Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.6 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
264 mg/m³
Explanation for the modification of the dose descriptor starting point:

Extrapolation from oral to inhalation exposure using route-to-route strategy described in Appendix R.8-2 of R.8 guidance

AF for dose response relationship:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for differences in duration of exposure:
2
Justification:
Default value proposed in ECHA R.8 guidance for sub chronic to chronic exposure ( table R 8.6)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling for inhalation studies (Appendix R8.2)
AF for intraspecies differences:
5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for the quality of the whole database:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for remaining uncertainties:
2.5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
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:
3 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:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Extrapolation from oral to dermal exposure using route-to-route strategy described in Appendix R.8-2 of R.8 guidance

AF for dose response relationship:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for differences in duration of exposure:
2
Justification:
Default value proposed in ECHA R.8 guidance for sub chronic to chronic exposure ( table R 8.6)
AF for interspecies differences (allometric scaling):
4
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.3)
AF for intraspecies differences:
5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for the quality of the whole database:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for remaining uncertainties:
2.5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

1. Acute/short-term exposure-systemic effects:

Cutaneous route

In the key study (Tuffnell, 1992) no mortality and no local changes were noted at a limit dose of 2000 mg/kg. The dermal LD50 is therefore greater than 2000 mg/kg and ITC 288/S is not classified as hazardous via the dermal route.

No short-term systemic DNEL needs to be derived for cutaneous exposure, (ECHA guidance document R8.1.2.5)

Inhalation route

No data are available for acute short term exposure via this route of administration. 

No DNEL could be calculated. However, the Occupational Exposure limits for the inhalable airborne fraction (particles < 100 µm) of 10 mg/m3 which is applied in many countries can be considered as a worst-case since the ITC288/S median particle size is between 106 and 150 µm and the possibility to have the inhalable fraction in the respiratory tractus is very low.

2. Acute/short-term exposure-local effects:

Cutaneous route

ITC 288/S was classified in category 1, H317 ( May cause an allergic skin reaction) according to the CLP regulation (1272/2008) and as a sensitiser to guinea pig skin (Xi, R43) according to the Directive 67/548/EEC based on the sensititisation study conducted according to the Guinea-Pig Maximisation test (see section 7.4).

Considering these data, it is very difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs), (R8 -10, p125).

Inhalation route

No data are available for acute short term exposure via this route of administration. 

No DNEL could be calculated. However, the Occupational Exposure limits for the inhalable airborne fraction (particles < 100 µm) of 10 mg/m3 which is applied in many countries can be considered as a worst-case since the ITC288/S median particle size is between 106 and 150 µm and the possibility to have the inhalable fraction in the respiratory tractus is very low.

3. Long-term exposure-inhalation route:

3.1 Long-term exposure-inhalation route/Systemic effects

The long-term DNEL inhalation exposure for systemic effects cannot be derived from repeated dose toxicity study by inhalation since this study is not available. However, a route to route extrapolation can be realised from an oral repeated dose toxicity study (OECD 408), selected as a key study for repeated dose toxicity endpoint (Parr, 2014 - reliability 1). There was systemic toxicity identified at the maximal dose tested in the repeated dose study by the oral route,There was a dose-related decrease in body weights and body weight gains in males at all doses which reached statistical significance at 1000 mg/kg/day. At necropsy, test item-related lower mean body weights were noted in males treated at 1000 mg/kg/day. Macroscopic test item-related abnormal growth or irregular color of lower incisor teeth was observed in some males and females treated at 1000 mg/kg/day. The NOAEL /oral/rat = 300 mg/kg bw/day can be considered for a route to route extrapolation to derive a DNEL for inhalation route. The following Table indicates the inhalation DNEL for systemic toxicity calculation

Table 3.1/1 DNEL calculation for long-term exposure by inhalation:

Worker

Systemic long-term DNEL

Step a: determination of the critical dose

Key study

Parr (2014).OECD 408, tested doses: 0, 100, 300 and 1000 mg/kg b.w/day, (Kr: 1).

Relevant dose descriptor

NOAEL/oral/rat (males and females) = 300 mg/kg bw/day, ( a slight change in body weight, gross and microscopic findings in teeth)

Etape b : Correct starting point-factor and route to route extrapolation

 

NAEC Worker (8h)

a factor of 2 is applied due to oral to inhalation absorption difference.

NOAEL (rat)/0.38*6.7/10 / 2

= 264 mg/kg bw/d

Step c : assessment factors

Intraspeciesdifferences

(worker)

5

 

Duration extrapolation

(sub-chronic to chronic)

2

Remaining uncertainties

2.5

 Overall assessment factor

 50
  

DNEL Long-term by inhalation route proposed(mg/m3)

 10,6

The inhalation DNEL long-term for systemic effects is = 10,6 mg/m3 for workers.

3.2 Long-term exposure-inhalation route/local effects

The Occupational Exposure limits for the inhalable airborne fraction (particles < 100 µm) of 10 mg/m3 which is applied in many countries can be considered as a worst-case since the ITC288/S median particle size is between 106 and 150 µm and the possibility to have the inhalable fraction in the respiratory tractus is very low.

Conclusion:

ITC288/S is a white powder (median particle size between 106 and 150 µm) and is considered as very soluble in water based on

water solubility above 2333 g/L at 20°C. As recommended in the R.8.7.1, p 54, for significantly soluble dusts, if the derived DNEL for inhalation is above the general dust limit (10 mg/m3for the inhalable airborne fraction) might apply. Considering these data and in order to protect the workers, the general dust limit of 10 mg/m3for the inhalable airborne fraction (more conservative) was selected. This general dust limit covers the specific and non-specific effects of the substance.

4. Long-term exposure-dermal route:

4.1 Long-term exposure-systemic effects/dermal route:

No repeated dose toxicity by the dermal route is available. However, no evidence of systemic toxicity was observed in the acute dermal toxicity (Tuffnell, 1992). There was systemic toxicity identified at the maximal dose tested in the repeated dose study by the oral route,There was a dose-related decrease in body weights and body weight gains in males at all doses which reached statistical significance at 1000 mg/kg/day. At necropsy, test item-related lower mean body weights were noted in males treated at 1000 mg/kg/day. Macroscopic test item-related abnormal growth or irregular color of lower incisor teeth was observed in some males and females treated at 1000 mg/kg/day. The NOAEL /oral/rat = 300 mg/kg bw/day can be considered for a route to route extrapolation to derive a DNEL for dermal route. The following Table indicates the dermal DNEL for systemic toxicity calculation

Table 4.1/1 DNEL calculation for long-term exposure by dermal route:

Worker

Systemic long-term DNEL

Step a: determination of the critical dose

Key study

Parr (2014).OECD 408, tested doses: 0, 100, 300 and 1000 mg/kg b.w/day (Kr: 1).

Relevant dose descriptor

NOAEL/oral/rat (males and females) = 300 mg/kg bw/day (worst case),( a slight change in body weight, gross and microscopic findings in teeth  )

 

Etape b : Correct starting point-factor and route to route extrapolation

Dermal NAEL(corrected)

NOAEL oral-rat/1 = 300 mg/kg bw/d

 (On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral to dermal extrapolation)

Step c : assessment factors

Interspecies differences :

- allometric scaling for metabolic rate

- remaining differences (toxicokinetics and toxicodynamics)

 

 4 (rat)

 

2.5

Intraspecies differences

5 (worker)

 

Duration extrapolation

 

2

(sub-chronic to chronic extrapolation)

Issues related to dose-response

1 (NOAEL (worst case))

Quality of whole database

1

Overall assessment factor

100

DNEL Long-term by dermal route proposed(mg/kg bw/day)

3

The Dermal DNEL long-term for systemic effects is 3 mg/kg bw/day in the worker. However, no long-term dermal exposure is expected at this high level based on the precautions taken to prevent skin sensitisation effects.

4.2 Long-term exposure-local effects/dermal route:

The sensititisation study was conducted according to the Guinea-Pig Maximisation test (see section 7.4) ans showed positive results for the ITC 288/S (classified as skin sensitizer in Cat.1, H317). Considering these data, it is very difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs), (R8 -10, p125).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.6 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:
130 mg/m³
Explanation for the modification of the dose descriptor starting point:

Extrapolation from oral to inhalation exposure using route-to-route strategy described in Appendix R.8-2 of R.8 guidance

AF for dose response relationship:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for differences in duration of exposure:
2
Justification:
Default value proposed in ECHA R.8 guidance for sub chronic to chronic exposure ( table R 8.6)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling for inhalation studies (Appendix R8.2)
AF for intraspecies differences:
10
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for the quality of the whole database:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for remaining uncertainties:
2.5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
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:
1.5 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:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Extrapolation from oral to dermal exposure using route-to-route strategy described in Appendix R.8-2 of R.8 guidance

AF for dose response relationship:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for differences in duration of exposure:
2
Justification:
Default value proposed in ECHA R.8 guidance for sub chronic to chronic exposure ( table R 8.6)
AF for interspecies differences (allometric scaling):
4
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.3)
AF for intraspecies differences:
10
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for the quality of the whole database:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for remaining uncertainties:
2.5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
1.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route ro route extrapolation

AF for dose response relationship:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for differences in duration of exposure:
2
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for interspecies differences (allometric scaling):
4
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.3)
AF for intraspecies differences:
10
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for the quality of the whole database:
1
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
AF for remaining uncertainties:
2.5
Justification:
Default value proposed in ECHA R.8 guidance ( table R 8.6)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

1. Acute/short-term exposure-systemic effects:

Cutaneous route

In the key study (Tuffnell, 1992) no mortality and no local changes were noted at a limit dose of 2000 mg/kg. The dermal LD50 is therefore greater than 2000 mg/kg and ITC 288/S is not classified as hazardous via the dermal route.

No short-term systemic DNEL needs to be derived for cutaneous exposure, (ECHA guidance document R8.1.2.5)

Inhalation route

No data are available for this route of administration. However, the acute inhalation study does not need to be conducted as the substance is tested by two routes (oral + dermal), the LD50 oral (rat): > 5000 mg/kg bw and the LD50 dermal (rat): > 2000 mg/kg bw. These results leading to the conclusion that ITC 288/S is not toxic by acute exposure.

Oral route

In the key study (Tuffnell, 1992) no mortality, no signs of systemic toxicity and no abnormalities were noted at necropsy at a limit test of 5000 mg/kg bw. The oral LD50 combined of ITC 288/S was found to be greater than 5000 mg/kg bw, therefore it is not classified as hazardous via the oral route.

No short-term systemic DNEL needs to be derived for oral exposure, (ECHA guidance document R8.1.2.5)

2. Acute/short-term exposure-local effects:

Cutaneous route

ITC 288/S was classified in category 1, H317 ( May cause an allergic skin reaction) according to the CLP regulation (1272/2008) and as a sensitiser to guinea pig skin (Xi, R43) according to the Directive 67/548/EEC based on thesensititisation study conducted according to the Guinea-Pig Maximisation test (see section 7.4).

Considering these data, it is very difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs), (R8 -10, p125).

Inhalation route

General population exposure to ITC 288/S as a dust or in aerosol form is not anticipated. No short-term local DNEL needs to be derived for inhalation exposure.

3. Long-term exposure-inhalation route:

3.1 Long-term exposure-inhalation route/Systemic effects

The long-term DNEL inhalation exposure for systemic effects cannot be derived from repeated dose toxicity study by inhalation since this study is not available. However, a route to route extrapolation can be realised from an oral repeated dose toxicity study (OECD 408), selected as a key study for repeated dose toxicity endpoint (Parr, 2014 - reliability 1).

The NOAEL /oral/rat = 300 mg/kg bw/day can be selected as the relevant dose descriptor, therefore a route to route extrapolation can be made to derive a DNEL for inhalation route.The following Table indicates the inhalation DNEL for systemic toxicity calculation.

Table 3.1/1 DNEL calculation for long-term exposure by inhalation:

General population

Systemic long-term DNEL

Step a: determination of the critical dose

Key study

Parr (2014).OECD 408, tested doses: 0, 100, 300 and 1000 mg/kg b.w/day (Kr: 1).

Relevant dose descriptor

NOAEL/oral/rat (males and females) = 300 mg/kg bw/day,  

(a slight change in body weight, gross and microscopic findings in teeth at the highest tested dose)

Etape b : Correct starting point-factor and route to route extrapolation

NAEC human (24h)

NOAEL(rat) /1.15 = 260 mg/ m3

Step c : assessment factors

Intraspeciesdifferences

(General population)

10

Duration extrapolation

(sub-chronic to chronic)

2

Remaining uncertaintites

5

Overall assessment factor

100

  

DNEL Long-term by inhalation route proposed(mg/m3)

2,6 

The inhalation DNEL long-term for systemic effects is = 2.6 mg/m3in the general population. However, general population exposure to ITC 288/S as a dust or in aerosol form is not anticipated.

3.2 Long-term exposure-inhalation route/local effects

General population exposure to ITC 288/S as a dust or in aerosol form is not anticipated. No long-term local DNEL needs to be derived for inhalation exposure.

4. Long-term exposure-dermal route:

4.1 Long-term exposure-systemic effects/dermal route:

No repeated dose toxicity by the dermal route is available. However, no evidence of systemic toxicity was observed in the acute dermal toxicity (Tuffnell, 1992). There was systemic toxicity identified at the maximal dose tested in the repeated dose study by the oral route,There was a dose-related decrease in body weights and body weight gains in males at all doses which reached statistical significance at 1000 mg/kg/day. At necropsy, test item-related lower mean body weights were noted in males treated at 1000 mg/kg/day. Macroscopic test item-related abnormal growth or irregular color of lower incisor teeth was observed in some males and females treated at 1000 mg/kg/day. The NOAEL /oral/rat = 300 mg/kg bw/day can be considered for a route to route extrapolation to derive a DNEL for inhalation route.The following Table indicates the dermal DNEL for systemic toxicity calculation

Table 4.1/1 DNEL calculation for long-term exposure by dermal route:

General population

Systemic long-term DNEL

Step a: determination of the critical dose

Key study

Parr (2014).OECD 408, tested doses: 0, 100, 300 and 1000 mg/kg b.w/day (Kr: 1).

Relevant dose descriptor

NOAEL/oral/rat (males and females) = 300 mg/kg bw/day (worst case), ( a slight change in body weight, gross and microscopic findings in teeth at the highest tested dose

)

 

Etape b : Correct starting point-factor and route to route extrapolation

Dermal NAEL(corrected)

NOAEL oral-rat/1 = 300 mg/kg bw/d

 (On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral to dermal extrapolation)

Interspecies differences :

- allometric scaling for metabolic rate

- remaining differences (toxicokinetics andtoxicodynamics)

 

4 (rat)

 

2,5

Intraspecies differences

10(General population)

 

Duration extrapolation

 

2

(sub-acute to chronic extrapolation)

Issues related to dose-response

1 (NOAEL (worst case))

Quality of whole database

1

Overall assessment factor

200

DNEL Long-term by dermal route proposed(mg/kg bw/day)

1,5

 

 The Dermal DNEL long-term for systemic effects is = 1,5 mg/kg bw/day in the general public. However, no long-term dermal exposure is expected at this high level based on the precautions taken to prevent skin sensitisation effects.

 4.2 Long-term exposure-local effects/dermal route:

The sensititisation study was conducted according to the Guinea-Pig Maximisation test (see section 7.4) ans showed positive results for the ITC 288/S. Considering these data, it is very difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs), (R8 -10, p125).

5. Long-term exposure-oral route:

5.1 Long-term exposure-systemic effects/oral route:

One study is available as a OECD 408 compliant GLP study (Parr, 2014).

Table 5.1/1 DNEL calculation for long-term exposure by oral route:

General population

Systemic long-term DNEL

Step a: determination of the critical dose

Key study

Parr (2014).OECD 408, tested doses: 0, 100, 300 and 1000 mg/kg b.w/day (Kr: 1)

Relevant dose descriptor

NOAEL/oral/rat (males and females) = 300 mg/kg bw/day, (worst case), (a slight change in body weight, gross and microscopic findings in teeth at the highest tested dose)

Step c : assessment factors

Interspecies differences

(rat/human)

4x1*

Intraspecies differences

(General population)

10

Duration extrapolation

(sub-chronic to chronic)

2

Remaining differences

2,5

Study quality

1

Overall assessment factor

200

DNEL Long-term by oral route proposed (mg/kg b.w/day)

1,5

The Oral DNEL long-term for systemic effects is = 1,5 mg/kg bw/day in the general public.