Methenamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.6 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

Dose descriptor starting point:

NOAEL

Value:

80

Modified dose descriptor starting point:

NOAEC

Value:

70 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

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:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

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:

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:

6.4 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:

NOAEL

Value:

320 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be 25 % of oral absorption.Fordetailsrefertothediscussion.

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:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

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:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

General

DNEL derivation for the substance methenamine 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 80 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in rats by Lijinsky (1977), was considered as key value for the chemical safety assessment and therefore, 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 worker a NOEC 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.

NOEC (Worker)inhalation = 80 mg/kg bw/day * 1/4 *70 kg * 1/10 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 70 mg/m³

Step 3: Use of assessment factors: 12.5

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

In conclusion the long term systemic inhalation DNEL workers was calculated to be 5.6 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). Furthermore, based on the physical parameters a peak exposure is not expected. The substance is solid with a very low vapour pressure. Inhalation exposure is regarded negligible as no particles below 125 µm were detected in particle size analysis (see section 4.5). 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. As the substance is not classified as skin and eye irritating also no adverse effects on respiratory system is expected (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). Based on the physical parameters a peak exposure is not expected. The substance is solid with a very low vapour pressure. Inhalation exposure is regarded negligible as no particles below 125 µm were detected in particle size analysis (see section 4.5). Thus, no DNEL and no qualitative risk assessment 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 80 mg/kg bw/day, obtained from chronic repeated dose oral toxicity testing in rats by Lijinsky (1977), was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

Step 2: Modification into a correct starting point:

Based on the physical chemical properties of the substance (high water solubility, log Pow value <0) a dermal absorption rate of 25 % through skin was deduced.

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat /ABS dermal human] = 80 mg/kg bw/day x (100/25) = 320 mg/kg bw/d.

Step 3: Use of assessment factors: 50

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF (chronic exposure period): 1

In conclusion the long term systemic dermal DNEL workers were calculated to be 6.4 mg/kg bw/day.

Acute short term dermal DNEL, worker

The test material is not classified and labelled for acute dermal 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.

Worker – Hazard for the eyes

According to the EU (DSD and GHS) criteria for classification and labelling requirements for dangerous substances and preparations the test item does not have to be classified and has no obligatory labelling requirement for eye irritation.

References

(not included as endpoint study record)

- 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 (2010). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2012.

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 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):

25

Dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

30 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

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:

1

Justification:

No assessment factor for duration of exposure is needed as the NOEC was derived from a chronic study.

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

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:

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:

3.2 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:

320 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be 25 % of oral absorption. For details refer to the discussion.

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:

1

Justification:

No assessment factor for duration of exposure is needed as the NOEC was derived from a chronic study.

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

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 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:

80 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation is required.

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:

1

Justification:

No assessment factor for duration of exposure is needed as the NOEC was derived from a chronic study.

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General

DNEL derivation for the substance methenamine 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 80 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in rats by Lijinsky (1977), was considered as key value for the chemical safety assessment and therefore, 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 = 80 mg/kg bw/day * 1/4 *60 kg * 1/20 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 30 mg/m³

Step 3: Use of assessment factors: 25

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: 1 (chronic study)

In conclusion, long term systemic inhalation DNEL, general population = 1.2 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 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.

 

Local effects

No data on respiratory irritation is available. As the substance is not classified as skin and eye irritating also no adverse effects on respiratory system is expected (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). Based on the physical parameters a peak exposure is not expected. The substance is solid with a very low vapour pressure. Inhalation exposure is regarded negligible as no particles below 125 µm were detected in particle size analysis (see section 4.5). Thus, no DNEL is required.

 

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 80 mg/kg bw/day, obtained from chronic repeated dose oral toxicity testing in rats by Lijinsky (1977), was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

Step 2: Modification into a correct starting point:

Based on the physical chemical properties of the substance (high water solubility, log Pow value <0) a dermal absorption rate of 25 % through skin was deduced.

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 80 mg/kg bw/day x (100/25) = 320 mg/kg bw/d.

Step 3: Use of assessment factors: 100

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 1 (chronic study)

 

In conclusion, long term systemic dermal DNEL, general population = 3.2 mg/kg bw/day 

Acute short term dermal DNEL, general population

The test material is not classified and labelled for acute dermal 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.

 

General population – Hazard for the eyes

According to the EU (DSD and GHS) criteria for classification and labelling requirements for dangerous substances and preparations the test item does not have to be classified and has no obligatory labelling requirement for eye irritation.

 

 

General population – Hazard via oral route

 

Long term systemic oral DNEL, general population

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

A chronic study in rats (Lijinski, 1977) 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 80 mg/kg bw/day.

Step 2: Modification of the starting point:

Not required.

Step 3: Use of assessment factors: 100

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 1 (chronic study)

In conclusion, long term systemic oral DNEL, general population = 0.8 mg/kg bw/day

Acute short term dermal DNEL, general population

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

 

References

(not included as endpoint study record)

 

- 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 (2010). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2012.

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