2,4,6-tri-n-propyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.021 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:

NOAEL

Value:

62.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

76.562 mg/m³

Explanation for the modification of the dose descriptor starting point:

Conversion of the oral rat NOAEL into a corrected NOAEC to assess human inhalatory exposure.

The oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For worker a NOAEC long-term, inhalation was calculated assuming 70 kg per person, 8h light activity (10 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes. Additionally, a factor of 7/5 was added for the exposure days per week (test animals 7 days/ worker 5 days). NOAEC (Worker) inhalation = 62.5 mg/kg bw/day * 1/4 *70 kg * 1/10 m³ * 50 % Abs, (oral) / 100 % Abs, (inhal) = 76.5625 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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:

Recommended AF for interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.583 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):

300

Dose descriptor starting point:

NOAEL

Value:

62.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Although the physical chemical properties of the substance (molecular mass <500 g/mol, log Pow value =0 (estimated) which is in the range [-1, 4]), indicate a high dermal uptake rate of the substance (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”), the available data from the acute dermal toxicity study and the in vivo skin sensitisation study do not confirm this assumption due to the absence of clinical signs, although local skin effects were observed. As the molecular mass is still <500 and water solubility is >1000 mg/L (due to hydrolysis) and therefore favours dermal uptake, absorption through skin can however not be excluded and an absorption rate of 50 % was deduced. Additionally, a factor of 7/5 was added for the exposure days per week (test animals 7 days/ worker 5 days).

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 62.5 mg/kg bw/day x (100/50) = 175 mg/kg bw/d.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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

 

 

General

 

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Workers – Hazard via inhalation route

 

Long term systemic inhalation DNEL, worker

Calculation of dose descriptor

 Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation a inhalation NOAEC was derived by route to route extrapolation.

The oral NOAEL of 62.5 mg/kg bw/day, obtained from a subacte oral repeated dose toxicity testing in rats was considered as key value for the chemical safety assessment and therefore most relevant starting point.

 Step 2: Modification into a correct starting point:

The oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For worker a NOAEC long-term, inhalation was calculated assuming 70 kg per person, 8h light activity (10 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes. Additionally, a factor of 7/5 was added for the exposure days per week (test animals 7 days/ worker 5 days).

NOAEC (Worker) inhalation = 62.5 mg/kg bw/day * 1/4 *70 kg * 1/10 m³ * 50 % Abs, (oral) / 100 % Abs, (inhal) * 7/5= 76.5625 mg/m³

 Step 3: Use of assessment factors: 75

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

time extrapolation AF: 6

In conclusion the long term systemic inhalation DNEL workers was calculated to be 1.0208 mg/m³ bw/day.

 

Short term acute inhalation DNEL, worker

The test material is not classified and labelled for acute dermal and oral toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.

 

Workers – Hazard via dermal route

Long term systemic dermal DNEL, worker

Calculation of dose descriptor

 Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation a dermal NOAEL was derived by route to route extrapolation.

The oral NOAEL of 62.5 mg/kg bw/day, obtained from a subacute repeated dose oral toxicity testing in rats, was considered as key value for the chemical safety assessment and therefore most relevant starting point.

 Step 2: Modification into a correct starting point:

Although the physical chemical properties of the substance (molecular mass <500 g/mol, log Pow value =0 (estimated) which is in the range [-1, 4]), indicate a high dermal uptake rate of the substance (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”), the available data from the acute dermal toxicity study and the in vivo skin sensitisation study do not confirm this assumption due to the absence of clinical signs, although local skin effects were observed. As the molecular mass is still <500 and water solubility is >1000 mg/L (due to hydrolysis) and therefore favours dermal uptake, absorption through skin can however not be excluded and an absorption rate of 50 % was deduced.

Additionally, a factor of 7/5 was added for the exposure days per week (test animals 7 days/ worker 5 days).

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 62.5 mg/kg bw/day x (100/50) = 175 mg/kg bw/d. 

 

 Step 3: Use of assessment factors: 300

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF (subacute exposure period): 6

In conclusion the long term systemic dermal DNEL workers were calculated to be 0.5833 mg/kg bw/day.

 

Local effects, long term dermal exposure

The substance is classified as corrosive to skin (cat. 1B) according to Regulation (EC) No 1272/2008  (CLP).  The substance is therefore allocated to the medium hazard band (according to "Guidance on information requirements and chemical safety assessment part E: risk characterisation", May 2016).

 

Acute short term dermal DNEL, worker

Local dermal effects are covered by the long term local risk assessment and no quantitative acute local dermal assessment is required.

 

Worker – Hazard for the eyes

The substance is classified as corrosive to skin (cat. 1B) according to Regulation (EC) No 1272/2008 (CLP) and is therefore allocated to the medium hazard band. A qualitative risk assessment is conducted (according to “Guidance on information requirements and chemical safety assessment part E: risk characterization”, May 2016).

 

 

References

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.

- ECHA (2017). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. June 2017

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

- ECHA (2016).Guidance on information requirements and chemical safety assessment part E: risk characterization. May 2016.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.156 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):

150

Dose descriptor starting point:

NOAEL

Value:

62.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

23.438 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For general population a NOEC long-term, inhalation was calculated assuming 60 kg per person, 24h light activity (20 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.

NOEC (General population) inhalation = 62.5 mg/kg bw/day * 1/4 *60 kg * 1/20 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 23.4375 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is used.

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:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.208 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

62.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Although the physical chemical properties of the substance (molecular mass <500 g/mol, log Pow value =0 (estimated) which is in the range [-1, 4]), indicate a high dermal uptake rate of the substance (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”), the available data from the acute dermal toxicity study and the in vivo skin sensitisation study do not confirm this assumption due to the absence of clinical signs, although local skin effects were observed. As the molecular mass is still <500 and water solubility is >1000 mg/L (due to hydrolysis) and therefore favours dermal uptake, absorption through skin can however not be excluded and an absorption rate of 50 % was deduced. In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 62.5 mg/kg bw/day x (100/50) = 125 mg/kg bw/d. 

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.104 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):

600

Dose descriptor starting point:

NOAEL

Value:

62.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation was used as one repeated oral exposure study was available. For details on calculations please refer to the additional information.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The test item is not classified for acute oral toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required. 

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General

 

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

General population – Hazard via inhalation route

Long term systemic inhalation DNEL, general population

Calculation of dose descriptor

 

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation a inhalation NOAEC was derived by route to route extrapolation.

The oral NOAEL of 62.5 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in rats was considered as key value for the chemical safety assessment and therefore the most relevant starting point.

 

Step 2: Modification into a correct starting point:

In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For general population a NOEC long-term, inhalation was calculated assuming 60 kg per person, 24h light activity (20 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.

NOEC (General population) inhalation = 62.5 mg/kg bw/day * 1/4 *60 kg * 1/20 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 23.4375 mg/m³

 

Step 3: Use of assessment factors: 150

Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

In conclusion, long term systemic inhalation DNEL, general population = 0.1563 mg/m3

 

Short term acute inhalation DNEL, general population

The test material is not classified and labelled for acute oral and dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.

Local effects

No data on respiratory irritation is available. The substance is classified as corrosive to skin (cat. 1B) according to Regulation (EC) No 1272/2008 (CLP) and is therefore allocated to the medium hazard band (according to “Guidance on information requirements and chemical safety assessment part E: risk characterization”, May 2016).

 

General population – Hazard via dermal route

Long term systemic dermal DNEL, general population

Calculation of dose descriptor

 

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation a dermal NOAEL was derived by route to route extrapolation.

The oral NOAEL of 62.5 mg/kg bw/day, obtained from a subacute repeated dose oral toxicity testing in rats, was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point:

Although the physical chemical properties of the substance (molecular mass <500 g/mol, log Pow value =0 (estimated) which is in the range [-1, 4]), indicate a high dermal uptake rate of the substance (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”), the available data from the acute dermal toxicity study and the in vivo skin sensitisation study do not confirm this assumption due to the absence of clinical signs, although local skin effects were observed. As the molecular mass is still <500 and water solubility is >1000 mg/L (due to hydrolysis) and therefore favours dermal uptake, absorption through skin can however not be excluded and an absorption rate of 50 % was deduced. In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 62.5 mg/kg bw/day x (100/50) = 125 mg/kg bw/d. 

 

Step 3: Use of assessment factors: 600

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

In conclusion, long term systemic dermal DNEL, general population = mg/kg bw/day

 

Local effects, long term dermal exposure

The test item is classified as corrosive to skin (cat. 1B) according to Regulation (EC) No 1272/2008 (CLP) and is therefore allocated to the medium hazard band (according to “Guidance on information requirements and chemical safety assessment part E: risk characterization”, May 2016).

 

Acute short term dermal DNEL, general population

Local dermal effects are covered by the long term local risk assessment and no quantitative acute local dermal assessment is required.

 

General population – Hazard for the eyes

The substance is classified as corrosive to skin (cat. 1B) according to Regulation (EC) No 1272/2008 (CLP) and is therefore allocated to the medium hazard band (according to “Guidance on information requirements and chemical safety assessment part E: risk characterization”, May 2016).

 

General population – Hazard via oral route

Long term systemic oral DNEL, general population

 

Step 1: Selection of the relevant dose descriptor (starting point):

A subacute study in rats is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 62.5 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Not required.

 

Step 3: Use of assessment factors: 600

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

In conclusion, long term systemic oral DNEL, general population = 0.1042 mg/kg bw/day

 

Acute short term oral DNEL, general population

The acute oral systemic DNEL is not required as the substance is not classified for acute oral toxicity.

 

References

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.

- ECHA (2017). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. June 2017

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

- ECHA (2016). Guidance on information requirements and chemical safety assessment part E: risk characterization. May 2016.