Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 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
Modified dose descriptor starting point:
NOAEC
Value:
176.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for workers is derived as: oral NOAEL x (1/0.38 m3/kg/day) x (6.7 m3/10m3 (8 h)) x (% oral absorption/ % inhalation absorption) = 200 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 176.3 mg/m3
AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolating from a subchronic study to chronic exposure
Justification:
The application of a factor for allometric scaling is not required for the inhalation route
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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:
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:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 200 mg/kg bw/day x (50/50) = 200 mg/kg bw/day.
AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolating from a subchronic study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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

Identity of the substance and approach to meeting the data requirements

2 -allyloxymethyl-2 -ethylpropanediol

Toxicokinetics

Based on physicochemical data, toxicity data and theoretical assessment, the basic toxicokinetics of 2 -allyloxymethyl-2 -ethylpropanediol can be adequately characterised. The substance is likely to be rapidly and extensively absorbed following oral or inhalation exposure, absorption following dermal exposure is likely to be less extensive and more gradual. Rapid and extensive distribution is predicted. Extensive hepatic metabolism of the substance is predicted, indicating that excretion is rapid and bioaccumulation is unlikely.

Acute toxicity

The acute oral and dermal toxicity of 2-allyloxymethyl-2-ethylpropanediol is low. The oral LD50 of the substance in the rat is 4930 mg/kg bw. The dermal LD50 of the substance in the rabbit is > 15800 mg/kg bw. A waiver is proposed in accordance with Column 2 of Annex VIII of the REACH Regulation for acute inhalation toxicity on the basis that acute toxicity data are available for the oral and dermal routes. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

Irritation/corrosion

Based on existing datasets and structural and chemical considerations, read-across from 2-allyloxymethyl-2-ethylpropanediol to skin and eye irritation studies on 2,2 -bis(allyloxymethyl)butan-1 -ol is appropriate to meet the REACH Annex VII-IX data requirements. Studies on 2,2 -bis(allyloxymethyl)butan-1 -ol show the substance is a mild irritant but do not trigger classification of the substance as a skin or eye irritant; classification of 2-allyloxymethyl-2-ethylpropanediol for skin and eye irritation is not required.

Skin sensitisation

Based on existing datasets and structural and chemical considerations, read-across from 2-allyloxymethyl-2-ethylpropanediol to a skin sensitisation study on 2,2-bis(allyloxymethyl)butan-1-ol is appropriate to meet the REACH Annex VII-VIIII data requirements. No evidence of skin sensitisation was seen in a Maximisation assay performed using 2,2-bis(allyloxymethyl)butan-1-ol: 2-allyloxymethyl-2-ethylpropanediol is not therefore expected to have skin sensitisation potential.

Repeated dose toxicity

A NOEL of 40 mg/kg bw/day was determined for the sub-acute repeated dose oral toxicity of 2-allyloxymethyl-2-ethylpropanediol in a 28-day study, based on clinical signs (hypoactivity). Based on existing datasets and structural and chemical considerations, read-across from 2-allyloxymethyl-2-ethylpropanediol to a sub-chronic repeated dose toxicity studty on 2,2-bis(allyloxymethyl)butan-1-ol is appropriate to meet the REACH Annex VII-IX data requirements. The NOAEL for the sub-chronic (90 day) repeated dose toxicity of 2,2-bis(allyloxymethyl)butan-1-ol was determined to be 200 mg/kg bw/day, based on observations of liver weight change and possible adaptive effects on other liver parameters, in conjunction with bodyweight changes and adverse clinical observations at the highest dose level.

Genetic toxicity

No evidence of mutagenicity was seen for 2-allyloxymethyl-2-ethylpropanediol in a bacterial reverse mutation assay (Ames test). Based on available datasets and chemical and structural considerations, read across from 2-allyloxymethyl-2-ethylpropanediol to mammalian in vitro genotoxicity studies on 2,2-bis(allyloxymethyl)butan-1 -ol is appropriate to address the REACH Annex VII-IX data requirements. In a mouse lymphoma assay, a weak positive response was reported in the presence of metabolic activation and only at concentrations associated with marked cytogenicity. No evidence of clastogenicity was seen in a standard mouse micronucleus assay.

Toxicity to reproduction

No data are available on the reproductive toxicity of 2-allyloxymethyl-2-ethylpropanediol. Histopathological changes in reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. In this respect, repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

In a study on the sub-acute oral repeated dose toxicity of 2 -allyloxymethyl-2 -ethylpropanediol in rats, no evidence of an effect on the reproductive organs was seen at dose levels of up to and including 200 mg/kg bw/day for 28 days (Perstorp, 2010). Read-across to the findings from a 90-day repeated dose toxicity study and a prenatal developmental toxicity study using 2,2 -bis(allyloxymethyl)butan-1 -ol is considered appropriate to provide a characterisation of the reproductive hazard of 2 -allyloxymethyl-2 –ethylpropanediol. On the basis that no effects were observed on any reproductive parameters in these studies, 2 -allyloxymethyl-2 –ethylpropanediol is not predicted to be a reproductive toxicant.

 

Based on existing datasets and structural and chemical considerations, read-across from 2 -allyloxymethyl-2 -ethylpropanediol to a developmental toxicity study using 2,2 -bis(allyloxymethyl)butan-1 -ol is appropriate to meet the REACH Annex VII-IX data requirements. Based on the results of this study, the maternal No Observed Effect Level (NOEL) was 50 mg/kg bw/day and the maternal No Observed Adverse Effect Level (NOAEL) was 200 mg/kg bw/day due to slight food consumption decreases and liver weight changes at 200 and 800 mg/kg bw/day, and bodyweight changes at 800 mg/kg bw/day. The NOAEL for developmental toxicity was considered to be 800 mg/kg bw/day (i.e. the highest dose tested).

DNEL derivation [Workers]

Based on the data available, the substance is of low acute toxicity, is not a skin or eye irritant or a skin sensitiser and is not mutagenic, a developmental or reproductive toxin.

The relevant (lowest) NOAEL for systemic toxicity for DNEL derivation is the NOAEL of 200 mg/kg bw/day from an OECD Test Guideline 408 90-day repeated dose toxicity study conducted on the read-across substance 2,2 -bis(allyloxymethyl)butan-1-ol.

Local effects

DNEL values for local effects are not derived. The substance is not a skin or eye irritant or a skin sensitiser. DNELs for local effects are not therefore derived.

Systemic effects

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore DNELs for acute systemic effects are not proposed.

The relevant (lowest) NOAEL for systemic toxicity for DNEL derivation is the NOAEL of 200 mg/kg bw/day from an OECD Test Guideline 408 90-day repeated dose toxicity study conducted on the read-across substance 2,2 -bis(allyloxymethyl)butan-1-ol.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 200 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 200 mg/kg bw/day x (50/50) = 200 mg/kg bw/day. 

The use of assessment factors according to REACH guidance is considered below:

Intraspecies: default values of 4 (allometric scaling: rat) and 2.5 (remaining differences) are proposed.

Interspecies: a default value of 5 is proposed for workers.

Exposure duration: a default value of 2 is proposed for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default value of 1 is proposed.

An overall assessment factor of 100 for long-term dermal effects is therefore calculated for workers.

Applying the assessment factor of 100 to the dermal equivalent NOAEL of 200 mg/kg bw/d gives a dermal DNEL value of 2 mg/kg bw/day for long-term systemic effects.

[Inhalation – long-term systemic DNEL]

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 200 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for workers is derived as: oral NOAEL x (1/0.38 m3/kg/day) x (6.7 m3/10m3(8 h)) x (% oral absorption/ % inhalation absorption) = 200 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 176.3 mg/m3

The use of assessment factors according to REACH guidance is considered below:

Intraspecies: a default value of 2.5 (remaining differences) is proposed (the application of a factor for allometric scaling is not required for the inhalation route).

Interspecies: a default value of 5 is proposed for workers.

Exposure duration: a default value of 2 is proposed for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default value of 1 is proposed

An overall assessment factor of 25 for long-term inhalational effects is therefore calculated for workers.

Applying the assessment factor of 25 to the corrected inhalation NOAEC of 176.3 mg/m3gives an inhalation DNEL value of 7.0 mg/m3for long-term systemic effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.7 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:
It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for the general population is derived as: oral NOAEL x (1/1.15 m3/kg/day) x (% oral absorption/ % inhalation absorption) = 200 mg/kg bw/day x (1/1.5) x (50/100) = 87 mg/m3.
AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolating from a subchronic study to chronic exposure
Justification:
A factor for allometric scaling is not required for the inhalation route
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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:
1 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
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 200 mg/kg bw/day x (50/50) = 200 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolating from a subchronicstudy to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 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
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolating from a subchronic study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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

Based on the data available, the substance is of low acute toxicity, is not a skin or eye irritant or a skin sensitiser and is not mutagenic, a developmental or reproductive toxin.

The relevant (lowest) NOAEL for systemic toxicity for DNEL derivation is the NOAEL of 200 mg/kg bw/day from an OECD Test Guideline 408 90-day repeated dose toxicity study conducted on the read-across substance 2,2 -bis(allyloxymethyl)butan-1 –ol.

Local effects

DNEL values for local effects are not derived. The substance is not a skin or eye irritant or a skin sensitiser. DNELs for local effects are not therefore proposed.

Systemic effects

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore DNELs for acute systemic effects are not proposed.

The relevant (lowest) NOAEL for systemic toxicity for DNEL derivation is the NOAEL of 200 mg/kg bw/day from an OECD Test Guideline 408 90-day repeated dose toxicity study conducted on the read-across substance 2,2 -bis(allyloxymethyl)butan-1 –ol.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 200 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 200 mg/kg bw/day x (50/50) = 200 mg/kg bw/day. 

The use of assessment factors according to REACH guidance is considered below:

Intraspecies: default values of 4 (allometric scaling: rat) and 2.5 (remaining differences) are proposed.

Interspecies: a default value of 10 is proposed for the general population.

Exposure duration: a default value of 2 is proposed for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default value of 1 is proposed

An overall assessment factor of 200 for long-term dermal effects is therefore calculated for the general population

Applying the assessment factor of 200 to the dermal equivalent NOAEL of 200 mg/kg bw/d gives a dermal DNEL value of 1 mg/kg bw/d for long-term systemic effects.

[Inhalation – long-term systemic DNEL]

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 200 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for the general population is derived as: oral NOAEL x (1/1.5 m3/kg/day) x (% oral absorption/ % inhalation absorption) = 200 mg/kg bw/day x (1/1.5) x (50/100) = 87 mg/m3

The use of assessment factors according to REACH guidance is considered below:

Intraspecies: a default value of 2.5 (remaining differences) is proposed (the application of a factor for allometric scaling is not required for the inhalation route).

Interspecies: a default value of 10 is proposed for the general population.

Exposure duration: a default value of 2 is proposed for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default value of 1 is proposed

An overall assessment factor of 50 for long-term inhalational effects is therefore calculated for the general population.

Applying the assessment factor of 50 to the corrected inhalation NOAEC of 87 mg/m3gives an inhalation DNEL value of 1.7 mg/m3for long-term systemic effects.

[Oral – long term systemic DNEL]

Applying the assessment factor of 200 to the oral NOAEL of 200 mg/kg bw/day gives an oral DNEL of 1 mg/kg bw/day.