Reaction products of methacrylic acid and 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Endpoint summary

Description of key information

Evaluation for acute toxicity, oral route was based on two studies. The first one, supporting study, was carried out according to appraisal of the safety of chemicals in foods, drugs and cosmetics, FDA, 1959. The second one, key study, was carried out according to OECD Guideline 401 (Acute Oral Toxicity). The first study showed that the LD50 (14 d) of Small Vinyl Ester was 14.15 ml/kg bw (13.38 -14.92 ml/kg bw). The key study showed that the single-dose LD50 in rats via oral route of administration is above 5110 mg/kg bw.
Testing for acute dermal toxicity is waived according to REACH Annex VIII, 8.5.3.(3). QSAR estimations using the US-EPA DERMWIN v2.01 program makes it foreseeable that the LD50 is larger than 2,000 mg/kg bw. In addition, Small Vinyl Ester is placed on the market as an approximately 50% solution in a reactive diluent for industrial and professional use only. Use of personal protection equipment is required to avoid the possible skin exposure to the marketed solution of Small Vinyl Ester. 
Testing for acute inhalation toxicity is waived according to REACH Annex VIII, 8.5.2. Inhalation of vapours in toxic amounts is unlikely. Small Vinyl Ester has a negligible vapour pressure (2E-10 Pa) as estimated using US-EPA EPISuite v4.0. Small Vinyl Ester is placed on the market as an approximately 50% solution in a reactive diluent for industrial and professional use only. Use of personal protection equipment will eliminate any possible inhalation of vapour or aerosols.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: Appraisal of the safety of chemicals in foods, drugs and cosmetics, FDA, 1959

Deviations:

not specified

Remarks:

Deviations from guideline not described

Principles of method if other than guideline:

The experimental procedure is in essence similar to, but uses more animals and higher dosages than would be required, if conducted following the most recent guidelines, Annex V to Dir 67/548/EEC Part B.1 bis: "Acute Oral Toxicity - Fixed Dose Procedure" or OECD TG 420 (2001).

GLP compliance:

no

Remarks:

No description of GLP or similar procedures

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zucht Winkelmann, Paderborn, Germany
- Age at study initiation: Not described
- Weight at study initiation: Between 160 and 240 g (individual weights available in data sheets)
- Fasting period before study: Food, but not water, was removed 16 hours prior to study initiation.
- Housing: Single cages.
- Diet: Standard laboratory diet (Ssniff, Intermast) ad libitum
- Water: Ad libitum
- Acclimation period: Not described

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C
- Humidity (%): 45 - 55
- Air changes (per hr): Not described
- Photoperiod (hrs dark / hrs light): 12 hrs dark /12 hrs light.

IN-LIFE DATES: From - To: Not described

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

Test substance was diluted to a concentration of 50% in Oleum arachidis.

VEHICLE
- Concentration in vehicle: 50% (vol/vol)
- pH Value of test substance in vehicle: 5.5
- Volume of test substance in solution: from 3.2 ml at the lowest dosage to 8.0 ml at the highest dosage.
- Justification for choice of vehicle: Not described
- Lot/batch no.: Not described
Purity: Not described

MAXIMUM DOSE VOLUME APPLIED: Male rats: 8.0 ml; Female rats: 6.8 ml

CLASS METHOD
- Rationale for the selection of the starting dose: Starting dose found at preliminary study

DOSAGE PREPARATION: Dosis range with intervals of log 0.1.

Doses:

Four groups of animals were given increasing doses of test substance, diluted to 50% in arachis oil. A single dose was given orally. Listed dosages refers to the undiluted test substance (in ml test substance/kg bodyweight). The given volume of diluted test substance is given as a range in paranthesis:
Group 1: 10.0 ml/kg (3.2 - 3.7 ml)
Group 2: 12.6 ml/kg (4.2 - 5.2 ml)
Group 3: 15.9 ml/kg (5.1 - 6.4 ml)
Group 4: 20.0 ml/kg (5.8 - 8.0 ml)

No. of animals per sex per dose:

Group 1: 10.0 ml/kg : 5 males / 5 females
Group 2: 12.6 ml/kg : 5 males / 5 females
Group 3: 15.9 ml/kg : 5 males / 5 females
Group 4: 20.0 ml/kg : 5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Observationdata are logged for the following time points after ingestion of the test substance: 20 min, 1 h, 3 h, 24 h, 48 h, 6 and 7 days, and 14 days. Weighing of animals was done at the beginning of the test and after 14 days (survivors only).

- Necropsy of survivors performed: no

- Other examinations performed:
Observation of clinical signs of toxicity was noted at the following time points after ingestion: 20 min, 1 h, 3 h, 24 h, 7 days, and 14 days. Parameters were: Level of consciousness, emotional state, behavioural symptoms (from the CNS), coordination and posture, muscle tonus, reflexes, autonomic functions.
Body weight: at beginning and end of test
Organ weights and macroscopic pathology: performed on animals if they died during test period.
Histopathology was not performed.

Statistics:

Not described

Preliminary study:

Not described in report.

Key result

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 20 mL/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality within first 24 h

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 14.15 mL/kg bw

Based on:

test mat.

95% CL:

> 13.38 - < 14.92

Remarks on result:

other: Mortality occurred between 48 h and 7 d after exposure

Mortality:

Mortality occurred after 24 h, but within 7 days of ingestion. In the groups dosed with 15.9 ml and 20.0 ml test substance the majority of mortal incidences occurred within 48 h of ingestion.

Mortality
Group Dosage 24 hours 14 days
I 10.0 ml/kg 0/10 0/10
II 12.6 ml/kg 0/10 3/10
III 15.9 ml/kg 0/10 7/10
IV 20.0 ml/kg 0/10 10/10

Clinical signs:

other: With increasing dosage the test substance did cause the following clinical symptoms of toxicity, starting 20 minutes after ingestion and seizing 24 hours after ingestion. Symptoms (increasing level with increasing dosage): lower activity level, mild coor

Gross pathology:

In animals dying during the test period, acute mortality within 48 hours and delayed mortality within 7 days after ingestion, autopsy findings included erythematous gastric and enteric mucosa, whereas pathological examination revealed no observable changes in other organs incl. CNS, lungs, heart, liver, spleen, kidneys, reproductive organs and the lymphatic system.

Other findings:

- Organ weights: no data described
- Histopathology: Not performed
- Potential target organs: Not described
- Other observations: Females showed a higher mortality rate at 15.9 ml/kg BW than males.

None

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Even the lowest dosage is above the 2000 mg/kg bw limit for classification of substances as toxic Criteria used for interpretation of results: not specified

Conclusions:

Based on a fixed dose acute oral toxicity study in rats, the LD50 (14 d) of Small Vinyl Ester was determined: 14.15 ml/kg bw (13.38 -14.92 ml/kg bw). The LD50 (24 h) was not calculated due to lack of mortality within the first 24 h.The study and data are below current standard, and should be used for supporting data only.

Executive summary:

The acute oral toxicity of Small Vinyl Ester in the rat, was tested in a single dose procedure with a 14 day follow up period. The study was conducted following recommendations from "Appraisal of the safety of chemicals in foods, drugs and cosmetics", by the Staff of the Division of Pharmacology, FDA, 1959. Four groups, each including 5 male and 5 female SPF-Wistar rats, were given a single dose of a test solution, containing 50% test substance and 50% arachidis oil, by gavage, and observed for clinical/behavioural signs of toxicity and mortality. Dose range of the undiluted Small Vinyl Ester was 10.0, 12.6, 15.9, and 20 ml/kg bw. Since the test solution was a 50% dilution of the Small Vinyl Ester the actual volume doses given to the rats were 20.0, 25.2, 31.8 , and 40.0 ml/kg bw.

Clinical symptoms, includin lower activity level, mild coordination disturbances, and disturbances in posture, piloerektion, and diarrheoa, started after 20 min and seized after 24 h, when surviving animals returned to normal habitus. Mortality occurred after 48 h up to 7 d after ingestion. The mortality after 14 days (actually 7 days) was 0/10 in group 1, 3/10 in group II, 7/10 in group III, and 10/10 in group IV. Pathological post mortem examination of the dead animals revealed erythematous gastric and enteric mucosa, but no other observable pathology was found.

On this basis a calculated LD₅₀ after 14 days was 14.15 ml/kg bw (13.38 -14.92 ml/kg bw). The LD₅₀ after 24 h was not calculated due to lack of mortality within the first 24 h.

The given volumes of Small Vinyl Ester and test solutions prepared with 50% arachidis oil are 2-4 times higher than the recommended maximum volumes for acute toxicity testing. Thus it cannot be ruled out that the observed mortality, clinical symptoms and pathology is a result of giving very high volumes of oily solution in a single dose. Still the survival of all animals in groups I (doses of 10.0 ml/kg bw) indicates that Small Vinyl Ester is practically nontoxic. The dose in group I was 10.0 ml/kg bw corresponds to a dose of 11.7 g/kg bw (density of test substanc: 1.17 g/ml, results from Liddiard and Koban, 2008), which is above the recommended upper fixed doses for testing in current standards of acute oral toxicity.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Feb. 15, 1988 - Feb. 29, 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EEC Guideline 84/449/EEC

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Wistar Bor: WISW (SPFTNO)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: Males 55 days, females 62 days
- Weight at study initiation: Males 155-170 g, females 137-148 g
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum): Standard diet ad libitum, ssniff (R), "Special Diet for Rats", supplied by ssniff Spezialfutter GmbH, D-4770 Soest
- Water (e.g. ad libitum): Water was provided ad libitum in drinking water quality from the Stadtwerke Bielefeld (Municipal Works). An automatic watering system with drinking nipples was used.
- Acclimation period: The animals were kept at least 5 days under test conditions before administration of the test substance. Veterinary supervision of the animals was doen before start of study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22 °C
- Humidity (%):40 - 65%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 6 1.m. - 6 p.m. artificial lighting, 6 p.m. - 6 a.m. natural light-dark-rhythm

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 511 mg/ml
- Amount of vehicle (if gavage): 10 ml

MAXIMUM DOSE VOLUME APPLIED: 511 mg/ml

Doses:

Dose, mg/kg Concentration/content, mg/ml Administration volume, ml/kg Animals per dose
Males
5110 511 10.0 5
Females
5110 511 10.0 5

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were continously observed for the first 4 to 8 hours after administration and then checked daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Llimit test.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 110 mg/kg bw

Based on:

test mat.

Mortality:

No

Clinical signs:

other: Dose mg/kg Female Male Symptoms 5110 x/5 5110 x/5 Salivation 2 2 No symptoms 3 3 Salivation lasted for 20 minutes

Gross pathology:

No abnormalities

Other findings:

None

Acute toxicity LD50 Values

Method Limit test (1, 2)

	LD50 (mg/kg)
Male animals	>5110
Female animals	>5110

 

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

A dose of 5110 mg/kg produced no signs of toxicity except for salivation in some individuals that lasted up to 20 minutes.
No animals died from the exposure. The animals were sacrificed and necropsied after a 14 day observation period. At necroscopy no abnormalities were detected.

The LD0s were
for male rats: >5110 mg/kg bw (limit test)
for female rats: >5110 mg/kg bw (limit test)

Executive summary:

Small Vinyl Ester was studied for acute toxicity following oral administration in rats. Small Vinyl Ester, available as a colourless to yellowish liquid, was given in peanut oil with a concentration of 511 mg/ml. The administration dose was 5110 mg/kg for males and females (limit test). No signs of toxicity except for salivation in some individuals that lasted up to 20 minutes. No animals died from the exposure. The animals were sacrificed and necropsied after a 14 day observation period. At necroscopy no abnormalities were detected.

The LD₀ values were above 5110 mg/kg bw (limit test) for both gender, i.e. LD₅₀ > 5110 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 110 mg/kg bw

Quality of whole database:

Sufficient to address requirements.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Additional information

Based on a fixed dose acute oral toxicity study in rats, the LD50 (14 d) of Small Vinyl Ester was determined: 14.15 ml/kg bw (13.38 -14.92 ml/kg bw). The LD50 (24 h) was not calculated due to lack of mortality within the first 24 h. The study and data are below current standard, and should be used for supporting data only. It is found in the key study that the single-dose LD50 for Small Vinyl Ester in rats via oral route of administration is above 5110 mg/kg bw.

Testing for acute dermal toxicity is waived according to REACH Annex VIII, 8.5.3. QSAR estimations using the US-EPA DERMWIN v2.01 program show that extremely small amounts of Small Vinyl Ester's constituents may enter into the body through the naked skin. Thus, it is foreseeable that the results of acute dermal toxicity testing of Small Vinyl Ester will find a LD50 is larger than 2,000 mg/kg bw. Small Vinyl Ester is placed on the market as an approximately 50% solution in a reactive diluent for industrial and professional use only. Use of personal protection equipment is required to avoid the possible skin exposure to the marketed solution of Small Vinyl Ester.

Testing for acute inhalation toxicity is waived according to REACH Annex VIII, 8.5.2. Small Vinyl Ester has a negligible vapour pressure. Thus, inhalation of vapours of Small Vinyl Ester in toxic amounts is unlikely. Small Vinyl Ester is placed on the market as an approximately 50% solution in a reactive diluent for industrial and professional use only. In spray applications, the aerosol size is larger than 65 µm, cf. the measurement of particle sizes under typical spray conditions (attachment to Section 7.2.2). Thus, inhalation of aerosols is unlikely, i.e. Small Vinyl Ester will not be systemically bioavailable by inhalation. Furthermore, respirators are prescribed for work processes that generate aerosols.

Justification for classification or non-classification

Acute oral toxicity studies show that LD₅₀ of the substance is larger than 5000 mg/kg bw.

QSAR estimations on the constituents of Small Vinyl Ester show that acute dermal toxicity most likely is larger than 2000 mg/kg bw.

Acute inhalation toxicity studies are waived because the vapour pressure of Small Vinyl Ester is negligible and consequently inhalation of toxic amounts unlikely. Furthermore, Small Vinyl Ester is placed on the market as an approximately 50% solution in an reactive diluent for industrial and professional use only. In spray applications, the aerosol particles sizes at different spraying conditions are too large to be inhaled, even when the reactive diluent had evaporated. Furthermore, respirator is prescribed for work processes that generate aerosols.

Based on the findings of a reliable acute toxicity study conducted on the substance, classification of the substance is not justified.