Reaction mass of 2-(3-ethylphenyl)oxirane and 2,2’-(1,3-phenylene)dioxirane and 2,2'-(1,4-phenylene)dioxirane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.58 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

Additional information - workers

Acute Toxicity

The acute oral and the acute dermal median lethal doses (LD50) of the test material in the female Wistar strain rat were each estimated to be greater than 2000 mg/kg bodyweight and therefore the submission substance was considered to have no significant acute toxic risk if swallowed or via skin contact. The submission substance therefore did not meet the criteria for classification as toxic or harmful by oral or dermal route exposure according to EU labelling regulations during the study.

The study to determine the toxicity by the inhalation route was not conducted as it was deemed inappropriate as exposure to humans via inhalation is unlikely to occur as the substance does not have a high vapour pressure, and will not be used in a manner likely to produce aerosols, particles or droplets of an inhalable size.

Irrritation/Corrosion

The test material was considered to be Irritant according to the EU labelling regulations during the dermal irritation study.The symbol “I” and the risk phrase R 38 “IRRITATING TO SKIN” are therefore required.

However, the test material did not meet the criteria for classification as an irritant to the eye according to the EU labelling regulations. No symbol or risk phrases are required.

Skin Sensitisation

A study was performed to assess the skin sensitisation potential of the test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. The method was designed to meet the requirements of the OECD Guideline for the Testing of Chemicals No. 429 "Skin Sensitisation: Local Lymph Node Assay" (adopted 24 April 2002) and Method B42 Skin Sensitisation (Local Lymph Node Assay) of CommissionRegulation (EC) No. 440/2008. The test material was considered to be a sensitiser under the conditions of the test and classified as a sensitiser according to EU labelling regulations Commission Directive 2001/59/EC.  The test material is also classified as a skin sensitizer (Category 1) and according to the Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging (CLP) of substances and mixtures.

Genetic Toxicity

The submission substance is not classified with regard genetic toxicity. The substance was found to be mutagenic to bacterial cells (Ames study), clastogenic to human lymphocytes in vitro ( chromosome aberration study). However, any concerns regarding mutagenicity are mitigated by a negative (i.e. non-genotoxic) in-vivo mouse micronucleus study.

Repeated Dose Toxicity

The submission substance did not meet the criteria for classification as toxic or harmful by the oral route of exposure during a 28 -day repeat dose toxicity study in the rat.

Toxicity to Reproduction

The submission substance did not meet the criteria for classification as regards impairing fertility or reproduction, or causing harm to the unborn child.

Derivation of DNELs for the substance Reaction mass of bis(epoxyethyl)benzene and (ethylphenyl) oxirane (DVBDO)

 

From the hydrolysis study it is known that the substance Reaction mass of bis(epoxyethyl)benzene and (ethylphenyl) oxirane (DVBDO) rapidly hydrolyses under physiological conditions. Acute toxicity studies in rats are available for the oral (Sanders 2009a) and dermal routes (Sanders 2009b).

 

No mortality occurred at oral or dermal doses of 2000 mg/kg bw/day. Adverse effects that were associated with acute exposure to the substance via the oral and dermal routes included hunched posture, decreased respiratory rate and laboured respiration which may be an indication of adverse local effects in the intestine and lungs. The observations tend to show a bioavailability of the substance via the gastrointestinal tract and the skin and potential excretion of substance via the lungs. Animals in the dermal acute toxicity studies (24 hours exposure period) exhibited signs of clear skin irritation/corrosion after the observation period of 14 days. The potential of the substance to irritate skin was also predicted in an in vitro test in a reconstituted human epidermis model.

 

A combined repeated dose toxicity/reproductive toxicity/developmental toxicity study via the oral route is available (Dunster 2010). The substance was dissolved in arachis oil and daily administered by gavage to male Wistar rats during 42 days and to female Wistar rats during 54 days. The test animals showed signs of local irritancy in the forestomach at oral doses of 100 and 200 mg/kg bw/day and the NOEL for this effect was 50 mg/kg bw/day. No systemic, reproductive or developmental effects were anticipated with the oral dose of 200 mg/kg bw/day.

 

In conclusion, local adverse effects occurred after oral and dermal exposure. Similar local effects can be expected for the respiratory tract, however, experimental data on respiratory irritancy are lacking. Dose-response data are available from a repeated dose toxicity study via the oral route. Local gastrointestinal irritation was not observed at a dose of 50 mg/kg bw/day. Systemic, reproductive and developmental effects were not seen at a dose level of up to 200 mg/kg bw/day. As a worst case it may be assumed that systemic effects could occur at slightly higher doses and the oral dose of 200 mg/kg bw/day is considered as the NOAEL for potentially adverse systemic effects and thus as the starting point for DNEL derivation.

 

Acute and long-term local effects:

No DNELs for acute and long-term local effects were derived as appropriate dose-response data are lacking for the dermal and inhalation routes. The substance and its hydrolytic products have to be considered as irritating/corrosive to the skin. Workers who may come into direct contact with DVBDO need to wear appropriate dermal protection such as chemical resistant gloves and working suits in order to avoid dermal exposure as much as possible. The repeated dose toxicity study indicated that no irritation of the gastrointestinal tract is to be expected at a repeated oral dose of 50 mg/kg bw/day. No significant direct and oral exposure is anticipated with the industrial and professional uses of the substance. In addition, no indirect oral exposure of humans via the environment is anticipated due to the rapid hydrolysis of the substance. The derivation of a DNEL for local effects due to oral exposure is deemed not necessary.

 

Worker DNELs for long-term Inhalation exposure

The worker DNEL for long-term inhalation exposure (systemic effects)was calculated from a corrected dose descriptor (NOEC of 43.8 mg/m³) that was obtained from the oral NOAEL by route-to-route extrapolation (intestinal:inhalation bioavailability = 50:100 as default; 8 hours inhalation exposure duration). The assessment factors were 2.5 (intraspecies differences), 5.0 (interspecies differences), 6.0 (study duration correction factor) and 1.0 (dose descriptor; data quality). The total assessment factor was 75. The DNEL value was 43.8 / 75 = 0.58 mg/m³.

 

Worker DNELs for long-term dermal exposure

The worker DNEL for long-term dermal exposure (systemic effects)was calculated from a corrected dose descriptor (NOAEL of 200 mg/kg bw/day) that was obtained from the oral NOAEL by route-to-route extrapolation (intestinal:dermal bioavailability = 50:50 as default). The assessment factors were 4.0 (allometric scaling), 2.5 (intraspecies differences), 5.0 (interspecies differences), 6.0 (study duration correction factor) and 1.0 (dose descriptor; data quality). The total assessment factor was 300. The DNEL value was 200 / 300 = 0.67 mg/kg bw/day.

 

General Population DNELs for long-term exposure

No DNELs for long-term exposure of the general public were derived. No direct exposure to the substance is anticipated as a result of the manufacture and industrial or professional use of DVBDO. No release of substance from articles treated with mixtures containing the substance is anticipated. Substance that is emitted into the environment is rapidly hydrolysed so that no secondary oral exposure is expected.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Additional information - General Population

General Population DNELs for long-term exposure

No DNELs for long-term exposure of the general public were derived. No direct exposure to the substance is anticipated as a result of the manufacture and industrial or professional use of DVBDO. No release of substance from articles treated with mixtures containing the substance is anticipated. Substance that is emitted into the environment is rapidly hydrolysed so that no secondary oral exposure is expected.