Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.56 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
28.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
Key 90-day oral toxicity study available; no repeated dose inhalation toxicity study available.
AF for dose response relationship:
1
Justification:
Clear NOAEL
AF for differences in duration of exposure:
2
Justification:
ECHA default for subchronic studies
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already applied in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECHA default
AF for the quality of the whole database:
1
Justification:
Based on high reliability study
AF for remaining uncertainties:
2
Justification:
Correction for route (in absence of data, inhalation is twice oral absorption)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
40 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Key 90-day oral toxicity study available; no repeated dose dermal toxicity study available.
AF for dose response relationship:
1
Justification:
Clear NOAEL
AF for differences in duration of exposure:
2
Justification:
ECHA default for subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECHA default
AF for the quality of the whole database:
1
Justification:
Based on high reliability study
AF for remaining uncertainties:
1
Justification:
Oral and dermal absorption considered to be worst case the same
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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

The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD rat was estimated to be in the range of 300 - 500 mg/kg bodyweight.Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were ataxia, hunched posture, lethargy, ptosis, decreased respiratory rate, laboured and gasping respiration, loss of righting reflex, exophthalmos, hypothermia and dehydration. Two animals treated with 2000 mg/kg were found comatose. No signs of systemic toxicity were noted in animals treated at a dose level of 200 mg/kg. The dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg bodyweight.

Test material was not irritating on skin and eye (Guidelines in Commission Directive 93/21/EEC), therefore diphenyl sulphone (DPS) does not have to be classified and has no obligatory labelling requirement for skin and eye irritation.

There was no evidence that diphenyl sulphone had caused skin hypersensitivity in the guinea pig, since no responses were observed in the experimental animals in the challenge phase. This result indicated a sensitation rate of 0%. Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC), diphenyl sulphone does not have to be classified and has no obligatory labelling requirement for sensitation by skin contact.

Sprague Dawley rats of received diets containing 100, 200 or 2000 ppm diphenyl sulphone for a period of 13 weeks, corresponding to mean test article intake values of 8, 16 and 164 mg/kg bw/day in males and 9, 19 and 206 mg/kg bw/day in females, respectively. NOEL was 100 ppm (8-9 mg/kg bw/day) and NOAEL was considered to be 200 ppm (16-19 mg/kg bw/day). Adaptive changes were seen at 200 ppm, as demonstrated by increased liver weights and cellular hypertrophy, whereas toxicological changes were seen at 2000 ppm (corresponding wiht 164 and 206 mg/kg bw/day) as demonstrated by changes in body weight gain, food intake, blood and urine chemistry, liver and kidney weights, histopathology, peroxisome proliferation and electron microscopy of liver.The NOAEL of 100 ppm (with 16 mg/kg bw/day as lowest corresponding value) was accepted as the descriptor to start calculations for long-term systemic DNELs.

Plasma samples (5animals/sex/group) were collected from 100, 200 and 2000 ppm diphenyl sulphone dosed treatment groups, including control groups, after 1 and 12 weeks of treatment (Taupin, 1981). The plasma diphenyl sulphone levels of treated animals showed a positive but non-linear correlation with dose. Circulating levels were comparable at the week 1 and 12 investigations for the 100 and 200 ppm dosed group. However, during week 12 group 2000 ppm dosed males showed a fall in plasma level when compared to week 1, whilst the plasma diphenyl sulphone level of 2000 ppm dosed females rose against the week 1 value. Consequently, on this occasion the plasma concentration shown by females was some four times higher than that of the males.

Aminopyrine N-demethylase (APDM) activities were further determined on individual liver samples (6 animals/sex/group) at the termination of the study using a colorimetric method supplied by the sponsor. A significant increase in mean APDM activities was apparent for rats of both sexes given 2000 ppm diphenylsulphone when compared to corresponding contro1 values (p<.01). There was no effect on APDM activity in rats given 100 or 200 ppm diphenylsulphone. The level of APDM activity in female controls was about half that of male controls. These results corresponded with morphological findings in the liver at this dose level, including increases in mean liver weight, hepatocellular hypertrophy and proliferation of liver smooth endoplasmic reticulum in both sexes.

For DNEL calculation, REACH assessment factors (ECHA Guidance on information requirements and chemical safety assessment, version 2, 2010) and worst case approach for absorption between routes were used.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 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):
100
Modified dose descriptor starting point:
NOAEC
DNEL value:
13.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
Key 90-day oral toxicity study available; no repeated dose inhalation toxicity study available.
AF for dose response relationship:
1
Justification:
Clear NOAEL
AF for differences in duration of exposure:
2
Justification:
ECHA default for subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already applied in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
10
Justification:
ECHA default
AF for the quality of the whole database:
1
Justification:
High quality study
AF for remaining uncertainties:
2
Justification:
Correction for route (in absence of data, inhalation is twice oral absorption)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
40 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Key 90-day oral toxicity study available; no repeated dose inhalation toxicity study available.
AF for dose response relationship:
1
Justification:
Clear NOAEL
AF for differences in duration of exposure:
2
Justification:
ECHA default for subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
10
Justification:
ECHA default
AF for the quality of the whole database:
1
Justification:
High quality study
AF for remaining uncertainties:
1
Justification:
Oral and dermal absorption considered to be worst case the same
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
0.08 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
16 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Clear NOAEL
AF for differences in duration of exposure:
2
Justification:
ECHA Default for subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA Default
AF for other interspecies differences:
2.5
Justification:
ECHA Default
AF for intraspecies differences:
10
Justification:
ECHA Default
AF for the quality of the whole database:
1
Justification:
High quality study
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD rat was estimated to be in the range of 300 - 500 mg/kg bodyweight.Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were ataxia, hunched posture, lethargy, ptosis, decreased respiratory rate, laboured and gasping respiration, loss of righting reflex, exophthalmos, hypothermia and dehydration. Two animals treated with 2000 mg/kg were found comatose. No signs of systemic toxicity were noted in animals treated at a dose level of 200 mg/kg.The dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg bodyweight.

Test material was not irritating on skin and eye (Guidelines in Commission Directive 93/21/EEC), therefore diphenyl sulphone (DPS) does not have to be classified and has no obligatory labelling requirement for skin and eye irritation.

There was no evidence that diphenyl sulphone had caused skin hypersensitivity in the guinea pig, since no responses were observed in the experimental animals in the challenge phase. This result indicated a sensitation rate of 0%. Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC), diphenyl sulphone does not have to be classified and has no obligatory labelling requirement for sensitation by skin contact.

Sprague Dawley rats of received diets containing 100, 200 or 2000 ppm diphenyl sulphone for a period of 13 weeks, corresponding to mean test article intake values of 8, 16 and 164 mg/kg bw/day in males and 9, 19 and 206 mg/kg bw/day in females, respectively. NOEL was 100 ppm (8-9 mg/kg bw/day) and NOAEL was considered to be 200 ppm (16-19 mg/kg bw/day). Adaptive changes were seen at 200 ppm, as demonstrated by increased liver weights and cellular hypertrophy, whereas toxicological changes were seen at 2000 ppm (corresponding wiht 164 and 206 mg/kg bw/day) as demonstrated by changes in body weight gain, food intake, blood and urine chemistry, liver and kidney weights, histopathology, peroxisome proliferation and electron microscopy of liver.The NOAEL of 100 ppm (with 16 mg/kg bw/day as lowest corresponding value) was accepted as the descriptor to start calculations for long-term systemic DNELs.

Plasma samples (5animals/sex/group) were collected from 100, 200 and 2000 ppm diphenyl sulphone dosed treatment groups, including control groups, after 1 and 12 weeks of treatment. The plasma diphenyl sulphone levels of treated animals showed a positive but non-linear correlation with dose. Circulating levels were comparable at the week 1 and 12 investigations for the 100 and 200 ppm dosed group. However, during week 12 group 2000 ppm dosed males showed a fall in plasma level when compared to week 1, whilst the plasma diphenyl sulphone level of 2000 ppm dosed females rose against the week 1 value. Consequently, on this occasion the plasma concentration shown by females was some four times higher than that of the males.

Aminopyrine N-demethylase (APDM) activities were further determined on individual liver samples (6 animals/sex/group) at the termination of the study using a colorimetric method supplied by the sponsor. A significant increase in mean APDM activities was apparent for rats of both sexes given 2000 ppm diphenylsulphone when compared to corresponding contro1 values (p<.01). There was no effect on APDM activity in rats given 100 or 200 ppm diphenylsulphone. The level of APDM activity in female controls was about half that of male controls. These results corresponded with morphological findings in the liver at this dose level, including increases in mean liver weight, hepatocellular hypertrophy and proliferation of liver smooth endoplasmic reticulum in both sexes.

For DNEL calculation, REACH assessment factors (ECHA Guidance on information requirements and chemical safety assessment, version 2, 2010) and worst case approach for absorption between routes were used.