C8-18 alkylampho(di)propionates

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance. Although there were no adverse effects observed at the highest recommended test dose, a DNEL was derived conservatively.

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

2 286 mg/m³

Explanation for the modification of the dose descriptor starting point:

No evidence is available that route-to-route extrapolation is not possible

AF for dose response relationship:

1

Justification:

Value is NOAEL (NB: No significant adverse effects observed at the maximum dose recommended)

AF for differences in duration of exposure:

6

Justification:

Subacute study; chronic exposure worker

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies

AF for remaining uncertainties:

1

Justification:

Not relevant

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

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:

8.64 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance. Although there were no adverse effects observed at the highest recommended test dose, a DNEL was derived conservatively.

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

2 593 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No evidence is available that route-to-route extrapolation is not possible

AF for dose response relationship:

1

Justification:

Value is NOAEL (NB: No significant adverse effects observed at the maximum dose recommended)

AF for differences in duration of exposure:

6

Justification:

Subacute study; chronic exposure worker

AF for interspecies differences (allometric scaling):

4

Justification:

Rat to human

AF for other interspecies differences:

2.5

Justification:

Additional factor for remaining differences

AF for intraspecies differences:

5

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies

AF for remaining uncertainties:

1

Justification:

Not relevant

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

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

See the discussion below.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance. Although there were no adverse effects observed at the highest recommended test dose, a DNEL was derived conservatively.

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEC

Value:

1 127 mg/m³

Explanation for the modification of the dose descriptor starting point:

No evidence is available that route-to-route extrapolation is not possible

AF for dose response relationship:

1

Justification:

Value is NOAEL (NB: No significant adverse effects observed at the maximum dose recommended)

AF for differences in duration of exposure:

6

Justification:

Subacute study; chronic exposure general population

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation

AF for other interspecies differences:

2.5

Justification:

Additional factor for remaining differences

AF for intraspecies differences:

10

Justification:

Difference in sensitivity amongst general population

AF for the quality of the whole database:

1

Justification:

Reliable studies

AF for remaining uncertainties:

1

Justification:

Not relevant

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

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:

4.32 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance. Although there were no adverse effects observed at the highest recommended test dose, a DNEL was derived conservatively.

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

2 593 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No evidence is available that route-to-route extrapolation is not possible

AF for dose response relationship:

1

Justification:

Value is NOAEL (NB: No significant adverse effects observed at the maximum dose recommended)

AF for differences in duration of exposure:

6

Justification:

Subacute study; chronic exposure general population

AF for interspecies differences (allometric scaling):

4

Justification:

Rat to human

AF for other interspecies differences:

2.5

Justification:

Additional factor for remaining differences

AF for intraspecies differences:

10

Justification:

Difference in sensitivity amongst general population

AF for the quality of the whole database:

1

Justification:

Reliable studies

AF for remaining uncertainties:

1

Justification:

Not relevant

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

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:

4.32 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance. Although there were no adverse effects observed at the highest recommended test dose, a DNEL was derived conservatively.

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

2 593 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

Value is NOAEL (NB: No significant adverse effects observed at the maximum dose recommended)

AF for differences in duration of exposure:

6

Justification:

Subacute study (chronic exposure assumed)

AF for interspecies differences (allometric scaling):

4

Justification:

Remaining differences

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

Difference in sensitivity within population

AF for the quality of the whole database:

1

Justification:

Reliable studies with dose-response

AF for remaining uncertainties:

1

Justification:

Not relevant

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Introduction

The registered substance is Reaction products of 1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-(C7-C17 odd-numbered, C17-unsatd. alkyl) derivs. and methyl acrylate and sodium hydroxide (synonym: C8-18 alkylampho(di)propionates). Because the solvent (water) could not be removed without changing the composition, the registered UVCB substance includes also water and methanol as constituents. DNELs will be calculated, if applicable, for the substance and for the solid content of the substance (for the DNELs for methanol: see below).

Toxicological profile

Considering the available data on C8-18 alkylampho(di)propionates), the following starting points are considered relevant for setting of DNELs. Toxicological tests were performed with the registered test substance (including water and methanol).

 

Endpoint/test type	Result/effect	Classification
Acute toxicity, irritation, sensitisation
Rat oral LD50	>5000 mg/kg bw (>2000 mg solid content/kg bw)	no
Rat dermal LD50	>5190mg/kg bw (>2000 mg solid content/kg bw )	no
Rat inhalation LC50	No data	-
Skin irritation	Not irritating	no
Eye irritation	Corrosive (due to lack of data on reversibility of effects)	Cat 1
Sensitisation	Sensitising (GPMT)	Cat 1B
Repeated dose toxicity (subacute/subchronic)
OECD 422, rat	NOAEL: 2593 mg/kg bw/d (1000 mg solid content/kg bw)	no
Genotoxicity
Ames test	Negative (+/-S9)	no
Mouse Lymphoma Assay	- Substance: Negative (-S9); Positive (+S9); 3.3-fold increase only at one cytotoxic concentration. Effects reproduced in a repeat experiment (up to 2.5-fold increase) (*) - Solid content: Negative (+/-S9)
Chromosome aberration test	Negative (+/-S9)
Long term toxicity and carcinogenicity
No study available
Reproductive/developmental toxicity
OECD 422, rat	NOAEL reproduction /developmental: 2593 mg/kg bw/d (1000 mg solid content/kg bw)	no

(*) Related to the low levels of methanol by-product. Methanol is not considered a mutagenic substance based on weight of evidence from numerous in vitro and in vivo studies.

In addition, because methanol is listed in Annex VI of the CLP Regulation (index # 603-001-00-X) with specific concentration limits, an additional hazard classification is applied to the registered substance by calculation when the methanol content is above 3%: STOT SE cat.2, H371. The risks specifically related to the classification triggered by the methanol content will be assessed separately using the DNELs specific to methanol (see below).

Route-to-route extrapolation

Based on the performed toxicokinetic assessment, the following values are considered for absorption:

Oral absorption: 50 %

Dermal absorption: 50%

Inhalation absorption: 100%

 

Derivation of DNELs (for the substance and for the solid content of the registered substance)

The DNELs for human exposure are derived according to the ECHA Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterization of dose [concentration]-response for human health, Nov 2012.

 

C8-18 alkylampho(di)propionates is not classified for acute oral and dermal effects, and therefore, no acute systemic DNELs have to be derived for the registered substance. The long-term systemic DNEL is considered sufficient to ensure that effects from acute exposure to the substance do not occur, assuming no peak exposure occurs for oral and dermal exposure (as per ECHA Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterization of dose [concentration]-response for human health, Nov 2012 and Part B: Hazard Assessment, chapter B.8 Scope of Exposure Assessment, v2.1, December 2011). However, the risk related to hazard classification STOT SE2 associated with the methanol content above 3% will be assessed using the DNEL available on methanol.

 

C8-18 alkylampho(di)propionates is not irritating to the skin, but can cause serious damage to the eyes (reversibility was not assessed). As no quantitative DNEL can be derived from an eye irritation/corrosion study, qualitative risk assessment will be performed taking into consideration the personal protective equipment recommended as RMM.

 

The substance has sensitizing properties. As no quantitative DNEL can be derived from a GPMT test, a dermal systemic DNEL will not be derived from this study, and a qualitative risk assessment will be conducted and appropriate RMM applied.

 

The starting point for DNELs is the no adverse effect level in a relevant study. With regard to the systemic toxicity, a repeated dose toxicity (28-day) combined with a reproductive/developmental toxicity screening by the oral route in rats showed no evidence of adverse effects at the maximum dose of 2593 mg/kg/day for the substance as registered, or 1000 mg solids/kg/day. Based on the guidance document R8, a DNEL is not normally required in this case. However, to further assess the risk related to the uncertainty of the incomplete database, a conservative DNEL was derived using the maximum recommended test dose as a starting point.

 

For the endpoint mutagenicity, a positive result has been found in the in vitro mouse lymphoma assay, indicating a potential mutagenic activity (chromosome aberrations and point mutations). However the other available in vitro assays, an in vitro chromosome aberration assay and a reverse mutation assay in bacteria, were both negative both in the presence and absence of metabolic activation. Also an in vitro Mouse Lymphoma Assay with a freeze dried sample of the substance, representing the solid content of the registered substance, has been performed. Based on the results of this study, it was concluded that the solid content of the registered substance is not mutagenic in the absence as well as in the presence of S9-mix in this assay. The observed effects are related to the low levels of methanol by-product. Methanol is not considered a mutagenic substance based on weight of evidence from numerous in vitro and in vivo studies. A qualitative approach and risk management measures/OC taken to minimise exposure / risks associated with other identified effects (in particular, sensitisation) are anticipated to ensure strict control.

DNELs to use for PPP use

For assessing the risks of co-formulants used in Plant Protection Products (PPP) to operators, workers and bystanders, a specific tool (ECPA OWB) has been developed by the European Crop Protection (ECPA). ECPA OWB is a simple to use spreadsheet tool, which provides a more realistic assessment in comparison to the use of ECETOC Targeted Risk Assessment (TRA) as it is specifically designed to assess crop protection uses. ECPA OWB covers operator exposure during spray applications as well as during mixing & loading operations. ECPA OWB is largely based on specific exposure models that have been used for many years for the authorisation of plant protection products in Europe.

Operators do not use the PPP's every day, especially in the case of a herbicide. Typically operators may encounter the product up to 10 times per year, within 3 - 4 weeks. Therefore worker-DNELs should be sub-chronic DNELs, instead of chronic DNELs. Although for bystanders acute DNELs are considered appropriate, sub-acute/short-term DNELs should be conservative enough to account for the uncertainty of the route-to-route extrapolation (ECPA Guidance on REACH Chemical Safety Assessment for Co-formulants Used in Crop Protection Products, June 2010).

For the dermal exposure, the exposure is to the co-formulant, which is the registered substance (aqueous form). For the inhalation, the exposures to the surfactant fraction and to the methanol have been assessed separately, with the use of their respective DNELs and vapour pressures. Because the registered aqueous substance is diluted further in an aqueous herbicide formulation, the vapour pressure and DNEL for the solid content (i.e. surfactant fraction) of the registered substance is used for estimating the inhalative exposure in the ECPA OWB tool. The model is designed to assess the contributions of both vapours and aerosols. For the contribution of aerosols to the exposure, no correction is made for the solid content, thus the model conservatively assimilates the solid content to the average co-formulant concentration (no details provided by the model). As the contribution of the surfactant dissolved in the PPP is assessed, the inhalative DNELs are expressed in solid content of the registered substance.

Worker-DNELs:

AF for differences in duration of exposure: 3 (subacute study to subchronic exposure, workers)

Systemic effects, sub-chronic, inhalation (overall AF: 37.5): 23.6 mg solids/m3

Systemic effects, sub-chronic, dermal (overall AF: 150): 17.3 mg/kg bw/day

General population-DNELs (for by-standers/residents during use of the PPP):

AF for differences in duration of exposure: 1 (subacute study, subacute exposure, general population)

Systemic effects, short-term/sub-acute, inhalation (overall AF: 25): 17.4 mg solids/m3

Systemic effects, short-term/sub-acute, dermal (overall AF: 100): 25.9 mg/kg bw/day

DNELs of methanol

The following DNELs of methanol are used (based on Methanol registration dossier):

Worker-DNELs:

Systemic effects, long-term, inhalation: 260 mg/m3

Systemic effects, acute, inhalation: 260 mg/m3

Systemic effects, long-term, dermal: 40 mg/kg bw/day

Systemic effects, acute, dermal: 40 mg/kg bw/day

General population-DNELs (for by-standers/residents during use of the PPP):

Systemic effects, acute, inhalation: 50 mg/m3

Systemic effects, acute, dermal: 8 mg/kg bw/day