Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
28 mg/m³
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:
0.5 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
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

As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is too conservative because:

1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL.

2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. It can be concluded that 60 mg/kg/day is a dose close to the No-effect-level (NOEL)].

Overall, the LOAEL of 60 mg/kg/day reported in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test will be taken as the starting point for the DNEL calculation.

The most sensitive endpoint is systemic toxicity. Potential effects on fertility or developmental toxicity were investigated in an OECD 422 screening study and a comprehensive developmental toxicity study according to OECD 414. Effects on fertility and developmental toxicity were observed only in doses were systemic toxicity was seen. Consequently potential effects on fertility and developmental toxicity are covered by the systemic DNEL.

Long-term inhalation route-systemic (worker) using extrapolations factors:

LOAEL (rat) oral: 60 mg/kg bw/day

For interspecies differences rat vs. human: 4

60 mg/kg: 4 = 15 mg/kg bw/d

Body weight worker = 70 kg bw/person

15 mg/kg * 70 kg bw/person= 1050 mg/person/d

Respiratory volume worker = 10 m³/person (8h exposure; light activity for worker)

1050 mg/person/d: 10 m³/person = 105 mg/m³/8h

LOAEC worker (8h) = 105 mg/m³

For remaining interspecies differences: 1*[In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010)].

References:

-ECETOC 2003, Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

-ECETOC 2010, Guidance on Assessment Factors to Derive DNELs: in preparation

-Evaluation of risk assessment factors for interspecies

and time-extrapolation

Monika Batke, Sylvia Escher, Annette Bitsch, Inge Mangelsdorf

Fraunhofer Institute for Toxicology and Experimental Medicine -ITEM, Hannover, Germany

For extrapolation of exposure duration subchronic to chronic: 3** [8 weeks study]

For intraspecies differences in worker: 5

For reliability of dose response : 2 *** [No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. It can be concluded that 60 mg/kg/day is a dose close to the No-effect-level (NOEL)].

For quality of whole database: 1

Overall factor: 30

Worker DNEL long-term for inhalation route-systemic = 3.5 mg/m³/8h

Long-term oral route-systemic (worker) using extrapolation factors:

LOAEL (rat) oral: 60 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in worker: 5

For extrapolation of exposure duration subchronic to chronic: 3**

For reliability of dose response: 2***

For quality of whole database: 1

Overall factor: 120

Worker-DNEL long-term for oral route systemic = 0.5 mg/kg bw/d

Long-term dermal route-systemic (worker) using extrapolation factors:

LOAEL (rat) oral: 60 mg/kg bw/day

Dermal NOAEL= oral NOAEL* (ABS derm-rat) / (ABS derm-human)

= dermal NOAEL = oral NOAEL (ABS 100%) / (ABS 100%)

LOAEL (rat) dermal: 60 mg/kg bw/day

For interspecies differences rat vs. human 4

For remaining interspecies differences: 1*

For intraspecies differences in worker 5

For extrapolation of exposure duration subchronic to chronic: 3**

For reliability of dose response 2***

For quality of whole database 1

Overall factor: 120

Worker-DNEL long-term for dermal route systemic = 0.5 mg/kg bw/d

Acute Toxicity worker:

Due to the limited database and missing reliable acute inhalation study an alternative method to derive a DNEL for acute dermal and inhalation toxicity might be followed which is based on the DNELs for repeated dose toxicity and the application of an additional assessment factor (TRGS 900).

Since Disphenyl cresyl phosphate is of very low toxicity in acute toxicity experiments factor of 8 applied to the long-term DNEL is expected to be very conservative (TRGS 900). The derived DNEL for acute toxicity would be in this case:

-> oral: 4 mg/kg bw/d

-> dermal: 4 mg/kg bw/d

-> inhalation: 28 mg/m³

.

Summary DNELS:

Endpoint for DNEL/ Route/ Population/ DNEL value

Long term exposure (rat) / Inhalation/ Worker/ 3.5 mg/m³/8h

Long term exposure (rat) / Oral/ Worker/ 0.5 mg/kg bw/d

Long term exposure (rat) / Dermal/ Worker/ 0.5 mg/kg bw/d

Short term exposure (rat) / Oral/ Worker/ 4 mg/kg bw/d

Short term exposure (rat) / Dermal/ Worker/ 4 mg/kg bw/d

Short term exposure (rat) / Inhalation/ Worker/ 28 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

References:

-ECETOC 2003, Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

-ECETOC 2010, Guidance on Assessment Factors to Derive DNELs: in preparation

-Evaluation of risk assessment factors for interspecies

and time-extrapolation

Monika Batke*, Sylvia Escher, Annette Bitsch, Inge Mangelsdorf

Fraunhofer Institute for Toxicology and Experimental Medicine -ITEM, Hannover, Germany

** 8 weeks study

*** As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is too conservative because:

1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL.

2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. It can be concluded that 60 mg/kg/day is a dose close to the No-effect-level (NOEL).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.875 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 mg/m³
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:
0.25 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
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:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Basis for calculation of DNEL:

As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is to conservative because: 1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL. 2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. It can be concluded that 60 mg/kg/day is a dose close to the No-effect-level (NOEL)]. Overall, the LOAEL of 60 mg/kg/day reported in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test will be taken as the starting point for the DNEL calculation. The most sensitive endpoint is systemic toxicity. Potential effects on fertility or developmental toxicity were investigated in an OECD 422 screening study and a comprehensive developmental toxicity study according to OECD 414. Effects on fertility and developmental toxicity were observed only in doses were systemic toxicity was seen. Consequently potential effects on fertility and developmental toxicity are covered by the systemic DNEL.

Long-term inhalation route-systemic (general population) using extrapolations factors:

LOAEL (rat) oral: 60 mg/kg bw/day

For interspecies differences rat vs. human: 4

60 mg/kg: 4 = 15 mg/kg bw/d

Body weight general public = 70 kg bw/person

15 mg/kg * 70 kg bw/person= 1050 mg/person/d

Respiratory volume general population: 20 m³/person (24h exposure; general population)

1050 mg/person/d: 20 m³/person = 52.5 mg/m³/24 h

LOAEC general population (24h) = 52.5 mg/m³/24h

For remaining interspecies differences: 1 * In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

References:

-ECETOC 2003, Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

-ECETOC 2010, Guidance on Assessment Factors to Derive DNELs: in preparation

-Evaluation of risk assessment factors for interspecies

and time-extrapolation

Monika Batke*, Sylvia Escher, Annette Bitsch, Inge Mangelsdorf

Fraunhofer Institute for Toxicology and Experimental Medicine -ITEM, Hannover, Germany

For extrapolation of exposure duration subchronic to chronic: 3** [8 weeks study]

For intraspecies differences in general population: 10

For reliability of dose response: 2 *** [ As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is to conservative because:

1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL.

2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. It can be concluded that 60 mg/kg/day is a dose close to the No-effect-level (NOEL)].

For quality of whole database: 1

Overall factor: 60

General population DNEL long-term for inhalation route systemic = 0.875 mg/m³/24 h

Long-term oral route-systemic (general population) using extrapolation factors:

LOAEL (rat) oral: 60 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in general population 10

For extrapolation of exposure duration subchronic to chronic: 3**

For reliability of dose response: 2***

For quality of whole database: 1

Overall factor: 240

General population-DNEL long-term for dermal (oral) route systemic = 0.25 mg/kg bw/d

Long-term dermal route-systemic (general population) using extrapolation factors:

LOAEL (rat) oral: 60 mg/kg bw/day

Dermal NOAEL= oral NOAEL* (ABS derm-rat) / (ABS derm-human)

= dermal NOAEL = oral NOAEL (ABS 100%) / (ABS 100%)

LOAEL (rat) dermal: 60 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 3**

For reliability of dose response: 2***

For quality of whole database: 1

Overall factor: 240

General population-DNEL long-term for dermal route systemic = 0.25 mg/kg bw/d

Acute Toxicity general population:

Due to the limited database and missing reliable acute inhalation study an alternative method to derive a DNEL for acute dermal and inhalation toxicity might be followed which is based on the DNELs for repeated dose toxicity and the application of an additional assessment factor (TRGS 900).

Since Disphenyl cresyl phosphate is of very low toxicity in acute toxicity experiments factor of 8 applied to the long-term DNEL is expected to be very conservative (TRGS 900). The derived DNEL for acute toxicity would be in this case:

-> oral: 2 mg/kg bw/d

-> dermal: 2 mg/kg bw/d

-> inhalation: 7 mg/m³

Summary DNELS:

Endpoint for DNEL/ Route/ Population/ DNEL value

Long term exposure (rat) / Inhalation/ General population/ 0.875 mg/m³/24 h

Long term exposure (rat) / Oral/ General population/ 0.25 mg/kg bw/d

Long term exposure (rat) / Dermal/ General population/ 0.25 mg/kg bw/d

Short term exposure (rat) / Oral/ General population/ 2 mg/kg bw/d

Short term exposure (rat) / Dermal/General population/ 2 mg/kg bw/d

Short term exposure (rat) / Inhalation/ General population/ 7 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

References:

-ECETOC 2003, Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

-ECETOC 2010, Guidance on Assessment Factors to Derive DNELs: in preparation

-Evaluation of risk assessment factors for interspecies

and time-extrapolation

Monika Batke, Sylvia Escher, Annette Bitsch, Inge Mangelsdorf

Fraunhofer Institute for Toxicology and Experimental Medicine -ITEM, Hannover, Germany

** 8 weeks study

*** As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is to conservative because:

1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL.

2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. It can be concluded that 60 mg/kg/day is a dose close to the No-effect-level (NOEL).