Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 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):
75
Dose descriptor starting point:
LOAEC
Modified dose descriptor starting point:
LOAEC
Explanation for the modification of the dose descriptor starting point:

The starting point is converted using an oral-to-inhalation route extrapolation (assuming100% absorption for both exposure routesand standard respiratory volumes of 0.38 m3/kg over 8 hours for rats, 6.7 m3/person over 8 hours and 10 m3/person over 24 hours for humans):

LOAEC worker (8 h)= 70 x (1 / 0.38) x (6.7 / 10)= 123.4 mg/m3

AF for dose response relationship:
3
Justification:
For the use of an LOAEL
AF for differences in duration of exposure:
2
Justification:
ECHA R8 guidance default factor (subchronic to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA R8 guidance default factor for rats
AF for other interspecies differences:
2.5
Justification:
ECHA R8 guidance default factor
AF for intraspecies differences:
5
Justification:
ECHA R8 guidance default factor
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

No acute data by inhalation is available. However, in the case of TBC, there is no potential for high peak exposure in normal conditions of exposure. Consequently the long-term DNEL is considered sufficient to cover the acute effect and ensure that they will not occur.

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

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

1. Acute / short-term exposure - systemic effects

 

1.1 For oral route:

The oral route is not relevant to workers.

 

1.2 For inhalation route:

No valid data are available for this route of administration which is not the most relevant comparing to oral and dermal route. 

No DNEL could be calculated. Furthermore there is no potential for high peak exposure in normal conditions of production for this substance.

 

1.3 For dermal route:

The dermal rat acute toxicity study (CIT, 1992b), where 500 mg/kg was a LOAEL, was taken into consideration. The relevant systemic effects considered are the clinical signs (hypokinesia, sedation and dyspnea) observed within the few hours following cutaneous application. Furthermore local effects characterized by a severe cutaneous reaction were observed at all doses tested.

 

Due to corrosive effect and regarding the value of the LOAEL, it is possible that local effects always appear before any systemic effects caused by cutaneous absorption. The derivation of an acute worker DNEL by dermal route for systemic effects was therefore considered not relevant. The corrosive effect is considered to appear without threshold. Percutaneous absorption measured in toxicokinetics study confirm that local effect appeared before dermal absorption and seems to facilitate the dermal absorption, without threshold.

 

Therefore qualitative risk assessment is recommended.

2. Acute / short-term exposure - local effects

 

For local effects, no sufficient information as to concentration-response relationship of irritation or corrosion is available to enable DNEL derivation.The corrosive effects observed should be considered as the most important hazard and qualitative risk assessment performed for the local effects.

3. Long term exposure - systemic effects

 

For systemic effects, DNEL derivation was performed following the method proposed in the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8.

3.1 For oral route:

The oral route is not relevant to workers.

 

3.2 For inhalation route:

Determination of the human DNEL from rat oral study:

The 14-week rat dietary toxicity study (US NTP, 2002), where the low dose of 781 ppm, equivalent to 70 mg/kg, was a LOAEL, was selected for DNEL derivation. This study was selected preferably to its counterpart in mice, because the rat species appeared more sensitive to the test substance toxicity than the mouse species at the dose levels selected. The relevant systemic effects considered are the changes in hematology and clinical chemistry seen at all dose levels, based on the limited relevance of forestomach lesions also observed in the study but not relevant to humans. These effects were considered to bear a threshold mode of action.

-      Modification of the starting point:

The starting point is converted using an oral-to-inhalation route extrapolation (assuming 100% absorption for both exposure routes and standard respiratory volumes of 0.38 m3/kg over 8 hours for rats, 6.7 m3/person over 8 hours and 10 m3/person over 24 hours for humans):

LOAEC worker (8 h)= 70 x (1 / 0.38) x (6.7 / 10)= 123.4 mg/m3

 

-      Assessment factors:

The following assessment factors were applied:

·    Remaining interspecies differences (mainly toxicodynamic): 2.5 (default value)

·    Intraspecies differences: 5 (default value for workers)

·    Differences in duration of exposure: 2 (default value for subchronic to chronic extrapolation)

·    Issues related to severity and dose-response: 3 (because of the use of LOAEL as a starting point)

·    Quality of whole database: 1 (reliability 1 study).

Global assessment factor = 2.5 x 5 x 2 x 3 x 1= 75

 

-        DNEL:

Worker-DNEL long-term for inhalation route-systemic = 123.4 / 75 = 1.6 mg/m3

3.3 For dermal route:

No repeated-dose dermal toxicity data that would enable DNEL derivation are available.

The corrosive effects observed should be considered as the most important hazard and qualitative risk assessment performed for the local effects.

4. Reproductive and developmental toxicity

Effects on reproductive parameters (sperm count and motility, and estrous cycle parameters) were also noted in the 14-week dietary study in rats (US NTP, 2002). These effects were observed at dose levels higher than those considered for the systemic effect DNEL derivation.

Therefore the long-term DNEL appears sufficiently protective and no specific DNEL for potential effects on fertility was calculated.

Based on the OECD 414 test guideline since the substance is not considered as teratogenic there is no need to derive a DNEL fot this endpoint.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
406 µg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
LOAEC
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
117 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
LOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

For systemic effects, DNEL derivation was performed following the method proposed in the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8.

1. Acute / short-term exposure - systemic effects

 

1.1 For oral route:

The oral rat acute toxicity study (CIT, 1992a), where 490 mg/kg was a LOAEL, was considered for DNEL derivation. The relevant systemic effects considered are the clinical signs (decreased activity, piloerection and dyspnea) observed which had reversed between days 8 and 14.

 

-      Modification of the starting point:

No modification of the starting point is applied as the routes and duration of exposure are globally the same in both species.

-      Assessment factors:

The following assessment factors were applied:

·    Interspecies differences (mainly toxicokinetic): 4 (default value)

·    Remaining interspecies differences (mainly toxicodynamic): 2.5 (default value)

·    Intraspecies differences: 10 (default value for humans exposed via environment)

·    Differences in duration of exposure: 1 (same acute exposure)

·    Issues related to severity and dose-response: 3 (because of the use of LOAEL as a starting point)

·    Quality of whole database: 1 (reliability 1 study).

Global assessment factor = 4 x 2.5 x 10x 3 = 300

 

-        DNEL:

Human via environment-DNEL short-term for oral route-systemic = 490 / 300 = 1.6 mg/kg bw

 

 

1.2 For inhalation route:

 

No valid data are available for this route of administration which is not the most relevant comparing to oral and dermal route. 

No DNEL could be calculated.

1.3 For dermal route:

The dermal rat acute toxicity study (CIT, 1992b), where 500 mg/kg was a LOAEL, was taken into consideration. The relevant systemic effects considered are the clinical signs (hypokinesia, sedation and dyspnea) observed within the few hours following cutaneous application. Furthermore local effects characterized by a severe cutaneous reaction were observed at all doses tested.

 

Due to corrosive effect and regarding the value of the LOAEL, it is possible that local effects always appear before any systemic effects caused by cutaneous absorption. The derivation of an acute DNEL for humans exposed via environment by dermal route for systemic effects was therefore considered not relevant. The corrosive effect is considered to appear without threshold. Percutaneous absorption measured in toxicokinetics study confirm that local effect appeared before dermal absorption and seems to facilitate the dermal absorption, without threshold.

 

Therefore qualitative risk assessment is recommended.

 

2. Acute / short-term exposure - local effects

 

For local effects, no sufficient information as to concentration-response relationship of irritation or corrosion is available to enable DNEL derivation. The corrosive effects observed should be considered as the most important hazard and qualitative risk assessment performed for the local effects.

 

3. Long term exposure - systemic effects

 

For systemic effects, DNEL derivation was performed following the method proposed in the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8.

3.1 For oral route:

The 14-week rat dietary toxicity study (US NTP, 2002), where the low dose of 781 ppm, equivalent to 70 mg/kg, was a LOAEL, was selected for DNEL derivation. This study was selected preferably to its counterpart in mice, because the rat species appeared more sensitive to the test substance toxicity than the mouse species at the dose levels selected. The relevant systemic effects considered are the changes in hematology and clinical chemistry seen at all dose levels, based on the limited relevance of forestomach lesions also observed in the study but not relevant to humans. These effects were considered to bear a threshold mode of action.

 

 

-      Modification of the starting point:

No modification of the starting point is applied as the routes of exposure are the same in both species.

 

-      Assessment factors:

The following assessment factors were applied:

·    Interspecies differences (mainly toxicokinetic): 4 (default value)

·    Remaining interspecies differences (mainly toxicodynamic): 2.5 (default value)

·    Intraspecies differences: 10 (default value for humans exposed via environment)

·    Differences in duration of exposure: 2 (default value for subchronic to chronic extrapolation)

·    Issues related to severity and dose-response: 3 (because of the use of LOAEL as a starting point)

·    Quality of whole database: 1 (reliability 1 study).

Global assessment factor = 4 x 2.5 x 10x 2 x 3 = 600

 

-        DNEL:

Human via environment-DNEL long-term for oral route-systemic = 70 / 600 = 117 µg/kg bw/day

 

3.2 For inhalation route:

Determination of the human DNEL from rat oral study:

The same 14-week rat dietary toxicity study (US NTP, 2002), where the low dose of 781 ppm, equivalent to 70 mg/kg, was a LOAEL, was selected for DNEL derivation, using route-to-route extrapolation.

-      Modification of the starting point:

The starting point is converted using an oral-to-inhalation route extrapolation (assuming 100% absorption for both exposure routes and standard respiratory volumes of 1.15 m3/kg over 24 hours for rats):

LOAEC humans via environment (24 h) = 70 x (1 / 1.15) = 60.9 mg/m3

-      Assessment factors:

The following assessment factors were applied:

·    Remaining interspecies differences (mainly toxicodynamic): 2.5 (default value)

·    Intraspecies differences: 10 (default value for humans exposed via environment)

·    Differences in duration of exposure: 2 (default value for subchronic to chronic extrapolation)

·    Issues related to severity and dose-response: 3 (because of the use of LOAEL as a starting point)

·    Quality of whole database: 1 (reliability 1 study).

Global assessment factor = 2.5 x 10x 2 x 3 = 150

 

-      DNEL:

Human via environment-DNEL long-term for inhalation route-systemic = 60.9 / 150 = 406 µg/m3

3.3 For dermal route:

No repeated-dose dermal toxicity data that would enable DNEL derivation are available.

 

The corrosive effects observed should be considered as the most important hazard and qualitative risk assessment performed for the local effects.

 

4. Reproductive and developmental toxicity

 

Effects on reproductive parameters (sperm count and motility, and estrous cycle parameters) were also noted in the 14-week dietary study in rats (US NTP, 2002). These effects were observed at dose levels higher than those considered for the systemic effect DNEL derivation.

Therefore the long-term DNEL appears sufficiently protective and no specific DNEL for potential effects on fertility was calculated.

Based on the OECD 414 test guideline since the substance is not considered as teratogenicthere is no need to derive a DNEL fot this endpoint.