Reaction mass of 2,2'-[methylenebis(oxymethylene)]bis[2-ethylpropane-1,3-diol]and propylidynetrimethanol and 2,2'-[oxybis(methylene)]bis[2-ethylpropane-1,3-diol]

Endpoint summary

Description of key information

The acute oral toxicity of the Reaction mass of 2,2'-[methylenebis(oxymethylene)]bis[2-ethylpropane-1,3-diol] and 2,2'-[oxybis(methylene)]bis[2-ethylpropane-1,3-diol] and propylidynetrimethanol is low. The oral LD50 of 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 (Robertson, 2012).   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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23rd May 2012 to 9th August 2012.

Reliability:

1 (reliable without restriction)

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

not specified

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Limited, Manston Road, Margate, Kent, UK
- Age at study initiation: 8 to 11 weeks old.
- Weight at study initiation: 226.1 to 244.2g.
- Fasting period before study: Animals were fasted overnight prior to dosing.
- Housing: Animals were housed in groups of 3 in appropriately sized solid-bottomed polycarbonate cages with stainless steel mesh tops. Cages were suspended on movable racks and wood shavings were used as bedding.
- Diet (e.g. ad libitum): SDS Rat and Mouse (modified) No. 1 Diet SQC Expanded was provided ad libitum throughout the study.
- Water (e.g. ad libitum): Water from public supply was provided ad libitum.
- Acclimation period: At least 9 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The environmental daily average temperature was approximately 20°C.
- Humidity (%): The range of daily average relative humidity was approximately 45% to 57%.
- Air changes (per hr): Minimum of 10 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 h light/dark cycle

IN-LIFE DATES: From: To:

Route of administration:

oral: gavage

Vehicle:

other: Milli-Q water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10mL/kg.

DOSAGE PREPARATION (if unusual):
Formulations were prepared on each day of dosing. The test item was placed in a sealed bag and immersed in a water bath that was set to a maximum temperature of 80°C until it was visibly homogeneous. The required amount of HB TMP was weighed into a pre-labelled container and formulations were made up to the final volume by adding the requisite amount of Milli-Q water. Formulations were stirred using a magnetic stirrer.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: 300 mg/kg was selected as a suitable starting dose level for administration to Group 1 animals, as recommended in OECD Guideline No. 423. There were no adverse signs recorded in any animal. In order to minimise the number of animals used, the repeat administration of the 300 mg/kg dose level to Group 2 animals was not performed and instead selected a dose level of 2000 mg/kg from the 4 fixed dose levels presented in the OECD Guideline. There were no signs of systemic toxicity in these animals either and so a third group of rats was treated at the same dose level to complete the study.

Doses:

300 and 2000 mg/kg.

No. of animals per sex per dose:

3 females per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Prior to dosing on day 1 and on Days 8 and 15.
- Necropsy of survivors performed: yes. The necropsy consisted of an examination of the cranial, thoracic and abdominal organs and tissues in situ.
- Other examinations performed: clinical signs, body weight, other: mortality and moribundity.

Statistics:

No formal statistic analysis was conducted.

Preliminary study:

Not applicable.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths during the observation period.

Clinical signs:

other: Clinical signs were restricted to 2 animals that were treated with HB TMP at 2000 mg/kg. Animal 6 displayed a red nasal discharge predose and immediately and approximately 30 min post dose on Day 1. Staining around the muzzle of Animal 4 and Animal 6 wa

Gross pathology:

Necropsy on Day 15 revealed no macroscopic abnormalities in any animal.

Other findings:

No additional information applicable.

No additional information.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the LD50 of HB TMP in Sprague-Dawley was not classified.

Executive summary:

The acute oral toxicity of HB TMP was investigated in an study conducted using the Acute Toxic Class method, according to OECd Test Guideline 423. In the study, a single oral (gavage) dose of the test substance at 300, 2000 or 2000 mg/kg bw was administered to three respectie groups of female Sprague-Dawley rats. Animals were observed for 14 days after the day of dosing. All animals survived treatment. No treatment-related adverse clinical skigns and no macroscopic abnormalities were recorded in any animal. Bodyweights were considered to be acceptable for rats of this age and strain. Under the condistions of the study, the median lethal dose of HB TMP in Sprague-Dawley rats was > limit dose of 2000 mg/kg and the substance was therefore considered to be unclassofied according to the Globally Harmonised Classification System.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch score = 1. Study compliant with current test guidelines and GLP.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity

The acute oral toxicity of the Reaction mass of 2,2'-[methylenebis(oxymethylene)]bis[2-ethylpropane-1,3-diol] and 2,2'-[oxybis(methylene)]bis[2-ethylpropane-1,3-diol] and propylidynetrimethanol is low. The acute oral median lethal dose (LD₅₀) of the substance was determined to be > 2000 mg/kg bw in an acute oral toxicity study conducted in rats according to OECD Test Guideline 423 (Acute Toxic Class method; Robertson, 2012).

In the study, a single oral (gavage) dose of the test substance at 300, 2000 or 2000 mg/kg bw was administered to three respective groups of female Sprague-Dawley rats. Animals were observed for 14 days after the day of dosing. All animals survived treatment. No treatment-related adverse clinical signs and no macroscopic abnormalities were recorded in any animal. Bodyweights were considered to be acceptable for rats of this age and strain. Under the conditions of the study the median lethal dose of the Reaction mass of 2,2'-[methylenebis(oxymethylene)]bis[2-ethylpropane-1,3-diol] and 2,2'-[oxybis(methylene)]bis[2-ethylpropane-1,3-diol] and propylidynetrimethanol in Sprague-Dawley rats was > the limit dose of 2000 mg/kg and the substance was therefore considered to be unclassified according to the Globally Harmonised Classification System. 

Acute dermal toxicity

No acute dermal toxicity studies on the substance are available. A waiver is proposed for this endpoint on scientific grounds and for reasons of animal welfare. No adverse effects or mortalities were seen in an acute oral toxicity study performed with the substance at a limit dose of 2000 mg/kg bw. No signs of systemic toxicity were seen in a skin irritation study or in a skin sensitisation study using the substance. It can therefore be concluded that the substance has low acute toxicity. Dermal absorption of the substance is unlikely to exceed oral absorption and significant differences in the toxicity of the substance due to the route of exposure are not predicted. Testing of the substance is therefore not considered to be scientifically justified and additionally cannot be supported on grounds of animal welfare.

Acute inhalation toxicity

A waiver is proposed for acute inhalation toxicity studies in accordance with Column 2 of Annex VIII of the REACH Regulation for this endpoint 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. The substance is a non-volatile liquid and the use pattern indicates that significant inhalation exposure is unlikely. No additional testing is therefore warranted.

Justification for selection of acute toxicity – oral endpoint
Sole study providing data from a guideline compliant study.

Justification for classification or non-classification

The oral LD₅₀of the Reaction mass of 2,2'-[methylenebis(oxymethylene)]bis[2-ethylpropane-1,3-diol] and 2,2'-[oxybis(methylene)]bis[2-ethylpropane-1,3-diol] and propylidynetrimethanol in rats is > 2000 mg/kg bw. The substance does not meet the criteria for classification for acute oral toxicity according to Directive 67/548/EEC or Regulation 1272/2008/EC.