Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

67 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

59.1 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) = 67 mg/kg bw/d x (1/0.38) x 0.67 x (50/100) = 59.1 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 sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Not required: already accounted for

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Default factor: high quality database

AF for remaining uncertainties:

1

Justification:

Default factor: no significant remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

other toxicological threshold

Value:

5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

other toxicological threshold

Value:

9 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

67 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

67 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) = 67 mg/kg bw/day x (50/50) = 67 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 sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor (rat study)

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Default factor: high quality database

AF for remaining uncertainties:

1

Justification:

Default factor: no significant uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Identity of the substance and approach to meeting the data requirements

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consist of formic acids (at concentrations up to 59 % w/w), propylidynetrimethanol -esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol -esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. Therefore, toxicity of the substance can therefore be characterised based from available data on formic acid, propylidynetrimethanol and pentaerythritol.

Toxicokinetics

The toxicokinetic behaviour of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is considered based on available information on its components. Formic acid may be absorbed via the oral, dermal, and inhalation routes of exposure. Local toxicity may be seen due to its corrosivity. Systemically, formic acid will be present as the formate anion at physiological pH values. Formate is metabolised by hepatic folate-dependent reactions and does not accumulate. Formate blood levels are generally low. Levels may be high during poisoning, e.g. with formate salts or methanol, because the limited human formate metabolism capacity may be exceeded. Systemic toxicity (acidosis and related metabolic disorders; photoreceptor damage) may then occur.

Propylidynetrimethanol and pentaerythritol, and their respective esters, are likely to be extensively absorbed following oral and inhalation exposure, absorption following dermal exposure is likely to be less extensive and more gradual. Rapid and extensive distribution is predicted. Extensive hepatic metabolism and urinary excretion of metabolites is likely to limit systemic exposure and no bioaccumulation is predicted

Acute toxicity

Guideline studies on the acute oral toxicity (OECD Test Guideline 401) and on the inhalation toxicity (OECD Test Guideline 403) of formic acid in the rat are available. In accordance with test guidelines, the dermal toxicity of the substance was not examined because of the corrosive properties of formic acid.

Pentaerythritol and propylidynetrimethanol are demonstrated to be of very low acute toxicity by all routes investigated. Similar low acute toxicity is predicted for their respective esters. The acute toxicity ofthe reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acidis therefore driven by the main component: formic acid.

Based on a concentration of 59% w/w and an acute oral LD₅₀value of 730 mg/kg bw/day for neat formic acid, the acute toxicity estimate (ATE) for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is determined to be 1237 mg/kg bw/day. The substance meets the criteria for classification as Category 4 “Harmful if swallowed” (H302) according to EC Regulation 1272/2008.

Based on a concentration of 59% w/w and an acute inhalation LC₅₀value of 7.3 mg/L for neat formic acid vapour, the acute toxicity estimate (ATE) for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is determined to be 12.4 mg/L. The substance meets the criteria for classification as Category 4 “Harmful if inhaled” (H332) according to EC Regulation 1272/2008. The additional hazard statement EH071 “Corrosive to the respiratory tract” must be used since the inhalation toxicity results from the corrosivity of formic acid.

Irritation/corrosion

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid contains formic acid at concentrations up to 59% w/w. Formic acid is classified as corrosive and causing eye damage, based on experience from human exposures and experimental data from animal tests. On the basis of a 59% w/w formic acid content, the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is considered to be caustic and is expected to cause severe burns to the skin and eye damage. The substance meets the criteria for classification as “causes severe burns”, Risk Phrase R34 according to Directive 67/548/EEC and as CLP Category 1B “causes severe skin burns and eye damage” (GHSS05 Dgr; H314) according to the Regulation 1272/2008/EC.

Skin sensitisation

Formic acid, propylidynetrimethanol and pentaerythritol do not have the potential to induce skin sensitisation based on skin sensitisation studies or read-across. On this basis,the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acidis not predicted to have any skin sensitisation potential.

Repeated dose toxicity

Due to its corrosive properties, the local effects of formic acid prevail over systemic effects following exposures via all routes; no signs of systemic toxicity have been observed in sub-chronic and chronic studies using formate salts. Propylidynetrimethanol and pentaerythritol are of low toxicity following repeated dose, showing only unspecific effects of limited toxicological significance. The primary effect following repeated exposures to the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acidis local, site of contact toxicity due to the caustic properties of formic acid.

Genetic toxicity

No evidence of mutagenicity was seen for formic acid in a bacterial reverse mutation assay (Ames) test or in in vitro cytogenicity or gene mutation studies using mammalian cells. Formic acid was not genotoxic in vivo in Drosophia melanogaster. Neither propylidynetrimethanol nor pentaerythritol are mutagenic in bacterial or in mammalian tests systems in vitro: negative results were obtained in respective Ames tests, in chromosome aberration assays and gene mutation assays. Due to the lack of genotoxic potential demonstrated for its components, no genotoxic potential is predicted for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid.

Carcinogenicity

Potassium diformate did not show potential for carcinogenicity in two valid long-term rodent feeding studies at 2000 mg/kg bw/day. This can be extrapolated to formic acid.

Propylidynetrimethanol and pentaerythritol are not genotoxic and no histopathological alterations indicative for a potential carcinogenic effect were observed in the available repeated dose toxicity studies. No carcinogenic potential is predicted for the esters of these substances. Based on the available evidence,the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not predicted to have any carcinogenic potential.

Toxicity to reproduction

Due to the corrosivity of formic acid, formate salts are used in studies requiring repeated dose testing. No reproductive effects were seen for sodium formate in a valid OECD Test Guideline 416 two generation study at the limit dose of 1000 mg/kg/day. This result can be extrapolated to formic acid (the calculated NOAEL for the reproductive toxicity of formic acid is 667 mg/kg bw/day). Repeated dose inhalation toxicity studies do not show that formic acid is a reproductive toxicant via the inhalation route.

No effects on fertility have been observed in studies in rats performed using propylidynetrimethanol or pentaerythritol conducted according to OECD Test Guideline 422. The available evidence indicates that the components of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid do not show any potential for reproductive toxicity

Developmental toxicity studies for sodium formate in rats and rabbits showed no effects on the developing fetuses with NOAEL values of 945 and 1000 mg/kg bw/day, respectively (Limit dose). These data can be extrapolated to formic acid (with restrictions due to its corrosivity). On this basis, no potential for any developmental toxicity is expected for formic acid

No developmental effects have been seen in respective OECD 422 combined repeated dose/reproductive/developmental toxicity studies using propylidynetrimethanol and pentaerythritol. The potential developmental toxicity of trimethylopropane will be characterised further in a planned prenatal study according to OECD TG 414. Based on the available evidence, the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not predicted to be developmental toxicant.

DNEL derivation [Workers]

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol-esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. Based on existing datasets and structural and chemical considerations, read-across to available data on formic acid (and formate salts), propylidynetrimethanol and pentaerythritol is appropriate to meet the REACH Annex VII-X data requirements for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid.

Based on read-across to available information, the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not predicted to be a skin sensitiser, genotoxic in bacterial or mammalian cells in vitro or in vivo or have any potential for carcinogenicity or developmental or reproductive toxicity. The substance is classified as corrosive to the skin and causing eye damage on the basis that the substance contains formic acid, a corrosive component, at concentrations up to 59% w/w. The primary hazard posed by the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid following acute and long-term dermal, oral and inhalation exposures is therefore local, site of contact toxicity mediated by the corrosive properties of the substance: the eyes, the skin following direct dermal contact; the upper respiratory tract following inhalation exposure and the mouth, larynx, pharynx, oesophagus, stomach, intestines after oral ingestion.

The occupational hazards associated with formic acid are well established. Due to the corrosive nature of the substance, dermal exposures in workers should be prevented through the application of appropriate operational conditions and risk management measures. Occupational exposure limits (OEL) for formic acid have been established in the European Union and in the member states for some time. OELs are considered to be appropriate for the derivation of DNELs for local inhalation effects (see discussion below).

Although local effects due to the formic acid content of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid are likely to be prevalent, consideration is also given to potential systemic effects associated with the components of the substance. Under physiological conditions, formic acid exists as formate. Read-across to repeated dose toxicity studies is therefore appropriate to characterise potential systemic toxicity. No signs of systemic toxicity have been observed in sub-chronic and chronic (52 week) studies using formate salts in rodents administered in the diet at doses up to 3000 and 2000 mg/kg bw/day. No treatment-related systemic effects have been observed in rodents exposed to formic acid vapours at concentrations up to 0.244 mg/L. Based on these findings, the formic acid component of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not associated with systemic toxicity.

No signs of systemic toxicity were reported in rats in a 28-day repeated dose toxicity study (OECD Test Guideline 407) using pentaerythritol, administered daily at the limit dose of 1000 mg/kg bw (NOAEL : 1000 mg/kg bw/day). In a combined repeated dose and reproductive/developmental study (OECD Test Guideline 422) in which rats received doses up to 1000 mg/kg bw/day, effects were limited to intermittent soft stools and diarrhoea at the 300 and 1000 mg/kg bw/day dose levels: not signs of systemic toxicity (NOAEL: 100 mg/kg bw).

Taking into account, the lack of systemic toxicity expected for the formic acid and the pentaerythritol-ester components of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid, consideration of sub chronic repeated dose toxicity data on propylidynetrimethanol is therefore relevant for deriving long-term, systemic DNELs for the substance.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 67 mg/kg bw/day observed in a sub-chronic repeated oral dose toxicity study using the read-across substance propylidynetrimethanol, based on effects consisting of slightly decreased hemoglobin levels and red blood cell counts and the presence of normoblasts and white blood cell fragments, increased relative weights of kidneys, liver and spleen and microscopical changes in liver and spleen observed at higher doses ((de Knecht van Eekelen and van der Neulen, 1969, at the request of Perstorp AB). In a combined repeated dose and reproductive/developmental toxicity study using propylidynetrimethanol conducted according to OECD TG 422 it was shown that the fertility of male and female rats was not impaired up to and including the highest test dose of 800 mg/kg bw /day. As this dose is much higher than the NOAEL from the sub-chronic study, the latter has been taken as the basis for setting DNELs for long term systemic effects for the dermal, oral and inhalation route as it is considered the derived DNELs cover the reproductive/developmental endpoint as well.

Local effects

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid contains the corrosive substance, formic acid at concentrations up to 59% w/w. Taking into account the classification concentration limits for formic acid, the substance meets the criteria for classification as “causes severe burns”, Risk Phrase R34 according to Directive 67/548/EEC and as CLP Category 1B “causes severe skin burns and eye damage” (GHSS05 Dgr; H314) according to the Regulation 1272/2008/EC. Medium hazard is assigned according to ECHA CSA Guidance Part E Table E3-1. DNEL values for local dermal effects following acute and dermal exposures are not therefore derived: the hazards are characterised based on a qualitative approach.

Based on a concentration of 59% w/w and an acute inhalation LC₅₀value of 7.3 mg/L for neat formic acid vapour, the acute toxicity estimate (ATE) for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is determined to be 12.4 mg/L. The substance meets the criteria for classification as Category 4 “Harmful if inhaled” (H332) according to EC Regulation 1272/2008. The additional hazard statement EH071 “Corrosive to the respiratory tract” must be used since the inhalation toxicity results from the corrosivity of formic acid. The acute inhalation toxicity of the substance is considered to be due to a corrosive mode of action, mediated locally, rather than a systemic effect. Similarly, based on repeated dose inhalation studies using formic acid vapours, local effects in the respiratory tract are predicted for the substance following long-term inhalation exposures to the substance.

Occupational exposure limits (OEL) for formic acid relevant to short-term and long-term exposures in workers have been established in the European Union. These OELs are considered appropriate for deriving inhalation DNELs for local effects for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid

For short-term occupational exposures, the EU Indicative Occupational Exposure Limit (IOEL) for formic acid, published in the regulation 2006/15/EC is 5 ppm (9 mg/m³; STEL: 9 mg/m³). As the IOEL is based on irritating properties, no additional factor for a short term exposure is required.

The National German formic acid OELs are comparable with the EU IOEL:

- Binding Federal AGW: 5 ppm (9.5 mg/m³; STEL: factor 2). OEL set in 01/2006. Reference: TRGS 900 (02 July 2009)

- MAK-value: 5 ppm (9.5 mg/m³; STEL: factor 2 = 19 mg/m3). Reference: Deutsche Forschungsgemeinschaft (2006) MAK- und BAT-Werte-Liste 2009. Wiley-VCH, Weinheim. A document on the delineation of the MAK-value is publicly accessible. Reference: H.Greim, ed. (2003) Occupational Medicine 19, 169-180.

The pungent odour of formic acid is a warning sign that indicates exposure to formic acid and prevents extended exposure periods and exposures towards irritating concentrations. It is therefore expected that the acute inhalation DNEL also protect against systemic effects.

The acute inhalation DNELs for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid, considered to be protective towards local and systemic effects following short term and long term exposures respectively are considered to be 19 mg/m³and 9.5 mg/m³

Systemic effects

The substance is of low systemic toxicity. The acute toxicity hazard of the substance is mediated by local, site of contact effects due to the corrosive properties of the formic acid content of the substance and not due to systemic toxicity. DNELs for acute systemic dermal and inhalation effects are not therefore proposed.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 67 mg/kg bw/day from a sub-chronic 90 day repeated oral dose toxicity study conducted using similar methods to OECD Test Guideline 408.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 67 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) = 67 mg/kg bw/day x (50/50) = 67 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.

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 factor of 1 is used

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 67 mg/kg bw/d gives a dermal DNEL value of 0.67 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 67 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) = 67 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 59.1 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 worker.

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 factor of 1 is used

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 59.1 mg/m³gives an inhalation DNEL value of 2.4 mg/m³for long-term systemic effects.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.58 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

67 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

29.13 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) = 67 mg/kg bw/day x (1/1.5) x (50/100) = 29.13 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 sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Not applied to inhalation route

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default factor: general population

AF for the quality of the whole database:

1

Justification:

Default factor: high qulaity database

AF for remaining uncertainties:

1

Justification:

Default factor: no significant remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

other toxicological threshold

Value:

1.7 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

other toxicological threshold

Value:

9 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.34 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

67 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

67 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) = 67 mg/kg bw/day x (50/50) = 67 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Default factor: based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

2

Justification:

Default factor for extrapolating from a sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default factor for the general population

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.34 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

67 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

67 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Modification of the starting point is not required; a NOAEL from an oral study is used.

AF for dose response relationship:

1

Justification:

Default factor: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

2

Justification:

Default factor for extrapolating from a sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default factor: general population

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol-esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. Based on existing datasets and structural and chemical considerations, read-across to available data on formic acid (and formate salts), propylidynetrimethanol and pentaerythritol is appropriate to meet the REACH Annex VII-X data requirements for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid.

Based on read-across to available information, the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not predicted to be skin sensitiser, genotoxic in bacterial or mammalian cells in vitro or in vivo or have any potential for carcinogenicity or developmental or reproductive toxicity. The substance is classified as corrosive to the skin and causing eye damage on the basis that the substance contains formic acid, a corrosive component, at concentrations up to 59% w/w. The primary hazard posed by the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid following acute and long-term dermal, oral and inhalation exposures is therefore local, site of contact toxicity mediated by the corrosive properties of the substance: the eyes, the skin following direct dermal contact; the upper respiratory tract following inhalation exposure and the mouth, larynx, pharynx, oesophagus, stomach, intestines after oral ingestion.

The occupational hazards associated with formic acid as well established. Occupational exposure limits (OEL) for formic acid have been established in the European Union and in several member states for some time. OELs are considered to be appropriate for the derivation of DNELs for local inhalation effects for the general population, with appropriate adjustment (see discussion below).

Although local effects due to the formic acid content of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid are likely to be prevalent, consideration is also given to potential systemic effects associated with the components of the substance. Under physiological conditions, formic acid exists as formate. Read-across to repeated dose toxicity studies is therefore appropriate to characterise potential systemic toxicity. No signs of systemic toxicity have been observed in sub-chronic and chronic (52 week) studies using format salts in rodents administered in the diet at doses up to 3000 and 2000 mg/kg bw/day. No treatment-related systemic effects have been observed in rodents exposed to formic acid vapours at concentrations up to 0.244 mg/L. Based on these findings, the formic acid component of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not associated with systemic toxicity.

No signs of systemic toxicity were reported in rats a 28-day repeated dose toxicity study (OECD TG 407) using pentaerythritol, administered daily at the limit dose of 1000 mg/kg bw (NOAEL : 1000 mg/kg bw/day). In a combined repeated dose and reproductive/developmental study (OECD TG 422) in which rats received doses up to 1000 mg/kg bw/day, effects we limited to intermittent soft stools and diarrhoea at the 300 and 1000 mg/kg bw/day dose levels: not signs of systemic toxicity (NOAEL: 100 mg/kg bw).

Taking into account, the lack of systemic toxicity expected for the formic acid and the pentaerythritol-ester components of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid, consideration of sub chronic repeated dose toxicity data on propylidynetrimethanol is therefore relevant for deriving long-term, systemic DNELs for the substance.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 67 mg/kg bw/day observed in a sub-chronic repeated oral dose toxicity study using the read-across substance propylidynetrimethanol, based on effects consisting of slightly decreased hemoglobin levels and red blood cell counts and the presence of normoblasts and white blood cell fragments, increased relative weights of kidneys, liver and spleen and microscopical changes in liver and spleen observed at higher doses ((de Knecht van Eekelen and van der Neulen, 1969, at the request of Perstorp AB). In a combined repeated dose and

reproductive/developmental toxicity study using propylidynetrimethanol conducted according to OECD TG 422 it was shown that the fertility of male and female rats was not impaired up to and including the highest test dose of 800 mg/kg bw /day. As this dose is much higher than the NOAEL from the sub-chronic study, the latter has been taken as the basis for setting DNELs for long term systemic effects for the dermal, oral and inhalation route as it is considered the derived DNELs cover the reproductive/developmental endpoint as well.

Local effects

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid contains the corrosive substance, formic acid at concentrations up to 59% w/w. Taking into account the classification concentration limits for formic acid, the substance meets the criteria for classification as “causes severe burns”, Risk Phrase R34 according to Directive 67/548/EEC and as CLP Category 1B “causes severe skin burns and eye damage” (GHSS05 Dgr; H314) according to the Regulation 1272/2008/EC. Medium hazard is assigned according to ECHA CSA Guidance Part E Table E3-1. DNEL values for local dermal effects following acute and dermal exposures are not therefore derived: the hazards are characterised based on a qualitative approach.

Based on a concentration of 59% w/w and an acute inhalation LC₅₀value of 7.3 mg/L for neat formic acid vapour, the acute toxicity estimate (ATE) for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is determined to be 12.4 mg/L. The substance meets the criteria for classification as Category 4 “Harmful if inhaled” (H332) according to EC Regulation 1272/2008. The additional hazard statement EH071 “Corrosive to the respiratory tract” must be used since the inhalation toxicity results from the corrosivity of formic acid. The acute inhalation toxicity of the substance is considered to be due to the corrosive mode of action, mediated locally, rather than a systemic effect. Similarly, based on repeated dose inhalation studies using formic acid vapours, local effects in the respiratory tract are predicted for the substance following long-term inhalation exposures to the substance.

Occupational exposure limits (OEL) for formic acid relevant to short-term and long-term exposures in workers have been established in the European Union. These OELs are considered appropriate for deriving inhalation DNELs for local effects for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid for the general population, with suitable adjustments.

For short-term occupational exposures, the EU Indicative Occupational Exposure Limit (IOEL) for formic acid, published in the regulation 2006/15/EC is 5 ppm (9 mg/m³; STEL: 9 mg/m³). The IOEL is based on irritating properties. This concentration can be used for the general population without correction factors for differences regarding exposure period and respiration volumes between workers and the general population. However, an assessment factor of 3 was applied to account for sensitive subpopulations and possible continuous exposure. Therefore, the long-term inhalation DNEL for local effects for the general population is determined to be 3 mg/m³. Short exposures up to the IOEL of 5 ppm (9.5 mg/m³; TWA 9.5 mg/m³) can be tolerated as peak concentrations as these exposure are extremely short and are unlikely to occur daily. The short-term DNEL inhalation for local effects for the general population is therefore determined to be 9.5 mg/m³

Systemic effects

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 67 mg/kg bw/day from a sub-chronic 90 day repeated dose toxicity study conducted using similar methods to OECD Test Guideline 408.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 67 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) = 67 mg/kg bw/day x (50/50) = 67 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 factor of 1 is used

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 67 mg/kg bw/d gives a dermal DNEL value of 0.34 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 67 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 (1/1.15 m³/kg/day) x (% oral absorption/ % inhalation absorption) = 67 mg/kg bw/day x (1/1.15) x (50/100) = 29.13 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.

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 factor of 1 is used

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 29.13 mg/m³gives an inhalation DNEL value of 0.58 mg/m³for long-term systemic effects.

[Oral – long-term systemic DNEL]

Applying the assessment factor of 200 to the oral NOAEL of 67 mg/kg bw/d gives an oral DNEL of 0.34 mg/kg bw/day.