Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
DNEL value:
88 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the absence of an inhalation study, a corrected inhalation starting point is derived based on the oral LOAEL of 100 mg/kg bw/d. The oral LOAEL is corrected for breathing rate (/0.38) and activity (*0.67) and assuming inhalation absorption is twice oral absorption, resulting in a corrected inhalation LOAEC of 88 mg/m3.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Not required. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor is not required. It is noted that this approach is protective compared to using the NOAEL of 1000 mg/kg bw/d from the 90-day study.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required: already considered
AF for other interspecies differences:
2.5
Justification:
Default value: starting point derived from a rat study
AF for intraspecies differences:
5
Justification:
Default value (workers)
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
3
Justification:
AF used to take into account the use of a LOAEC as a starting point
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:
0.7 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A study of repeated dose dermal toxicity is not available. Dermal absorption and oral absorption are assumed (worst case) to be equivalent). A corrected dermal LOAEL of 100 mg/kg bw/d is therefore derived.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Not required. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor is not required. It is noted that this approach is protective compared to using the NOAEL of 1000 mg/kg bw/d from the 90-day study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point derived from a rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value (workers)
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
3
Justification:
AF used to take into account the use of a LOAEC as a starting point
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Di-TMP is not classified for acute toxicity, is not a skin or eye irritant and is not a skin sensitiser. A NOAEL of 1000 mg/kg bw/d is reported for a 90-day oral toxicity study in the rat. A LOAEL of 100 mg/kg bw/d is reported for a rat PNDT study, based on apparently increased incidences of misshapen scapula in all treated groups. The relationship of this finding to treatment with diTMP and toxicological significance of this finding is unclear at present; it is therefore considered to be treatment-related and potentially adverse. The LOAEL of 100 mg/kg bw/d from the PNDT study is used as a starting point for DNEL derivation.

Worker DNEL Values

Inhalation DNELs

Systemic inhalation DNELs

Long-term systemic inhalation DNEL

A starting point (LOAEC) of 88 mg/m3is derived following correction of the oral LOAEL for breathing rate (/0.38) and activity (*0.67), and assuming that inhalation absorption is twice oral absorption. Applying individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 3 (for remaining uncertainties) results in an overall assessment factor of 37.5. Applying the overall assessment factor to the corrected starting point results in a DNEL of 2.4 mg/m3. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90 -day study.

Short-term systemic inhalation DNEL

diTMP is not classified for acute toxicity. A short-term systemic DNEL is not derived in the absence of any hazard.

Local inhalation DNELs

diTMP is not classified as a skin or eye irritant and there is no evidence to suggest respiratory irritation. Long-term and short-term local inhalation DNELs are not derived in the absence of any hazard.

Dermal DNELs

Systemic dermal DNELs

Long-term systemic dermal DNEL

A corrected starting point (LOAEL) of 100 mg/kg bw/d is derived, assuming (worst case) that dermal absorption is equivalent to oral absorption. Applying individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 3 (for remaining uncertainties) results in an overall assessment factor of 150. Applying the overall assessment factor to the corrected starting point results in a DNEL of 0.7 mg/kg bw/d. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90 -day.

Short-term systemic dermal DNEL

diTMP is not classified for acute toxicity. A short-term systemic DNEL is not derived in the absence of any hazard.

Local dermal DNELs

diTMP is not classified as a skin irritant or skin sensitiser. Long-term and short-term local dermal DNELs are not derived in the absence of any hazard.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
DNEL value:
43 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the absence of an inhalation study, a corrected inhalation starting point is derived from the oral LOAEL of 100 mg/kg bw/d.  The oral LOAEL is corrected for breathing rate (/1.15) and the extent of absorption, resulting in a corrected inhalation LOAEC of 43 mg/m3.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Not required. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90-day study.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required (already accounted for)
AF for other interspecies differences:
2.5
Justification:
Default value (rat study used as the starting point)
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
3
Justification:
Use of LOAEL as starting point
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:
0.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A study of repeated dose dermal toxicity is not available.  Dermal absorption and oral absorption are assumed (worst case) to be equivalent).  A corrected dermal LOAEL of 100 mg/kg bw/d is therefore derived.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Not required. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90-day study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point derived from a rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
3
Justification:
Use of LOAEL as starting point
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
LOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The starting point is derived from an oral study; correction is therefore not required.

AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
1
Justification:
Not required. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90-day study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point derived from a rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value (general population)
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
3
Justification:
Use of LOAEL as starting point
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Di-TMP is not classified for acute toxicity, is not a skin or eye irritant and is not a skin sensitiser. A NOAEL of 1000 mg/kg bw/d is reported for a 90-day oral toxicity study in the rat. A LOAEL of 100 mg/kg bw/d is reported for a rat PNDT study, based on apparently increased incidences of misshapen scapula in all treated groups. The relationship of this finding to treatment with diTMP and toxicological significance of this finding is unclear at present; it is therefore considered to be treatment-related and potentially adverse.

The LOAEL of 100 mg/kg bw/d from the PNDT study is used as a starting point for DNEL derivation.

General Population DNEL Values

Inhalation DNELs

Systemic inhalation DNELs

Long-term systemic inhalation DNEL

A starting point (LOAEC) of 43 mg/m3is derived following correction of the oral LOAEL for breathing rate (/1.15) and assuming that inhalation absorption is twice oral absorption. Applying individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 3 (for remaining uncertainties) results in an overall assessment factor of 75. Applying the overall assessment factor to the corrected starting point results in a DNEL of 0.6 mg/m3. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90-day study.

Short-term systemic inhalation DNEL

diTMP is not classified for acute toxicity. A short-term systemic DNEL is not derived in the absence of any hazard.

Local inhalation DNELs

diTMP is not classified as a skin or eye irritant and there is no evidence to suggest respiratory irritation. Long-term and short-term local inhalation DNELs are not derived in the absence of any hazard.


Dermal DNELs

Systemic dermal DNELs

Long-term systemic dermal DNEL

A corrected starting point (LOAEL) of 100 mg/kg bw/d is derived, assuming (worst case) that dermal absorption is equivalent to oral absorption. Applying individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 3 (for remaining uncertainties) results in an overall assessment factor of 300. Applying the overall assessment factor to the corrected starting point results in a DNEL of 0.3 mg/kg bw/d. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 28-day study and an AF of 6 to cover study duration.

Short-term systemic dermal DNEL

diTMP is not classified for acute toxicity. A short-term systemic DNEL is not derived in the absence of any hazard.

Local dermal DNELs

diTMP is not classified as a skin irritant or skin sensitiser. Long-term and short-term local dermal DNELs are not derived in the absence of any hazard.

Oral DNELs

Systemic oral DNELs

Long-term systemic oral DNEL

Correction of the starting point is not required. Applying individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 3 (for remaining uncertainties) results in an overall assessment factor of 300. Applying the overall assessment factor to the corrected starting point results in a DNEL of 0.3 mg/kg bw/d. Although the starting point is from a PNDT study (technically sub-acute in duration), exposure covers the sensitive period. Increased risk would not be expected from a study of longer duration, therefore an assessment factor for study duration is not required. It is noted that this approach is protective compared to using the alternative NOAEL of 1000 mg/kg bw/d from the 90 -day study.

Short-term systemic oral DNEL

diTMP is not classified for acute toxicity. A short-term systemic DNEL is not derived in the absence of any hazard.