Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
160 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
160 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.34 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
42
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

The DNELS proposed for TCDE are those derived for the read-across substance, DCPD.

Workers

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). DCPD is classified for acute oral and inhalation toxicity. It does not present an acute hazard following skin and exposure via the oral route is not relevant for workers. Hence an acute DNEL will be proposed for the inhalation route only.

In accordance with REACH guidance (Appendix R.8-13), scientific information is available which has been considered under REACH which was not considered in derivation of a MAK 0.5 ppm (2.75 mg/m3) and therefore this value cannot be sustained. There is no IOELV established for this substance.

Inhalation

Dose descriptor

The acute inhalation LC50 for lethality of DCPD in the rat (6 hr exposure) is 740.81 mg/m3. The NOAEC for irregular breathing, stereotypic behaviour in rats and mice has been reported to be 248.74 mg/m3.

Modification of dose descriptor

Initial modification of NOAEC for irregular breathing, stereotypic behaviour of 248.74 mg/m3 for light work (6.7 m3 / 10 m3) gives 166 mg/m3.

Adjust for duration only applying Haber’s law to derive the equivalent 15 min exposure:

(Ct=6)^3 x 6         = (Ct=0.25)^3 x 0.25

(Ct=0.25)^3         = (166)^3 x 24

Ct=0.25               = 479 mg/m3

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

default for inhalation route

Intraspecies differences

3

default workers

Differences in duration of exposure

1

default AF

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

2 species used

Overall AF

3

 

DNELacute        = 479 mg/m3 / 3

                             = 160 mg/m3

Local effects

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for DCPD and DNELs cannot therefore be determined. The DNELacute inhalation is considered protective for local effects from DCPD vapour.

However past decisions from the European Commission Working Group on Classification and Labelling of Dangerous Substances indicate that DCPD is irritating to the eyes, skin and the respiratory tract hence appropriate RMM and OCs should be employed.

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

For DCPD, the following NOAECs are presented in the IUCLID dossier:

Oral:
sub-chronic effects: male rat NOAEC = 4 mg/kg bw/d
reproductive effects: rat NOAEC = 20 mg/kg bw/d
developmental toxicity: rat NOAEC = 50 mg/kg bw/d

Inhalation:
sub-chronic effects: mouse NOAEC = 27.6 mg/m3
sub-chronic effects: rat NOAEC = 276 mg/m3

Dermal

Dose descriptor 

A mouse inhalation NOAEC of 27.6 mg/m3 will be used to derive the DNELl-t dermal.

Modification of dose descriptor

Correct the NOAEC to adjust for differences in duration of exposure; then convert the corrected mouse inhalation NOAEC (mg/m3) into a human dermal NOAEL (mg/kg bwt/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of DCPD after inhalation is 100% and, in the absence of data, dermal absorption is assumed to be the default of 100%.

correctedDermal NOAEL = NOAECinhalation x sRVmouse[1] x [ABSinhal-mouse/ABSdermal-human]

correctedDermal NOAEL = 27.6 x 0.514 x [100/100] = 14.19 mg/kg bwt/d

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

7

default for mouse

Intraspecies differences

3

ECETOC default AF for workers

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

42

 


DNELl-t dermal = 14.19 mg/kg bwt/d / 42

= 0.34 mg/kg bwt/d

Inhalation

Dose descriptor 

A mouse inhalation NOAEC of 27.6 mg/m3 will be used to derive the DNELl-t inhalation.

Modification of dose descriptor

Correct the NOAEC to adjust for differences in duration in the animal study (6 h) and the worker (8 h) and light work following the TGD Figure R.8-2:

27.6 mg/m3 x [6 h / 8 h] x [6.7 m3 / 10 m3] = 13.9 mg/m3

It is assumed that DCPD is similarly and efficiently (100%) absorbed after inhalation by mice and humans.

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

default for inhalation route

Intraspecies differences

3

default AF for workers

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

6

 

DNELl-t inhal          = 13.9 mg/m3/ 6

= 2.3 mg/m3

Long-term local effects

Information on local effects associated with repeated exposure to DCPD is limited to results from a rat and mouse repeated dose inhalation studies. In the rat study there were no significant clinical effects reported. In the mouse study there were no significant clinical effects reported prior to death. Incidence of mild conjunctivitis was reported in a single male mouse at the top dose of 51 ppm (276 mg/m3). It is considered that the long term systemic effect DNEL for inhalation is protective for local effects and therefore no specific DNEL for long-term local effects is derived here. In addition DCPD is classified R36 and R37 for eye and respiratory tract irritation. Risk management measures and other occupational controls are designed to limit local irritation effects will also protect against long term local eye and respiratory tract effects.

Dermal

No information is available to characterise the repeated local effects of DCPD on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. However DCPD is classified R38 hence risk management measures and other occupational controls are designed to limit skin irritation will also protect against long term local skin effects.

 


[1] 6 hour value calculated from TGD Table R.8-17 values (as per guidance Appx R.8-2, example B.4) – sRV for mouse (mean male/female) is 1.43 L/min/kg bw = 0.514 m3/kg bw for 6 hours

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.49 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
143 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.49 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
143 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

The DNELS proposed for TCDE are those derived for the read-across substance, DCPD.

General Population

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). DCPD is classified for acute oral and inhalation toxicity. It does not present an acute hazard following skin. The exposure scenario for the oral route for this substance is not predicted to have high peaks and it is considered that the long-term oral DNEL will ensure a sufficient level of protection. Hence an acute DNEL will be proposed for the inhalation route only.

Inhalation

Dose descriptor

The acute LC50 for lethality of DCPD in the rat (6 hr exposure) is 740.81 mg/m3. The NOAEC for irregular breathing, stereotypic behaviour in rats and mice has been reported to be 248.74 mg/m3.

Modification of dose descriptor

Adjust NOAEC for irregular breathing, stereotypic behaviour of 248.74 mg/m3 for duration applying Haber’s law to derive the equivalent 15 min exposure:

(Ct=4)^3 x 6         = (Ct=0.25)^3 x 0.25

(Ct=0.25)^3         = (248.74)^3 x 24

Ct=0.25                = 717 mg/m3

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

default for inhalation route

Intraspecies differences

5

ECETOC default AF for general population

Differences in duration of exposure

1

default AF

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

2 species used

Overall AF

5

 

DNELacute        = 717 mg/m3 / 5

                               = 143 mg/m3

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for DCPD and DNELs cannot therefore be determined. The DNELacute inhalation is considered protective for local effects from DCPD vapour.

However past decisions from the C&L work group indicate that DCPD is irritating to the eyes, skin and the respiratory tract hence appropriate RMM and OCs should be employed.

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

For DCPD, the following NOAECs are presented in the IUCLID dossier:

Oral:
sub-chronic effects: male rat NOAEC = 4 mg/kg bw/d
reproductive effects: rat NOAEC = 20 mg/kg bw/d
developmental toxicity: rat NOAEC = 50 mg/kg bw/d

Inhalation:
sub-chronic effects: mouse NOAEC = 27.6 mg/m3
sub-chronic effects: rat NOAEC = 276 mg/m3

Oral

Dose descriptor 

A male rat oral NOAEC of 4 mg/kg bwd will be used to derive the DNELl-t oral.

Modification of dose descriptor

No modification is required (daily dosing)

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

default (rat)

Intraspecies differences

5

ECETOC default AF for general population

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

40

 

DNELl-t oral       = 4 mg/kg bwt/d / 40

= 0.10 mg/kg bwt/d

Dermal

Dose descriptor 

A mouse inhalation NOAEC of 27.6 mg/m3 will be used to derive the DNELl-t dermal.

Modification of dose descriptor

Correct the NOAEC to adjust for differences in duration of exposure (as in 3.1.2); then convert the corrected mouse inhalation NOAEC (mg/m3) into a human dermal NOAEL (mg/kg bwt/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of DCPD after inhalation is 100% and dermal absorption, in the absence of additional relevant data, is also 100%.

Adjustment is made for the fact that the inhalation NOAEC is derived from a study where exposure was 5 days per week and exposure to the generation population might be every day.

correctedDermal NOAEL = NOAECinhalation x sRVmouse[1]x [ABSinhal-mouse/ABSdermal-human] x [5 d/7 d]

correctedDermal NOAEL = 27.6 x 0.514 x [100/100] x [5/7] = 10.13 mg/kg bwt/d

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

7

default for mouse

Intraspecies differences

5

ECETOC default AF for general population

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

70

 


DNELl-t dermal
      = 10.13 mg/kg bwt/d / 70

= 0.14 mg/kg bwt/d

Inhalation

Dose descriptor 

A mouse inhalation NOAEC of 27.58 mg/m3 will be used to derive the DNELl-t inhalation.

Modification of dose descriptor

Correct the NOAEC to adjust for differences in duration in the animal study (6 hr) and general population (24 h) following the TGD Figure R.8-2.

Adjustment is made for the fact that the inhalation NOAEC is derived from a study where exposure was 5 days per week and exposure to the generation population might be every day.

27.6 mg/m3 x [6 h /24 h] x [5 d/ 7 d] = 4.93 mg/m3

It is assumed that DCPD is similarly and efficiently (100%) absorbed after inhalation by mice and humans.

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

default for inhalation route

Intraspecies differences

5

ECETOC default AF for general population

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

10

 

DNELl-t inhal   = 4.93 mg/m3 / 10

= 0.49 mg/m3

Long-term local effects

Information on local effects associated with repeated exposure to DCPD is limited to results from a rat and mouse repeated dose inhalation studies. In the rat study there were no significant clinical effects reported. In the mouse study there were no significant clinical effects reported prior to death. Incidence of mild conjunctivitis was reported in a single male mouse at the top dose of 51 ppm (276 mg/m3). It is considered that the long term systemic effect DNEL for inhalation is protective for local effects and therefore no specific DNEL for long-term local effects is derived here. In addition DCPD is classified R36 and R37 for eye and respiratory tract irritation. Risk management measures and other occupational controls are designed to limit local irritation effects will also protect against long term local eye and respiratory tract effects.

Dermal

No information is available to characterise the repeated local effects of DCPD on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. No conclusion can therefore be reached for this endpoint. However DCPD is classified R38 hence risk management measures and other occupational controls are designed to limit skin irritation will protect against long term local skin effects also.

 


[1] 6 hour value calculated from TGD Table R.8-17 values (as per guidance Appx R.8-2, example B.4) – sRV for mouse (mean male/female) is 1.43 L/min/kg bw = 0.514 m3/kg bw for 6 hours