

Intraspecies factor (worker): 5

Exposure duration factor: 2 (subchronic to chronic)

Dose-response factor: 1

Quality of whole database factor: 1

 

The resulting worker DNEL inhalation is:

worker DNEL (inhalation exposure) = 176 mg/m³ / (2.5 x 5 × 2 × 1 × 1) = 7 mg/m³

As indicated this DNEL is refering to the systemic toxicity of 4,4'-Sulfonyldiphenol. Since the neat substance is a granular solid a potential impairment of the respiratory tract due to exposure to the dust additionally needs to be taken into account. E.g. the German Committee for Dangerous Substances derived a general limit value for low soluble dusts of 1.5 mg/m3 for the alveolar and 10 mg/m3 for the inhalable fraction.

 

Adaptation of the starting point - dermal:

In order to derive a worker DNEL a worst case dermal absorption rate of 50 % is assumed for 4,4'-Sulfonyldiphenol based on physico/chemical data (solid, low log Pow of 1.2, water solubility of 1.1 g/L; see toxicokinetics). This leads to a NOAEL dermal of 200 mg/kg bw/day.

 

The following assessment factors are used for the derivation the worker DNEL for dermal exposure to 4,4'-Sulfonyldiphenol:

Interspecies factor (rat to human): 4

Remaining differences: 2.5

Intraspecies factor (worker): 5

Exposure duration factor: 2 (subchronic to chronic)

Dose-response factor: 1

Quality of whole database factor: 1

worker DNEL (dermal exposure) = 200 mg/kg bw/day / (4 x 2.5 × 5 × 2 × 1 × 1) = 20 mg/kg bw/day.

 

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health".

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
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:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
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:
0.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
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

Acute/short-term exposure - systemic effects 

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, 4,4'-sulphonyldiphenol displays low acute toxicity as evidenced by an LD50 value of 2830 mg/kg bw determined in rats for the oral route. A weight of evidence for the dermal route of exposure is indicating a similar low acute toxicity with a LD50 value well above 2000 mg/kg bw. No experimental data for the inhalation route is available.

Therefore, 4,4'-sulphonyldiphenol is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation No 1272/2008, and consequently the derivation of general population DNELs for acute/short-term exposure - systemic effects is not required.

 

 

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, 4,4'-sulphonyldiphenol is not subject to classification for skin, eye and/or respiratory irritation and no general population DNEL for local effects following acute/short-term or long-term exposure is derived. In addition no skin sensitizing properties were observed.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health".

 

 

Long-term exposure - systemic effects

All three available oral repeated dose toxicity studies with rats well reflect common features of toxicity (see repeated dose toxicity: oral). Effect levels (LOAELs) were consistently at or above 200 mg/kg bw. The study with the longest exposure (sub-chronic, 90 day) is regarded as the most relevant study to derive a point of departure (NOAEL) for human health risk assessment.

In this study 4,4´-sulphonyldiphenol was administered by gavage to groups of 10 male and 10 female Wistar rats at dose levels of 0, 100, 300 and 1000 mg/kg bw/d (BASF SE, 2014). Due to a severely impaired body weight development in male animals of the high dose group, i.e. -20% on study day 63, the male animals were treated at a dose level of 600 mg/kg bw/d from study day 70 onwards. Female animals were continuously treated at the limit dose. 100mg/kg bw was identified as an overall NOAEL based on an adverse decrease in male body weights and histopathological lesions in the mammary gland observed in male animals of the mid dose group (300 mg/kg bw).

 

Adaptation of the starting point - inhalation:

In order to derive a general population DNEL and under the assumption of a daily exposure period of 24 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human)

with:

oral NO(A)EL: 100 mg/kg bw/day (from subchronic study, see above)

sRV(rat): 1.15 m³/kg bw (24 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

High rates of bioavailability via the lung can e.g occur for substances which can penetrate into the lower/alveolar region and well solubilize in the bonchioalveolar fluid. 4,4´-sulphonyldiphenol is a solid granula with a rather low solubility and only a minor share of the particles is in the respirable range (e.g. <4µm). Larger particles deposit in the upper/thoracic region of the respiratory tract in which an effective retrograde mucocilliary transport exists (see toxicokinetics). This is justifying a very conservative deviation from the ECHA guidance factor of 0.5 by anticipating an equal bioavailability in the respiratory- in comparison to the gastrointestinal- tract.

 

Accordingly, the oral NO(A)EL of 100 mg/kg bw/day is transformed in an inhalation NO(A)EC of 87 mg/m³.

                     

The following assessment factors are used for the derivation the general population DNEL for inhalation exposure to 4,4'-Sulfonyldiphenol:

Interspecies factor (rat to human): 1 (external concentration)

Remaining differences: 2.5

Intraspecies factor (general population): 10

Exposure duration factor: 2 (subchronic to chronic)

Dose-response factor: 1

Quality of whole database factor: 1

 

The resulting general population DNEL inhalation is:

General population DNEL (inhalation exposure) = 87 mg/m³ / (2.5 x 10 × 2 × 1 × 1) = 1.7 mg/m³

 

Adaptation of the starting point - dermal:

In order to derive a general population DNEL a worst case dermal absorption rate of 50 % is assumed for 4,4'-Sulfonyldiphenol based on physico/chemical data (solid, low log Pow of 1.2, water solubility of 1.1 g/L; see toxicokinetics). This leads to a NOAEL dermal of 200 mg/kg bw/day.

 

The following assessment factors are used for the derivation the general population DNEL for dermal and oral exposure to 4,4'-Sulfonyldiphenol:

Interspecies factor (rat to human): 4

Remaining differences: 2.5

Intraspecies factor (general population): 10

Exposure duration factor: 2 (subchronic to chronic)

Dose-response factor: 1

Quality of whole database factor: 1

general population DNEL (dermal exposure) = 200 mg/kg bw/day / (4 x 2.5 × 10 × 2 × 1 × 1) = 1 mg/kg bw/day.

general population DNEL (oral exposure) = 100 mg/kg bw/day / (4 x 2.5 × 10 × 2 × 1 × 1) = 0.5 mg/kg bw/day.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health".