Butyl 2,3-epoxypropyl ether

Endpoint summary

Description of key information

LD50 via oral route is 1530 mg/kg bw.

LC50 (4h) via inhalation is 10970 mg/m3.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

To evaluate the acute toxicity, groups of 5 mice were given graded doses (400, 800, 1600, and 3200 mg/kg bw) of the test substance, followed by a 10 day observation period.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Name as sited in report: Butyl glycidyl ether (BGE)

Species:

mouse

Strain:

other: Princeton

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hooper Foundation
- Weight at study initiation: 16-22 gram
- Housing: 5 to a cage
- Diet: Special green powdered diet obtained from the Simonsen Laboratories.

Route of administration:

other: intragastrically

Vehicle:

propylene glycol

Details on oral exposure:

Exposure by means of ball-point needle and syringe.

VEHICLE
- Concentration in vehicle: 20%

Doses:

400, 800, 1600, and 3200 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

The animals were held for a 10-day observation period after treatment, during which mortality records were kept and weight changes recorded. Surviving animals were sacrificed for necropsy. Animals were decapitated under light ether anaesthesia. Suitable tissues were taken for histological examination from all moribund animals and animals that died during laboratory hours.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 530 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 170 - <= 2 000

Mortality:

At 400 mg/kg bw: No mortality occurred
At 800 mg/kg bw: No mortality occurred.
At 1600 mg/kg bw: 3/5 animals died. Death occurred within 7-15 hours.
At 3200 mg/kg bw: All animals died. Death occurred within 5 minutes.

Gross pathology:

Animals subjected to necropsy showed no gross abnormalities. Histologic examination revealed severe pulmonary congestion in two cases and one case of focal inflammatory cells in the liver.

Interpretation of results:

Category 4 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 530 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Groups of 5 rats were exposed to graded concentrations of the test substance for 8 hours.

GLP compliance:

no

Test type:

traditional method

Limit test:

no

Specific details on test material used for the study:

Name as sited in report: Butyl glycidyl ether (BGE)

Species:

rat

Strain:

Long-Evans

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories (California)
- Weight at study initiation: 110 to 140 gram.
- Housing: 5 to a cage
- Diet: Special green powdered diet obtained from the Simonsen Laboratories.

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

A motor driven syringe delivered measured amounts of the test substance from a 10 mL Luer-Lok syringe into an evaporator through which metered air moved at a uniform rate. High concentration was obtained by bubbling air through a fritted glass disc immersed in the compound, which was held in a glass container. The rate of airflow was set at approximately 5 liters per minute, for concentrated vapors, and at 3 to 11 liters per minute for the graded concentrations. Nominal concentrations were calculated by the standard gas-concentration formula of Jacobs (1949) and were checked by determining the total quantity of material vaporized.

Duration of exposure:

8 h

Concentrations:

670, 1000, 1500, and 2300 ppm

No. of animals per sex per dose:

5

Control animals:

no

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

1 030 ppm

Based on:

test mat.

95% CL:

>= 890 - <= 1 240

Exp. duration:

8 h

Mortality:

At 670 ppm: No mortality occurred.
At 1000 ppm: 1/5 animals died. Death occurred within 16 hours.
At 1500 ppm: 5/5 animals died. Death occurred within 6-11 hours.
At 2300 ppm: 5/5 animals died. Death occurred within 1-14 days.

Clinical signs:

other: Depression with little activity was noted in rats exposed to 670 ppm. Rats huddled at the side of the chamber away from the vapour inlet. At 1000 ppm, their activity varied from extreme apathy to agitation and leaping at the chamber walls. Dyspnea was pre

Gross pathology:

The test substance caused distended stomachs and intestines; one rat had a ruptured stomach and distended enteric tract. Congestion was observed in the abdominal cavity, and the lungs had a mottled appearance. Microscopic examination of the rats that died showed only pulmonary congestion and autolysis of the gastric mucosa.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

10 970 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

To evaluate the acute percutaneous toxicity of the test substance, 2 male and 2 female rabbits per dose level were treated with 1000, 750, or 500 mg/kg bw.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ray Nichols Rabbitry, Lumberton, Texas.
- Housing: Housed singly
- Diet: Commercial laboratory chow (Palston Purina Company, St Louis, Missouri), ad libitum.
- Water: Well water, ad libitum.
- Acclimation period: At least 1 week

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: The entire trunk was clipped free of hair with electric clippers.
- Type of wrap if used: The undiluted test material was applied under a heavy-gauge plastic sleeve held in place with rubber bands. The plastic sleeve was covered with a cloth bandage taped securely to the marginal hair.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The sleeves were removed and the skins were washed with mild soap and water, rinsed thoroughly, and dried with a soft disposable towel.
- Time after start of exposure: After 24 hours

Duration of exposure:

24 hours

Doses:

1000, 750, and 500 mg/kg bw

No. of animals per sex per dose:

2

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The topical response at the test site of application was evaluated after removal of the plastic sleeve. The animals were observed frequently during exposure and for the following 2 weeks for signs of toxicity.
- Necropsy of survivors performed: At 2 weeks post-treatment, all surviving rabbits were submitted for gross pathological examination.

Statistics:

The acute percutaneous absorption LD50 was calculated by the moving average method as implemented in a computer program.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

778 mg/kg bw

Based on:

test mat.

95% CL:

>= 642 - <= 1 012

Mortality:

At 1000 mg/kg bw: 4/4 rabbits died.
At 750 mg/kg bw: 1/4 rabbits died.
At 500 mg/kg bw: 0/4 rabbits died.

Clinical signs:

other: Following treatment, the rabbits displayed signs of discomfort and became lethargic. The treated skin was necrotic with scabbing and scarring.

Gross pathology:

No internal lesions attributable to treatment were observed in the survivors upon gross pathological examination at 2 weeks.

Interpretation of results:

Category 3 based on GHS criteria

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

To assess the acute dermal toxicity, rabbits were clipped free of hair and exposed to graded doses (2000, 4000, 8000, and 16000 mg/kg bw) of the test substance to the skin.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Name as sited in report: Butyl glycidyl ether (BGE)

Species:

rabbit

Strain:

other: California Albino or New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: the Casa Ladrillo Rabbitry, California or the Simonsen Laboratories
- Weight at study initiation: 2.0 to 2.5 kg
- Housing: Single housing
- Diet: Standard rabbit pellets

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Animals were clipped free of hair in a cylindrical swath from the shoulders to the hips, 24 hours before application of the test substance.
- Type of wrap if used: The undiluted test material in graded doses was applied under rubber sleeves. The sleeved rabbits were wrapped to minimise evaporation and held in a multiple rabbit holder for seven hours.

Doses:

2000, 4000, 8000, and 16000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

4 930 mg/kg bw

Based on:

test mat.

95% CL:

>= 3 780 - <= 6 500

Mortality:

At 2000 mg/kg bw: No mortality occurred.
At 4000 mg/kg bw: 1/5 animals died. Death occurred within 3 days.
At 8000 mg/kg bw: 5/5 animals died. Death occurred within 1 day.
At 16000 mg/kg bw: 5/5 animals died. Death occurred within less than 1 day.

Clinical signs:

other: The test substance produced depression leading to death in 1 to 2 days at the highest level.

Gross pathology:

The viscera were usually normal in appearance but one rabbit had a dark an friable liver, hyperaemic lungs, and dark kidneys. Stomachs, intestines and bladders were often full. No abnormalities were reported on histologic examination.

Interpretation of results:

GHS criteria not met

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Principles of method if other than guideline:

The acute toxicity potential was assessed for 60 epoxy compounds, among which the test substance. For acute dermal toxicity the results of a range finding test were reported.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Name as cited in report: Butyl glycidyl ether

Species:

rabbit

Strain:

not specified

Sex:

male/female

Type of coverage:

not specified

Vehicle:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2.52 mL/kg bw

Based on:

test mat.

95% CL:

>= 1.28 - <= 4.97

Interpretation of results:

study cannot be used for classification

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Additional information

Acute oral toxicity:

Two acute oral toxicity studies were identified, one with mice and one with rats. In one acute oral toxicity study groups of 5 mice were given graded doses (400, 800, 1600, and 3200 mg/kg bw) of the test substance (US EPA, 1956). Exposure occurred by means of ball-point needle and syringe. The animals were held for a 10-day observation period after treatment, during which mortality records were kept and weight changes recorded. Surviving animals were sacrificed for necropsy. Animals were decapitated under light ether anaesthesia. Suitable tissues were taken for histological examination from all moribund animals and animals that died during laboratory hours. At 400 and 800 mg/kg bw no mortality occurred. At 1600 mg/kg bw 3/5 animals and at 3200 mg/kg bw all animals died. Clinical signs were not reported. Animals subjected to necropsy showed no gross abnormalities. Histologic examination revealed severe pulmonary congestion in two cases and one case of focal inflammatory cells in the liver. The LD50 was determined to be 1530 mg/kg bw (1170 -2000).

The same study was also performed with rats dosed with 800, 1600, 3200, and 6400 mg/kg bw (US EPA, 1956). At 800 and 1600 mg/kg bw no mortality occurred. At 3200 and 6400 mg/kg bw all animals died. At the 2 lowest dose levels, the rats showed no signs of toxicity. Animals which received 3200 mg/kg were depressed and somewhat ataxic 5 minutes after administration. Dyspnoea and hyperventilation appeared during the first 5 minutes. In 5-10 minutes the rats went into coma which lasted several hours, or until death occurred in less than 15 hours. The highest dose level was marked by almost immediate hyperventilation and depression, but death was delayed until 17 hours to six days. Pathological data was not reported. The LD50 was determined to be 2260 mg/kg bw.

Finally, in a published range finding study in which the acute toxicity potential was assessed for 60 epoxy compounds a LD50 value of 2050.0 mg/kg bw was reported for rats (Weil, 1963). For assessment purposes the study-methods were not documented in enough detail (only tabulated results were available).

 

Acute inhalation toxicity:

To assess the acute inhalation toxicity groups of 5 Long-Evans rats were exposed to graded concentrations (670, 1000, 1500, and 2300 ppm) of the vapours of the test substance (US EPA, 1956). The type of exposure was whole body for a duration of 8 hours. At 670 ppm no mortality occurred. At 1000 ppm 1/5 animals died. At the two highest concentrations of 1500 and 2300 ppm all animals died. Depression with little activity was noted in rats exposed to 670 ppm. Rats huddled at the side of the chamber away from the vapor inlet. At 1000 ppm, their activity varied from extreme apathy to agitation and leaping at the chamber walls. Dyspnoea was present at the highest levels. The test substance caused distended stomachs and intestines; one rat had a ruptured stomach and distended enteric tract. Congestion was observed in the abdominal cavity, and the lungs had a mottled appearance. Microscopic examination of the rats that died showed only pulmonary congestion and autolysis of the gastric mucosa. The LC50 was determined to be 1030 ppm (890-1240) which corresponds to 5485 mg/m³.

Prior to the start-up of a 28-day inhalation study a range-finding study was performed as an aid to establishing the concentrations for the 28-day study (US EPA, 1985). Groups of 2 males and 2 females were exposed to the test substances at doses of 11, 17, 23, and 28 mg/L air. The respirable atmospheres for this pre-test were produced using a Hospitek Nebulizer operated at an air pressure of 1 atm., and with a flow rate of 9 L of air per min. This aerosol was diluted to obtain the desired test concentration. 0, 3, 4 and 4 out of 4 animals died exposed to 11, 27, 23 and 28 mg/L air, respectively. The mortalities in these exposures exhibited lung congestion and consolidation. The LC50 was determined to be 14 mg/Lair with the 95% confidence limits of 10-20 mg/L air.

In another study groups of 5 or 6 mice were exposed to high concentrations of the test substance (US EPA, 1956). Only 1 death occurred in 10 animals exposed to concentrated substance (approximately 3500 ppm). This death occurred within 24 hours. Early clinical signs consisted of slight depression with lacrimation. Late in the exposure agitation was demonstrated by leaping at the sides of the chamber. Signs of irritation were pronounced in some animals, where convulsive gasping was noted. Based on the fact that only one concentration was administered, no LC50 was derived.

In addition, in a published range finding study in which the acute toxicity potential was assessed for 60 epoxy compounds, rats were exposed to 4000 ppm for 4 hours (Weil, 1963). At this exposure regime 1/6 rats died. For assessment purposes the study-methods as well as the results were not documented in enough detail (only tabulated results were available).

 

Out to the two studies that determined a LC50 the first study, in which the animals were exposed to the vaporized substance, was considered the be most reliable as the second was only a preliminary study (with limited method information). For assessment purposes it should be noted that, in general, a 4 hour exposure regime is considered appropriate. Therefore the modification of Haber's Law, Cn x t = k (with n=1), was applied, resulting in a 4h-LC50 of 2060 ppm which corresponds to 10970 mg/m³. Using the n=1 in the modification is considered to be conservative enough, as the preliminary study shows that with 4 hour exposure at 11000 mg/m³ 0 out of 4 animals died and at 17000 mg/m³ 3 out of 4 animals died. The calculated LC50 from that preliminary study is similar to the value calculated from the 8-hour study with n=1, indicating that there is no need for a more conservative recalculation.

 

Acute dermal toxicity:

To evaluate the acute percutaneous toxicity of the test substance, 2 male and 2 female New Zealand White rabbits per dose level were treated with 1000, 750, or 500 mg/kg bw, followed by a 14 day observation period (US EPA, 1982). The test substance was applied undiluted on the clipped trunk under occlusive conditions. After 24 hours the plastic sleeves were removed and the skins were washed with mild soap and water, rinsed thoroughly, and dried with a soft disposable towel. At 500 mg/kg bw no mortality occurred. At 750 mg/kg bw 1/4 animals died and at 1000 mg/kg all animals died. Following treatment, the rabbits displayed signs of discomfort and became lethargic. The treated skin was necrotic with scabbing and scarring. In addition, most survivors were slow to regain pre-treatment weight. No internal lesions attributable to treatment were observed in the survivors upon gross pathological examination at 2 weeks. The dermal LD50 was determined to be 778 mg/kg bw (642-1012).

In another acute dermal toxicity study (US EPA, 1956) 5 male rabbits per dose (2000, 4000, 8000, and 16000 mg/kg bw) were treated with the undiluted test substance. The material was applied to the clipped skin under occlusive conditions. At 2000 mg/kg bw no mortality occurred. At 4000 mg/kg bw 1/5 animals died. At 8000 and 16000 mg/kg all animals died. The test substance produced depression leading to death in 1 to 2 days at the highest level. The viscera were usually normal in appearance but one rabbit had a dark and friable liver, hyperaemic lungs, and dark kidneys. Stomachs, intestines and bladders were often full. No abnormalities were reported on histologic examination. The dermal LD50 was determined to be 4930 mg/kg bw (3780-6500) for male animals.

In addition in a published range finding study (Weil, 1963) in which the acute toxicity potential was assessed for 60 epoxy compounds, rabbits were dermally exposed to the test substance. In this study a LD50 of 2.52 mL/kg bw was reported. For assessment purposes the study-methods as well as the results were not documented in enough detail (only tabulated results were available).

 

Out of the three studies the first two were considered to be sufficiently reliable to evaluate the acute percutaneous toxicity, based on the amount of detail presented. The LD50 that is determined in these studies is however very different, even though the method described is similar. There is more than a factor 6 difference in the LD50 determined in the first study versus the LD50 determined in the second study. Solely based on the LD50 the first one would lead to a category 3 classification and the second one to no classification. According to OECD guideline 402 the test substance should be held in contact with the skin of the animal with a porous gauze dressing and non-irritating tape (semi-occlusive) throughout a 24-hour exposure period. In both of the studies presented above rabbits were exposed to the test substance under occlusive conditions. The circumstances under which these animals were exposed is therefore considered to be more severe than the conditions under the guideline. However, in the second study the exposure time is not clearly stated, which may explain the difference in LD50 (as it might be less severe due to a shorter exposure time). As both studies are relatively old, it is assumed that these were taken into account when the harmonised classification was determined. Taking this into consideration, by weight of evidence it is decided to retain the hazard assessment of the harmonised classification, which leads to no classification.

Justification for classification or non-classification

Based on the acute oral LD50 of 1530 mg/kg bw and the acute inhalation LC50 of 10970 mg/m³ the substance has to be classified as Acute Tox 4, H302: Harmful if swallowed and Acute Tox 4, H332: Harmful if inhaled in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

 

For acute dermal toxicity the harmonised classification is assumed, which is no classification.