Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.1 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:

278.6 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) = 316 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 278.6 mg/m3.

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic study to chronic exposure

Justification:

Not required

AF for other interspecies differences:

2.5

Justification:

Default value for remaining differences

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

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:

3.16 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:

316 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) = 316 mg/kg bw/day x (50/50) = 316 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

2

Justification:

Extrapolation for sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value for allometric scaling

AF for other interspecies differences:

2.5

Justification:

Default value for remaining differences

AF for intraspecies differences:

5

Justification:

Default value for workers

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

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

Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate

Toxicokinetics

Based on physicochemical data, toxicity data, theoretical assessment, the basic toxicokinetics of the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyratecan be adequately characterised.  

The four components of the substance are acid salts which will dissociate under physiological conditions to generate the cations (lithium or sodium) and the corresponding acids (3-hydroxy-2,2,4-trimethylpentanoic acid or isobutyric (2-methylpropanoic) acid). These constituents are rapidly and extensively absorbed following oral exposure. Absorption following dermal exposure is likely to be less extensive. Rapid and extensive distribution is predicted. Sodium and lithium ions are not subject to metabolism, whereas the acid components will undergo metabolic processes. Based on the theoretical assessment of the toxicokinetics, no bioaccumulation is predicted for the components of this substance.

Acute toxicity

The acute oral toxicity of the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrateis low. The oral LD₅₀of the substance was determined to be > 2000 mg/kg bw in an acute oral toxicity study conducted in rats using the Acute Toxic Class Method according to OECD Test Guideline 423 (Matting, 2013). A waiver is proposed for acute dermal toxicity on scientific grounds and for reasons of animal welfare: low acute dermal toxicity is predicted based on available information. 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 route and acute dermal toxicity is similarly predicted to be low. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

Irritation/corrosion

The Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyratewas not found to be irritating to skin in an in vitro skin irritation study conducted according to OECD Test Guideline 439 using the EpiSkin model. The substance was slightly irritating to the eyes in studies conducted in vitro using the isolated chicken eye model (OECD Test Guideline 438) and in vivo in rabbits (OECD Test Guideline 405), but did not meet the criteria for classification for eye irritation effects.

Skin sensitisation

The Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate was not found to cause skin sensitisation in a study conducted using the local lymph node assay. There is no evidence from experience of use that the substance has the potential to cause skin or respiratory sensitisation in exposed workers.

Repeated dose toxicity

Based on existing datasets and structural and chemical considerations, read-across from the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate to available repeated dose toxicity studies on isobutanol and isobutyl isobutyrate is appropriate to meet the REACH Annex VII-IX data requirements.In a sub-chronic, 90 day toxicity study using isobutanol in which rats were treated by oral gavage at 0,100,316 or 1000 mg/kg bw/day, the NOAEL was determined to be 316 mg/kg bw/day based on decreased bodyweight gain and transient hypoactivity and ataxia at the higher dose. The sub-chronic oral toxicity of isobutyl isobutyrate was determined to be low: the NOAEL was 1000 mg/kg bw/day (i.e. the highest dose tested).

Genetic toxicity

No evidence of mutagenicity was seen for the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyratein a bacterial reverse mutation assay (Ames test). The substance was found to be clastogenic to Chinese hamster cells in the absence of metabolic activation in an in vitro chromosome aberration assay but gave negative results in an in vivo micronucleus test conducted to assess the induction of micronuclei in the bone marrow erythrocytes of mice. The substance does not therefore have genotoxic potential in vivo.

Toxicity to reproduction

No studies are available on the reproductive toxicity of the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate. No evidence of an effect on the reproductive organs was seen in repeated dose toxicity studies or developmental toxicity studies using the read-across substances isobutanol and isobutyl isobutyrate. On this basis, the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate is not predicted to be a reproductive toxicant. In this respect, repeated dose toxicity studies should be considered to be sensitive and provide sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Based on existing datasets and structural and chemical considerations, read-across from the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate to available developmental toxicity studies on isobutanol is appropriate to meet the REACH Annex VII-IX data requirements.No effects were seem on developmental parameters in pre-natal developmental toxicity studies in which rats or rabbits were exposed to isobutanol at concentrations up to 1000 mg/m³(i.e. the highest dose tested).

DNEL derivation [workers]

Based on the available data, the substance is of low acute toxicity, is not a skin irritant or sensitiser, is not mutagenic in bacterial cells in vivo and is not predicted to be a developmental or reproductive toxicant.

Local effects

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

Systemic effects

The relevant (lowest) NOAEL for systemic toxicity for DNEL derivation is the NOAEL of 316 mg/kgbw/day from a 90-day repeated oral dose study on the read-across substance isobutanol

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 316 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) = 316 mg/kg bw/day x (50/50) = 316 mg/kg bw/day. 

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

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

Intraspecies: 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.

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 316 mg/kg bw/day gives a dermal DNEL value of 3.16 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 316 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) = 316 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 278.6 mg/m³

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

Interspecies: 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).

Intraspecies: 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.

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 278.6 mg/m³gives an inhalation DNEL value of 11.1 mg/m³for long-term systemic effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic 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 for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

There are no consumer uses.