Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.2 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):
12.5
Modified dose descriptor starting point:
LOAEC
Value:
102.7 mg/m³
Explanation for the modification of the dose descriptor starting point:
For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a TCPP specific factor of 0.8 (80% oral bioavailability; see European Union Risk Assessment Report (EU RAR) 2008) is taken forward for DNEL derivation. According to Figure R. 8-3 in the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012) additional correction is needed for scaling issues: Corrected inhalatory LOAEC = oral LOAEL * 80%/100% * 1/0.38 m³ per kg and day * 6.7 m³/10 m³ * 1.4 (based on the oral LOAEL of 52 mg/kg bw/day for systemic toxicity obtained in a 90-day feeding study on rats the starting point is calculated with 102.7 mg/m³. Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers).
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a LOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 3. However, in line with the EU RAR 2008 (chapter 4.1.3.2.4: ‘Normally a further factor of 3 would be used to take into account the use of a LOAEL rather than a NOAEL. However, this is not considered necessary here, as the adverse effect in the repeated dose toxicity study (mainly liver weight changes) are not considered particularly toxicologically significant and the LOAEL is probably quite close to the NOAEL.’) a factor of 1 was chosen.
AF for differences in duration of exposure:
1
Justification:
In accordance with the EU RAR 2008 (chapter 4.1.3.2.4: ‘In addition, a factor to allow for semi chronic to chronic extrapolation (usually a factor of 2) was not used here. It is not considered necessary, as relatively similar effects on the liver, at doses of a comparable order of magnitude were observed in both the 28-day and the 90-day studies and so it is felt that exposure duration is not significant.’) a factor of 1 was chosen.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in the ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in the ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by the ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22.6 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
282.1 mg/m³
Explanation for the modification of the dose descriptor starting point:
For the inhalation route there is no reliable animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a TCPP specific factor of 0.8 (80% oral bioavailability; see EU RAR 2008) is taken forward for DNEL derivation. According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 80%/100% * 1/0.38 m³ per kg bw * 6.7 m³/10 m³ (based on the oral NOAEL of 200 mg/kg bw for systemic toxicity obtained in an acute toxicity on rats the starting point is calculated with 282.1 mg/m³.
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in the ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default AF to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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:
2.91 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):
50
Modified dose descriptor starting point:
LOAEL
Value:
145.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose for humans. 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 (ECHA guidance R.8, chapter 8.4.2). According to EU RAR (2008) TCPP specific bioavailabilities of 80% for the oral route and 40% for der dermal route (worst case scenario) are taken forward for DNEL derivation. Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers)
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a LOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 3. However, in line with the EU RAR 2008 (chapter 4.1.3.2.4 ‘Normally a further factor of 3 would be used to take into account the use of a LOAEL rather than a NOAEL. However, this is not considered necessary here, as the adverse effect in the repeated dose toxicity study (mainly liver weight changes) are not considered particularly toxicologically significant and the LOAEL is probably quite close to the NOAEL.’) a factor of 1 was chosen.
AF for differences in duration of exposure:
1
Justification:
In accordance with the EU RAR 2008 (chapter 4.1.3.2.4: ‘In addition, a factor to allow for semi chronic to chronic extrapolation (usually a factor of 2) was not used here. It is not considered necessary, as relatively similar effects on the liver, at doses of a comparable order of magnitude were observed in both the 28-day and the 90-day studies and so it is felt that exposure duration is not significant.’) a factor of 1 was chosen.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
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

The updated hazard conclusions for TCPP follow the most recent and relevant ECHA Guidance Documents. Thus, only one DNEL or qualitative hazard conclusion is derived for each type of hazard based on the lowest and most relevant NOAEL/LOAEL or qualitatively, on the most relevant critical effect for the route and exposure duration. For TCPP the experimentally derived value of 80% oral absorption and the worst-case dermal absorption rate of 40% will be taken forward to risk characterisation.

 

For hazard assessment relating to repeated dose toxicity of TCPP a LOAEL of 52 mg/kg bw/day is taken forward. This LOAEL is based on liver weight increases and mild thyroid follicular cell hyperplasia observed in a 13-week feeding study in rats. This LOAEL covers the LOAEL of 99 mg/kg bw/day for maternal toxicity obtained in a 2-generation reproductive toxicity feeding study in rats. For male rats, a NOAEL of approximately 85 mg/kg bw/day was derived in this study. The LOAEL of 52 mg/kg bw/day thus represents the lowest and thus, most relevant starting point.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.45 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:
LOAEC
Value:
36.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a TCPP specific factor of 0.8 (80% oral bioavailability; see EU RAR 2008) is taken forward for DNEL derivation. According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory LOAEC = oral LOAEL * 80%/100% * 1/1.15 m³ per kg and day (based on the oral LOAEL of 52 mg/kg bw/day for systemic toxicity obtained in a 90-day feeding study on rats).
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a LOAEL according to ECHA Guidance (November 2012), R.8.4.3.1 the default assessment factor for dose response relationship is 3. However, in line with the EU RAR 2008 (chapter 4.1.3.2.4 ‘Normally a further factor of 3 would be used to take into account the use of a LOAEL rather than a NOAEL. However, this is not considered necessary here, as the adverse effect in the repeated dose toxicity study (mainly liver weight changes) are not considered particularly toxicologically significant and the LOAEL is probably quite close to the NOAEL.’) a factor of 1 was chosen.
AF for differences in duration of exposure:
1
Justification:
In accordance with the EU RAR 2008 (chapter 4.1.3.2.4: ‘In addition, a factor to allow for semi chronic to chronic extrapolation (usually a factor of 2) was not used here. It is not considered necessary, as relatively similar effects on the liver, at doses of a comparable order of magnitude were observed in both the 28-day and the 90-day studies and so it is felt that exposure duration is not significant.’) a factor of 1 was chosen.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.6 mg/m³
Most sensitive endpoint:
acute 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
Value:
139.1 mg/m³
Explanation for the modification of the dose descriptor starting point:
For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a TCPP specific factor of 0.8 (80% oral bioavailability; see EU RAR 2008) is taken forward for DNEL derivation. According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 80%/100% * 1/1.15 m³ per kg (based on the oral NOAEL of 200 mg/kg bw for systemic toxicity obtained in an acute toxicity on rats the starting point is calculated with 139.1 mg/m³.
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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:
1.04 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:
LOAEL
Value:
104 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose for humans. 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 (ECHA guidance R.8, chapter 8.4.2). According to EU RAR (2008) TCPP specific bioavailabilities of 80% for the oral route and 40% for der dermal route (worst case scenario) are taken forward for DNEL derivation.
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a LOAEL according to ECHA Guidance (November 2012), R.8.4.3.1 the default assessment factor for dose response relationship is 3. However, in line with the EU RAR 2008 (chapter 4.1.3.2.4 ‘Normally a further factor of 3 would be used to take into account the use of a LOAEL rather than a NOAEL. However, this is not considered necessary here, as the adverse effect in the repeated dose toxicity study (mainly liver weight changes) are not considered particularly toxicologically significant and the LOAEL is probably quite close to the NOAEL.’) a factor of 1 was chosen.
AF for differences in duration of exposure:
1
Justification:
In accordance with the EU RAR 2008 (chapter 4.1.3.2.4: ‘In addition, a factor to allow for semi chronic to chronic extrapolation (usually a factor of 2) was not used here. It is not considered necessary, as relatively similar effects on the liver, at doses of a comparable order of magnitude were observed in both the 28-day and the 90-day studies and so it is felt that exposure duration is not significant.’) a factor of 1 was chosen.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
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:
0.52 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:
LOAEL
Value:
52 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Oral data from the rat are used to decide on a corresponding oral dose for humans. TCPP specific oral bioavailability of 80% for the rat is suggested to be adequate also for humans. Therefore a route-to-route extrapolation is not necessary and the LOAEL from the rat study is used as starting point.
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a LOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 3. However, in line with the EU RAR 2008 (chapter 4.1.3.2.4: ‘Normally a further factor of 3 would be used to take into account the use of a LOAEL rather than a NOAEL. However, this is not considered necessary here, as the adverse effect in the repeated dose toxicity study (mainly liver weight changes) are not considered particularly toxicologically significant and the LOAEL is probably quite close to the NOAEL.’) a factor of 1 was chosen.
AF for differences in duration of exposure:
1
Justification:
In accordance with the EU RAR 2008 (chapter 4.1.3.2.4: ‘In addition, a factor to allow for semi chronic to chronic extrapolation (usually a factor of 2) was not used here. It is not considered necessary, as relatively similar effects on the liver, at doses of a comparable order of magnitude were observed in both the 28-day and the 90-day studies and so it is felt that exposure duration is not significant.’) a factor of 1 was chosen.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
Most sensitive endpoint:
acute 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
Explanation for the modification of the dose descriptor starting point:
Oral data from the rat are used to decide on a corresponding oral dose for humans. The NOAEL of 200 mg/kg bw obtained in an acute oral toxicity study is taken forward. TCPP specific oral bioavailability of 80% for the rat is suggested to be adequate also for humans. Therefore a route-to-route extrapolation is not necessary and the NOAEL from the rat study is used as starting point.
AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The updated hazard conclusions for TCPP follow the most recent and relevant ECHA Guidance Documents. Thus, only one DNEL or qualitative hazard conclusion is derived for each type of hazard based on the lowest and most relevant NOAEL/LOAEL or qualitatively, on the most relevant critical effect for the route and exposure duration. For TCPP the experimentally derived value of 80% oral absorption and the worst-case dermal absorption rate of 40% will be taken forward to risk characterisation.

 

For hazard assessment relating to repeated dose toxicity of TCPP a LOAEL of 52 mg/kg bw/day is taken forward. This LOAEL is based on liver weight increases and mild thyroid follicular cell hyperplasia observed in a 13-week feeding study in rats. This LOAEL covers the LOAEL of 99 mg/kg bw/day for maternal toxicity obtained in a 2-generation reproductive toxicity feeding study in rats. For male rats, a NOAEL of approximately 85 mg/kg bw/day was derived in this study. The LOAEL of 52 mg/kg bw/day thus represents the lowest and thus, most relevant starting point.