Polymer with 2-Butyne-1,4-Diol and (Chloromethyl-)Oxirane, Brominated, Dehydrochlorinated, Methoxylated

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.03 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

300 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

150.75 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the starting point (NOAEC of 300 mg/m3):

- Correction of exposure duration in study (6 hrs/day, 5 days/week) to default worker exposure (8 hrs/day, 5 days/week);

- Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEC

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

not for concentration

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

not applicable

AF for remaining uncertainties:

1

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:

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

Dose descriptor starting point:

NOAEL

Value:

150 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:

No route to route extrapolation applied. Since no substance specific absorption data is available, default values will be used: 100% for oral and 100% for dermal absorption.

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

Justification:

not applicable

AF for remaining uncertainties:

1

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

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH Guidance (R.8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since Polyol IXOL M125 is classified for acute oral toxicity, short-term DNELs should be derived. However, for workers no short-term DNELs for systemic effects are deemed necessary because the risk of peak exposures is managed considering the risk management measures prescribed for long-term exposure. The substance is not classified as irritating to the skin and is not sensitizing. Therefore no DNEL for local dermal effects and for sensitization needs to be derived. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived.

Long-term toxicity

The systemic NOAEC of 300 mg/m3 obtained in the 90 -day inhalation study with the structural analogue Polyol IXOL B350 was used to derive the long-term inhalation DNEL for systemic effects. As no repeated-dose toxicity studies are available for the dermal and oral route, the systemic NOAEL of 150 mg/kg bw/day from the oral EOGRTS study with the analogue Polyol IXOL B350 was used to derive the long-term DNEL for systemic dermal effects.

 

Worker DNELs

Long-term inhalation

Long-term – inhalation, local/systemic effects (based on the 90 days inhalation study in rats)   

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 300 mg/m^3	Exposure of rats to Polyol IXOL B350 at concentrations of 300 mg/m3 did not induce changes indicative of local or systemic toxicity (changes in haematology, clinical chemistry and organ weights). Therefore, 300 mg/m3 was considered to be the NOAEC for local and systemic toxicity in rats exposed for 6 hours/day, 5 days/week for a period of 90 days.
Step 2) Modification of starting point	6/8         6.7 m3/10 m3	Correction of exposure duration in study (6 hrs/day, 5 days/week) to default worker exposure (8 hrs/day, 5 days/week);   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).
Modified dose-descriptor	300 x 6.7 x 6 / (10 x 8) = 150.75 mg/m3
Step 3) Assessment factors
Interspecies	2.5	No factor for allometric scaling is needed in case of inhalation exposure. A default factor of 2.5 for remaining uncertainties is used.
Intraspecies	5	Default assessment factor
Exposure duration	2	Extrapolation from sub-chronic to chronic exposure
Dose response	1
Quality of whole database	1
DNEL	Value
	145.73 / (2.5 x 5 x 2 x 1 x 1) = 6.03 mg/m3

Long-term dermal

Long-term – dermal, systemic effects (based on the extended one-generation toxicity study in rats) 

As dermal repeated dose toxicity studies with Polyol IXOL M125 are not available, route to route extrapolation was applied to derive a DNEL for the dermal route,

based on the systemic NOAEL of 150 mg/kg bw/day from the oral EOGRTS study with the analogue Polyol IXOL B350.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 150 mg/kg bw/day	Oral exposure to Polyol IXOL B350 (OECD 443, GLP) at dosages of 0, 75, 150 and 450 mg/kg bw/day resulted in treatment-related adverse findings consisting of intratubular hemorrhage in the kidneys of F0 males administered 450 mg/kg/day and thyroid adenomas in F0 males administered>75 mg/kg/day, one female adminstered 450 mg/kg/day, and one F1 male administered 75 mg/kg/day. It should be noted that the relevance of such thyroid effects in rat studies - in quantitative terms - to humans is limited. Therefore the kidney effect is considered the most critical effect of Polyol IXOL B350 after repeated oral exposure. Based on the available study, the overall NOAEL for systemic effects by oral route is 150 mg/kg bw/day.
Step 2) Modification of starting point	1	As no substance specific data is available, default figures will be used:Conservative default for route to route: 100% for inhalation and 100% for dermal absorption
Modified dose-descriptor	150 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining uncertainties.
Intraspecies	5	Default assessment factor
Exposure duration	2	Extrapolation from sub-chronic to chronic exposure
Dose response	1
Quality of database	1
DNEL	Value
	150 / (4 x 2.5 x 5 x 2 x 1 x 1) = 1.5 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.07 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEC

Value:

300 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

53.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the starting point (NOAEC of 300 mg/m3):

- Correction of exposure duration in study (6 hrs/day, 5 days/week) to default exposure duration for general population (24 hrs/day, 7 days/week)

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEC

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

not for concentration

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

10

Justification:

default factor for general population

AF for the quality of the whole database:

1

Justification:

not applicable

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.2 mg/m³

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

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:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

150 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:

No route to route extrapolation applied. Since no substance specific absorption data is available, default values will be used: 100% for oral and 100% for dermal absorption.

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for the quality of the whole database:

1

Justification:

not applicable

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.25 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

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:

0.75 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:

150 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:

No route to route extrapolation applied.

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling

AF for other interspecies differences:

2.5

Justification:

Assessment factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default assessment factor for general population

AF for the quality of the whole database:

1

Justification:

Not applicable

AF for remaining uncertainties:

1

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

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH Guidance (R.8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since Polyol IXOL M125 is classified for acute oral toxicity, short-term DNELs should be derived. However, for workers no short-term DNELs for systemic effects are deemed necessary because the risk of peak exposures is managed considering the risk management measures prescribed for long-term exposure.The substance is not classified as irritating to the skin and is not sensitizing. Therefore no DNEL for local dermal effects and for sensitization needs to be derived. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived.

Long-term toxicity

The systemic NOAEC of 300 mg/m3 obtained in the 90 -day inhalation study with the structural analogue Polyol IXOL B350 was used to derive the long-term inhalation DNEL for systemic effects. As no repeated-dose toxicity studies are available for the dermal and oral route, thesystemic NOAEL of150 mg/kg bw/day from the oral EOGRTS study with the analogue Polyol IXOL B350 was used to derive the long-term DNEL for systemic dermal effects.

 

General population DNELs

Inhalation

Long-term – inhalation, systemic effects (based on the 90 days inhalation study in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 300 mg/m3	Exposure of rats to Polyol IXOL B350 at concentrations of 300 mg/m3 did not induce changes indicative of local or systemic toxicity (changes in haematology, clinical chemistry and organ weights). Therefore, 300 mg/m3 was considered to be the NOAEC for local and systemic toxicity in rats exposed for 6 hours/day, 5 days/week for a period of 90 days.
Step 2) Modification of starting point	6/24	Correction of exposure duration in study (6 hrs) to default exposure duration for general population (24 hrs).
Modified dose-descriptor	300 x 6 / 24 = 75 mg/m3
Step 3) Assessment factors
Interspecies	2.5	No factor for allometric scaling is needed in case of inhalation exposure. A default factor of 2.5 for remaining uncertainties is used.
Intraspecies	10	Default assessment factor
Exposure duration	2	Extrapolation from sub-chronic to chronic exposure
Dose response	1
Quality of whole database	1
DNEL	Value
	75 / (2.5 x 10 x 2 x 1 x 1) = 1.5 mg/m3

Dermal/Oral

Long-term – dermal/oral, systemic effects (based on the extended one-generation toxicity study in rats) 

As repeated dose toxicity studies with Polyol IXOL M125 are not available for the oral and dermal route, the systemic NOAEL of 150 mg/kg bw/day from the oral EOGRTS study with the analogue Polyol IXOL B350 was used to derive the long-term DNEL for systemic oral and dermal effects.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 150 mg/kg bw/day	Oral exposure to Polyol IXOL B350 (OECD 443, GLP) at dosages of 0, 75, 150 and 450 mg/kg bw/day resulted in treatment-related adverse findings consisting of intratubular hemorrhage in the kidneys of F0 males administered 450 mg/kg/day and thyroid adenomas in F0 males administered>75 mg/kg/day, one female adminstered 450 mg/kg/day, and one F1 male administered 75 mg/kg/day. It should be noted that the relevance of such thyroid effects in rat studies - in quantitative terms - to humans is limited. Therefore the kidney effect is considered the most critical effect of Polyol IXOL B350 after repeated oral exposure. Based on the available study, the overall NOAEL for systemic effects by oral route is 150 mg/kg bw/day.
Step 2) Modification of starting point	1	As no substance specific data is available, default figures will be used:Conservative default for route to route: 100% for inhalation and 100% for dermal absorption
Modified dose-descriptor	150 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining uncertainties.
Intraspecies	10	Default assessment factor
Exposure duration	2	Extrapolation from sub-chronic to chronic exposure
Dose response	1
Quality of database	1
DNEL	Value
	150 / (4 x 2.5 x 10 x 2 x 1 x 1) = 0.75 mg/kg bw/day