2,4,6-triallyloxy-1,3,5-triazine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.12 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

Value:

52.89 mg/m³

Explanation for the modification of the dose descriptor starting point:

According to predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100 %. The inhalative absorption is considered to be in the same order of magnitude as the oral absorption. Therefore no additional factor is applied for differences between the oral and inhalative intake.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable.

AF for differences in duration of exposure:

2

Justification:

Default conversion AF subchronic to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.

AF for intraspecies differences:

5

Justification:

Default AF for the worker.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further AFs are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

134.4 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

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEC

Value:

1 680 mg/m³

Explanation for the modification of the dose descriptor starting point:

According to predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100 %. The inhalative absorption is considered to be in the same order of magnitude as the oral absorption. Therefore no additional factor is applied for differences between the oral and inhalative intake.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.

AF for intraspecies differences:

5

Justification:

Default AF for the worker.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further AFs are required.

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:

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):

100

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

According to QSAR predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100%, whereas dermal uptake is predicted to be low (0.001 mg/cm2/event). Based on this, a dermal uptake of 20% is assumed. No differences in dermal absorption between rats and humans are presumed.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable.

AF for differences in duration of exposure:

2

Justification:

Default conversion AF subchronic to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for differences between rats and humans.

AF for other interspecies differences:

2.5

Justification:

There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.

AF for intraspecies differences:

5

Justification:

Default AF for the worker.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further AFs are required.

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

Workers might be exposed to triallyl cyanurate (liquid or vapour) during manufacture, processing or filling in appropriate containers. During formulation, triallyl cyanurate-coated silica particles containing 50 or 70 % TAC are obtained. Exposure may occur to liquid triallyl cyanurate or the vapour; however, the predominant relevant way of exposure is via triallyl cyanurate-coated silica particles.

Since no usable dose descriptors for the dermal and inhalation exposure route are available, the only usable dose descriptor (oral route) to derive long-term DNELs, the dermal as well as inhalation DNELs, regarding acute and long-term effects on workers were determined using route-to-route extrapolation, according to the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

For the derivation of all relevant DNELs a NOAEL of 30 mg/kg bw/day obtained in a 90-day gavage study in rats was used. The establishment of an acute toxicity DNEL set for effects occurring after a single exposure of a few minutes up to 24 hours is unnecessary for TAC, as the long-term DNEL is sufficient to ensure, that these effects do not occur. TAC has a very low vapour pressure at room temperature and as a consequence, the formation of aerosols can be considered negligible. Thus, peak exposure significantly higher than the average daily exposure and the long-term DNEL are very unlikely. In addition since TAC did not show any irritating effects, no DNELs for local effects were derived. The assessment of hazards for acute systemic effects and local effects are sufficiently covered by derivation of the DNEL for long-term systemic exposure.

 

As starting point for derivation of the DNELs, a NOAEL of 30 mg/kg bw/day (for systemic effects) was used which was found in a subchronic toxicity study performed according to OECD 408 (2012-0288-DGT). In this GLP guideline study TAC was administered via gavage at concentrations of 10, 30 and 120 mg/kg bw/day for 90 days. Additional satellite animals for the control, mid and high dose group for observation of reversibility, persistence or delayed occurrence of toxic effects were included for 56 days post treatment. A NOAEL of 30 mg/kg/day was derived based on the significant histopathological changes in the liver in male rats dosed with 120 mg/kg bw/day at the end of the treatment period (which have mainly subsided after the recovery period) and other evidence of toxicity as clinical signs, reduced body weight, effects on functional observational battery parameters, and increased liver weights observed in both female and male animals dosed with 120 mg/kg bw/day. Thus, the NOAEL value of 30 mg/kg bw/day was selected as relevant dose descriptor.

 

Dermal

 

To convert an oral NOAEL (in mg/kg bw/day) into a dermal NOAEL (in mg/kg bw/day, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. According to QSAR predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100%, whereas dermal uptake is predicted to be low (0.001 mg/cm2/event). Based on this, a dermal uptake of 20% is assumed. No differences in dermal absorption between rats and humans are presumed.

The conversion of the oral NOAEL into the dermal NOAEL is performed using the following equation:

Corrected dermal NOAEL = oral NOAEL x ABS oral / ABS dermal

= 30 mg/kg bw/day x 100 / 20 = 150 mg/kg bw/day

Subsequently, the following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (5) and duration extrapolation: subchronic - chronic (2), resulting in an overall assessment factor of 100.

As a consequence, the resulting DNEL for long-term dermal systemic effects is 1.5 mg/kg bw/day for workers.

 

Inhalation 

 

For calculation of the DNEL for long-term inhalative systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. According to QSAR predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100 %. The inhalative absorption is considered to be in the same order of magnitude as the oral absorption. Therefore no additional factor is applied for differences between the oral and inhalative intake.

The conversion of an oral NOAEL into an inhalation NOAEC is performed using the following equation:

For workers (light activity):

Corrected inhalatory NOAEC = oralNOAEL x 1/sRVanimal x ABSoral / ABS inhalation x sRVhuman / wRV

 

The standard respiratory volume for the 8 h exposure is 0.38 m3/kg bw for rats and 6.7 m3 (per person) in humans. The default 8-h respiratory volume of a worker is 10 m³ taking increased activity into account.

For a short-term scenario of 15 min exposure, different standard parameters are used. The standard respiratory volume for the 15 min exposure is 0.012 m3/kg bw for rats and 0.21 m3 in humans. The default 15 min respiratory volume of a worker is 0.3125 m³.

This results in the following equations:

For 8 h exposure:

Corrected inhalatory NOAEC = oralNOAEL x 1/0.38 m3/kg bw x 6.7 m3 / 10 m3

For 15 min exposure:

Corrected inhalatory NOAEC = oralNOAEL x 1 / 0.012m3/kg x 0.21 m3 / 0.3125 m3

Subsequently assessment factors (AF) are listed, which have to be taken into account for the final DNEL calculation: remaining interspecies-differences (2.5), intraspecies differences (5), duration extrapolation: subchronic - chronic (2), resulting in an overall assessment factor of 25 for long-term exposure and 12.5 for short-term exposure (no duration extrapolation applied). The inhalative DNELs for workers are calculated according to the formula DNEL = (corrected starting point)/(overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 2.12 mg/m³ and the resulting DNEL for short-term inhalative systemic effects is 134.4 mg/m³.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.52 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

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

26 mg/m³

Explanation for the modification of the dose descriptor starting point:

most relevant study

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

1

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

0.75 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

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Conversion of oral NOAEL into dermal NOAEL under consideration of dermal and oral absorption. Please refer to discussion. 

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

0.15 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

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

most relevant study

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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

Consumers might be exposed to triallyl cyanurate at mentioned life-cycle stages.  

Since no usable dose descriptors for the dermal and inhalation exposure route are available, the only usable dose descriptor (oral route) to derive long-term DNELs, the dermal as well as inhalation DNELs, regarding acute and long-term effects on workers were determined using route-to-route extrapolation, according to the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

For the derivation of all relevant DNELs a NOAEL of 30 mg/kg bw/day obtained in a 90-day gavage study in rats was used. The establishment of an acute toxicity DNEL set for effects occurring after a single exposure of a few minutes up to 24 hours is unnecessary for TAC, as the long-term DNEL is sufficient to ensure, that these effects do not occur. TAC has a very low vapour pressure at room temperature and as a consequence, the formation of aerosols can be considered negligible. Thus, peak exposure significantly higher than the average daily exposure and the long-term DNEL are very unlikely. In addition, since TAC did not show any irritating effects, no DNELs for local effects were derived. The assessment of hazards for acute systemic effects and local effects are sufficiently covered by derivation of the DNEL for long-term systemic exposure.

As starting point for derivation of the DNELs, a NOAEL of 30 mg/kg bw/day (for systemic effects) was used which was found in a subchronic toxicity study performed according to OECD 408 (2012-0288-DGT). In this GLP guideline study TAC was administered via gavage at concentrations of 10, 30 and 120 mg/kg bw/day for 90 days. Additional satellite animals for the control, mid and high dose group for observation of reversibility, persistence or delayed occurrence of toxic effects were included for 56 days post treatment. A NOAEL of 30 mg/kg/day was derived based on the significant histopathological changes in the liver in male rats dosed with 120 mg/kg bw/day at the end of the treatment period (which have mainly subsided after the recovery period) and other evidence of toxicity as clinical signs, reduced body weight, effects on functional observational battery parameters, and increased liver weights observed in both female and male animals dosed with 120 mg/kg bw/day. Thus, the NOAEL value of 30 mg/kg bw/day was selected as relevant dose descriptor.

 

Dermal

To convert an oral NOAEL (in mg/kg bw/day) into a dermal NOAEL (in mg/kg bw/day, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. According to QSAR predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100%, whereas dermal uptake is predicted to be low (0.001 mg/cm2/event). Based on this, a dermal uptake of 20% is assumed. No differences in dermal absorption between rats and humans are presumed.

The conversion of the oral NOAEL into the dermal NOAEL is performed using the following equation:

Corrected dermal NOAEL = oral NOAEL x ABS oral / ABS dermal

= 30 mg/kg bw/day x 100 / 20 = 150 mg/kg bw/day

Subsequently, the following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (10) and duration extrapolation: subchronic - chronic (2), resulting in an overall assessment factor of 200.

As a consequence, the resulting DNEL for long-term dermal systemic effects is 0.75 mg/kg bw/day for general population.

 

Inhalation 

For calculation of the DNEL for long-term inhalative systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. According to QSAR predictions obtained from the Danish (Q)SAR database (2009), gastrointestinal absorption is presumed to be 100 %. The inhalative absorption is considered to be in the same order of magnitude as the oral absorption. Therefore, no additional factor is applied for differences between the oral and inhalative intake.

The conversion of an oral NOAEL into an inhalation NOAEC is performed using the following equation (assuming 100 % absorption for both routes in both species):

For general population:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat

 = 30 x 1/1.15

The corrected inhalation NOAECgeneral population (24 h) is therefore:

= 26 mg/m³ (24 h)

The standard respiratory volume for the 8 h exposure is 0.38 m3/kg bw for rats and 6.7 m3 (per person) in humans. The default 8-h respiratory volume of a worker is 10 m³ taking increased activity into account.

Subsequently assessment factors (AF) are listed, which have to be taken into account for the final DNEL calculation: remaining interspecies-differences (2.5), intraspecies differences (10), duration extrapolation: subchronic - chronic (2), resulting in an overall assessment factor of 50 for long-term exposure.  The inhalative DNEL for general population are calculated according to the formula DNEL = (corrected starting point)/(overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 0.52 mg/m³.

 

Oral

Start value: NOAEL 30 mg/kg bw/d

Route of original study: oral (no route-to-route extrapolation required)

Subsequently assessment factors (AF) are listed, which have to be taken into account for the final DNEL calculation: allometric scaling factor (4), remaining interspecies-differences (2.5), intraspecies differences (10), duration extrapolation: subchronic - chronic (2), resulting in an overall assessment factor of 200 for long-term exposure.  The oral DNEL for general population are calculated according to the formula DNEL = (starting point)/(overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 0.15 mg/kg.