Methanaminium, N-[4-[[4-(dimethylamino)phenyl]phenylmethylene]-2,5-cyclohexadien-1-ylidene]-N-methyl-, ethanedioate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.98 mg/m³

Most sensitive endpoint:

carcinogenicity

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:

other: NAEC

Value:

12.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

NAEC worker (8h) = (7 mg/kg bw/day/0.38 m³/kg bw) * 6.7 m³/ 10 m³ [where: NAEC is the modified starting point; 7 mg/kg bw/day is the NOAEL for carcinogenicity (NTP, 2005); 0.38 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity)]

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

1

Justification:

Chronic data

AF for interspecies differences (allometric scaling):

1

Justification:

Scaling issues just evaluated in modified starting point

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Worker population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

No futher uncertainties

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

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:

medium hazard (no threshold derived)

Additional information - workers

The tests considered about toxicological information were performed on several salification forms at the same organic molecule; the salts are chloride, acetate and oxalate. In all cases for those end points the toxicological influence of those counter ions is negligible compared to the toxicity and the metabolic pathway of the organic molecule. Therefore all the studies can be used in read-across to assess the related end point.

INHALATION ROUTE

The Derived No Effect Levelfor inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the carcinogenicity experiment coducted over a period of 2 years in rats and mcie.

The No Observed Adverse Effect Level (NOAEL) was established as 7 mg/kg body weight/day (rat).

In general, the calculation of DNELs is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

Systemic effects long term exposure

Corrected starting point for the inhalation route for workers: NAEC worker (8h) = (7 mg/kg bw/0.38 m³/kg bw) * 6.7 m³/ 10 m³

[where: NAEC is the modified starting point; 7 mg/kg bw/day is the NOAEL for carcinogenicity (oral route) (NTP, 2005); 0.38 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure. For workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m³for base level, 10 m³/kgfor light activity)].

Thus, the corrected starting point NAEC was estimated to be 12.3 mg/m³.

Subsequently other assessment factors have been used to derived the DNEL:

- corrections for differences in duration of exposure are not needed

- remaining differences 2.5

- intraspecies differences 5, for worker population

DERMAL ROUTE

Currently there are no available methods to determine thresholds and DNELs for skin sensitizers. Therefore, substances classified as a skin sensitizer category 1, according to the CLP Regulation (EC 1272/2008), should normally result in a qualitative assessment for the moderate level of concern. Skin sensitizers are allocated to the moderate hazard band on the basis that exposure to such substances should be well-controlled.

Since sensitisation is essentially systemic in nature, it is important for the purposes of risk management to acknowledge that skin sensitisation may be acquired by other routes of exposure than dermal. There is therefore a need for cautious use of known contact allergens in products to which consumers or workers may be exposed by inhalation.

The DNEL derived for inhalation route of exposure can be considered as sufficient to reduce a risk of sensitisation by this pathway: the risk management measures and operational conditionsensure theminimumpossible exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.24 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

other: NAEC

Value:

6.09 mg/m³

Explanation for the modification of the dose descriptor starting point:

NAEC general population (24h) = (7 mg/kg bw/day/1.15 m³/kg bw) [where: NAEC is the modified starting point; 7 mg/kg bw is the NOAEL for carcinogenicity (NTP, 2005); 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

1

Justification:

Chronic data

AF for interspecies differences (allometric scaling):

1

Justification:

Scaling issues just evaluated in modified starting point

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

No futher uncertainties

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

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:

0.07 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

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:

7 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No default factor should be introduced when performing on the same route; 7 mg/kg bw/day is the NOAEL for carcinogenicity (NTP, 2005)

AF for dose response relationship:

1

Justification:

Data well supported

AF for differences in duration of exposure:

1

Justification:

Chronic data

AF for interspecies differences (allometric scaling):

4

Justification:

From rat to human

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

Good quality and reliability

AF for remaining uncertainties:

1

Justification:

No futher uncertainties

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

The tests considered about toxicological information were performed on several salification forms at the same organic molecule; the salts are chloride, acetate and oxalate. In all cases for those end points the toxicological influence of those counter ions is negligible compared to the toxicity and the metabolic pathway of the organic molecule. Therefore all the studies can be used in read-across to assess the related end point.

INHALATION ROUTE

The Derived No Effect Levelfor inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the carcinogenicity experiment coducted over a period of 2 years in rats and mcie.

The No Observed Adverse Effect Level (NOAEL) was established as 7 mg/kg body weight/day (rat).

In general, the calculation of DNELs is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

Systemic effects long term exposure

Corrected starting point for the inhalation route for general population: NAEC general population (24h) = 7 mg/kg bw/day/1.15 m³/kg bw

[where: NAEC is the modified starting point; 7 mg/kg bw/day is the NOAEL for carcinogenicity (oral route) (NTP, 2005); 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure].

Thus, the corrected starting point NAEC was estimated to be 6.09 mg/m³.

Subsequently other assessment factors have been used to derived the DNEL:

- corrections for differences in duration of exposure are not needed

- remaining differences 2.5

- intraspecies differences 10, for general population

DERMAL ROUTE

Currently there are no available methods to determine thresholds and DNELs for skin sensitizers. Therefore, substances classified as a skin sensitizer category 1, according to the CLP Regulation (EC 1272/2008), should normally result in a qualitative assessment for the moderate level of concern. Skin sensitizers are allocated to the moderate hazard band on the basis that exposure to such substances should be well-controlled.

Since sensitisation is essentially systemic in nature, it is important for the purposes of risk management to acknowledge that skin sensitisation may be acquired by other routes of exposure than dermal. There is therefore a need for cautious use of known contact allergens in products to which consumers or workers may be exposed by inhalation.

The DNEL derived for inhalation/oral routes of exposure can be considered as sufficient to reduce a risk of sensitisation by this pathway: the risk management measures and operational conditions ensures the minimum possible exposure.

ORAL ROUTE

The Derived No Effect Level for oral long-term exposure is estimated from the No Observed Effect Level obtained from the carcinogenicity assessment. The No Observed Adverse Effect Level (NOAEL) was established as 7 mg/kg body weight/day.

In general, the calculation of DNELs is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

Systemic effects long term exposure

Starting point for the oral route for general population: NOAEL = 7mg/kg bw

[where: 7 mg/kg bw/day is the NOAEL for carcinogenicity (oral route) (NTP, 2005)]

No default factor should be introduced when performing on the same route.

Subsequently other assessment factors have been used to derived the DNEL:

- corrections for differences in duration of exposure are not needed

- because the NOAEL was recorded in a study conducted on rats, for interspecies differences the allometric scaling of 4 has been used

- remaining differences 2.5

- intraspecies differences 10, for general population