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Administrative data

Description of key information

Studies on butanediol ether have demonstrated that the compound is acutely toxic following oral exposure, particularly in rats. The oral LD50 of butanediol diglycidyl ether in rats was determined to be 1163 mg/kg body weight by Ullman et al. (1988) and 1410 mg/kg body weight by Kobel et al. (1983) in studies performed according to test guidelines and in compliance with good laboratory practice. Other studies support that the oral LD50 value is less than 2000 mg/kg body weight in rats. Clinical signs included sedation, dyspnea, hunched posture, ruffled fur, exophalmus, and lateral body position. In higher dose groups, coma, ataxia, latero-abdominal body position, and spasms were also observed in rats.  In hamsters, the oral LD50 of butanediol diglycidyl ether was determined to be 3609 mg/kg body weight in a study performed according to test guidelines and in compliance with good laboratory practice. 
Butanediol diglycidyl ether is of low acute toxicity following dermal exposure. The dermal LD50 value for butanediol diglycidyl ether was reported to be greater than 2150 mg/kg body weight in rats in a study performed similar to test guidelines (Bathe, 1972). No rats died over the observation period, no signs of toxicity and no dermal reactions were observed, and no gross macroscopic changed were observed at necropsy.
In accordance with column 2 of REACh (Regulation (EC) No 1907/2006) Annex VIII, the acute toxicity by inhalation study (required in section 8.5.2) does not need to be conducted as acute toxicity studies are available for the oral and dermal routes of exposure.

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:
1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, according to accepted guidelines.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1987 followed, reliability scoring based on OECD Guideline 423.
Deviations:
yes
Remarks:
-Source of test substance not reported; animals not observed at least once during the first 30 minutes; no individual data for signs and symptoms
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
1984
Deviations:
yes
Remarks:
-Source of test substance not reported; animals not observed at least once during the first 30 minutes; no individual data for signs and symptoms
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: KFM-Han. Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf / Switzerland.
- Age at study initiation: 9 weeks (males); 11 weeks (females).
- Weight at study initiation: 198 to 238 g (males); 167 to 199 g (females).
- Fasting period before study: 12 to 18 hours.
- Housing: Groups of 5 in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, 4132 Muttenz, Switzerland).
- Diet (e.g. ad libitum): Pelleted standard Kliba 343, Batch 25/88 rat maintenance diet ("Kliba", Klingentalmuehle AG, 4303 Kaiseraugst, Switzerland), available ad libitum.
- Water (e.g. ad libitum): Community tap water from Itingen, available ad libitum.
- Acclimation period: At least 1 week under laboratory conditions, after veterinary examination.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3.
- Humidity (%): 40 to 70.
- Air changes (per hr): 10 to 15.
- Photoperiod (hrs dark / hrs light): 12 / 12.
Route of administration:
oral: gavage
Vehicle:
other: 4% solution of carboxymethylcellulose sodium salt purum in distilled water.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 4% solution of carboxymethylcellulose sodium salt purum in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 20 mL./kg body weight


DOSAGE PREPARATION (if unusual): The test article was placed into a glass beaker on a tared Mettler PK 300 balance, and the vehicle, was added. A weight by volume dilution was prepared using a homogenizer.
Doses:
600, 2000, and 5000 mg/kg body weight.
No. of animals per sex per dose:
5 per sex per dose.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing:
Mortality/Viability: 4 times during test Day 1, and daily during Days 2 to 15.
Body weights: Test Days 1 (pre-administration), 8, and 15.
- Necropsy of survivors performed: Yes.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: The animals were checked for the symptoms such as general behavior, respiration, eye, nose, motility, body posture, motor susceptibility, skin, etc.
Statistics:
The LOGIT-Model (COX, Analysis of Binary Data, London 1977) was applied to estimate the toxicity value. Additionally, the 90, 95, and 99% confidence limits for the toxicity for each sex and the slope of the dose response line were estimated.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 163 mg/kg bw
95% CL:
646.7 - 1 757
Remarks on result:
other: None
Sex:
male
Dose descriptor:
LD50
Effect level:
1 118 mg/kg bw
95% CL:
165 - 2 345
Remarks on result:
other: None
Sex:
female
Dose descriptor:
LD50
Effect level:
1 293 mg/kg bw
95% CL:
427 - 2 341
Remarks on result:
other: None
Mortality:
600 mg/kg body weight group: In males, 1 death on Day 2; no death in females.
2000 mg/kg body weight group: In males, 2 deaths at Hour 2, 1 death at Hour 3, and 1 death on Day 2; In females, 2 deaths at Hour 2, 2 deaths at Hour 3, and 1 death on Day 2.
5000 mg/kg body weight group: In males, 1 death at Hour 1, 1 death at Hour 2, 1 death at Hour 3, and 2 deaths at Hour 5; In females, 4 deaths at Hour 1, 1 death at Hour 2.
Clinical signs:
The following symptoms were observed:
600 mg/kg body weight: sedation, dyspnea, hunched posture, ruffled fur.
2000 mg/kg body weight: sedation, dyspnea, ataxia, ventral body position, hunched posture, spasms (males), diarrhea (males), ruffled fur.
5000 mg/kg body weight: sedation, coma, dyspnea, latero-abdominal position, hunched posture, spasms (males), ruffled fur.
See Attached File 1 for further details on signs and symptoms.
Body weight:
See Attached File 2 for body weight changes.
Gross pathology:
The following macroscopic organ changes were observed:
1) 600 mg/kg body weight group:
-Dead and sacrificed: no pathologic changes
2) 2000 mg/kg body weight group:
-Dead: lungs - not collapsed; no pathologic changes
-Sacrificed: no pathologic changes
3) 5000 mg/kg body weight group:
-Dead: lungs - not collapsed; no pathologic changes
Other findings:
No other information reported.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Harmful if swallowed Criteria used for interpretation of results: other: CLP (EC 1272/2008)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 163 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute Toxicity: Oral

The potential acute oral toxicity of butanediol diglycidyl ether was assessed in KFM-Han Wistar rats in a study performed according to OECD Guidelines for the Testing of Chemicals No. 401 and in compliance with Good Laboratory Practice (Ullman et al., 1988). Groups of 5 male and 5 female rats were orally administered the compound at doses of 600, 2000, or 5000 mg/kg body weight by gavage in a 4% solution of carboxymethylcellulose sodium salt purum in distilled water (vehicle). The animals were observed for 14 days and necropsy was performed on dead animals and on survivors at the end of the observation period. One male died in the 600 mg/kg body weight group, 4 males and all females died in the 2000 mg/kg body weight group, and all animals died in the 5000 mg/kg body weight group. In the 600 mg/kg body weight group, sedation, dyspnea, hunched posture, and ruffled fur were observed. In the 2000 mg/kg body weight group, sedation, dyspnea, ataxia, ventral body position, hunched posture, spasms, diarrhea, and ruffled fur were observed. In the 5000 mg/kg body weight group, sedation, coma, dyspnea, ataxia, latero-abdominal body position, hunched posture, spasms, and ruffled fur were observed. There were no macroscopic findings in dead or sacrificed animals. The oral LD50 for butanediol diglycidyl ether in male and female rats was calculated to be 1163 mg/kg body weight. Butanediol diglycidyl ether was classified as belonging to Toxicity Category IV: Harmful if swallowed, according to CLP criteria.

 

The potential acute oral toxicity of butanediol diglycidyl ether was also assessed in Tif:RAif (SPF) rats in a study performed according to OECD Guidelines for the Testing of Chemicals No. 401 (Kobel, 1983). Groups of 5 male and 5 female rats were orally administered the compound at doses of 600, 1000, 1800, or 3000 mg/kg body weight by gavage in distilled water (vehicle). Necropsy was performed on animals that died and on survivors. No animals died in the 600 mg/kg body weight group, 3 animals died in the 1000 mg/kg body weight group, 6 animals died in the 1800 mg/kg body weight group, and all animals died in the 3000 mg/kg body weight group. Clinical signs included dyspnea, exophthalmus, ruffled fur, sedation, lateral body position, and curved body position. The surviving animals recovered within 9 to 14 days. No gross lesions were found at necropsy. The oral LD50 of butanediol diglycidyl ether for male and female rats was determined to be 1410 mg/kg body weight. Butanediol diglycidyl ether was classified as Toxicity Category IV: Harmful if swallowed, according to CLP criteria.

 

The potential acute oral toxicity of butanediol diglycidyl ether was also assessed in Tif:RAC rats in a study with methodology similar to OECD Guidelines for the Testing of Chemicals No. 401 (Bathe, 1972). Groups of 5 male and 5 female rats were orally administered the compound at doses of 1000, 1470, 1670, or 2150 mg/kg body weight by gavage in polyethylene glycol (vehicle). Animals were observed for mortality at 1, 24, and 48 hours and 7 days after administration. After a 7-day observation period, the animals were killed and autopsied. No animals died in the 1000 mg/kg body weight group, 5 animals died in the 1470 mg/kg body weight group, 7 animals died in the 1670 mg/kg body weight group, and 9 animals died in the 2150 mg/kg body weight group. Within 2 to 3 hours of administration of the test article, the animals in all dose groups displayed dyspnea, lachrymation, ruffled fur, and curved position. The surviving animals recovered within 2 to 6 days. At necropsy, congested and blotchy liver were observed in animals that died before the end of the observation period. There were no test-article related changes observed at autopsy of the surviving animals. The oral LD50 for butanediol diglycidyl ether in male and female rats was reported to be 1500 mg/kg body weight. Butanediol diglycidyl ether was classified as Toxicity Category IV: Harmful if swallowed, according to CLP criteria.

 

The potential acute oral toxicity of butanediol diglycidyl ether was assessed in Tif:RAif (SPF) rats in a second study with similar methodology to OECD Guidelines for the Testing of Chemicals No. 401 (Sarasin, 1981). Groups of 5 male and 5 female rats were orally administered the compound at doses of 1000, 2500, or 5000 mg/kg body weight by gavage in 0.5% carboxymethylcellulose and 0.1% Tween 80 (vehicle). Physical condition and rate of deaths were monitored throughout the 14-day observation period. Necropsy was performed on animals that died during the observation period and those that survived to the end of the observation period. No animals died in the 1000 mg/kg body weight group, 9 animals died in the 2500 mg/kg body weight group, and all animals died in the 5000 mg/kg body weight group. In the 1000 and 2500 mg mg/kg body weight group, clinical signs included sedation, dyspnoea, exophthalmos, ruffled fur, and curved body position. In the 5000 mg mg/kg body weight group, clinical signs included sedation, dyspnoea, ruffled fur, convulsions, and curved, ventral, and lateral body position. The surviving animals recovered within 7 to 10 days. No test-article related gross lesions were found at necropsy. The oral LD50 of butanediol diglycidyl ether for male and female rats was determined to be 1882 mg/kg body weight. Butanediol diglycidyl ether was classified as Toxicity Category IV: Harmful if swallowed, according to CLP criteria.

 

In addition, the potential acute oral toxicity of butanediol diglycidyl ether was assessed in Chinese hamsters in a study performed according to OECD Guidelines for the Testing of Chemicals No. 401 (Kobel, 1983). Groups of 5 male and 5 female hamsters were orally administered the compound at doses of 2000, 4000, or 8000 mg/kg body weight by gavage in distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80 (vehicle). Necropsy was performed on animals that died during the observation period and on survivors. No animals died in the 2000 mg/kg body weight group, 7 animals died in the 4000 mg/kg body weight group, and all animals died in the 8000 mg/kg body weight group. Clinical signs included dyspnea, exophthalmus, ruffled fur, and curved body position. In addition, sedation was observed and occurred in a dose-dependent manner. The surviving animals recovered within 11 days. Two isolated cases of spotted lungs were observed at necropsy, but no other findings were observed. The oral LD50 of butanediol diglycidyl ether for male and female hamsters was determined to be 3609 mg/kg body weight. Butanediol diglycidyl ether was not classified as acutely toxic according to CLP criteria.

 

Acute Toxicity: Dermal

The potential acute dermal toxicity of butanediol diglycidyl ether was assessed in Tif:RAI/f rats in a study similar in methodology to OECD Guidelines for the Testing of Chemicals No. 402 (Bathe, 1972). Three male and 3 female rats were administered 2150 mg/kg body weight of the test article (use of vehicle not reported) with aluminum foil covering to the back of the rats for 24 hours. At the end of the exposure period, the foil was removed and the skin was washed with warm water to remove all traces of the suspension. The animals were observed for signs of toxicity for 7 days after dosing. Mortality was observed at 1, 24, and 48 hours, and at 7 days after administration. Necropsy was performed on surviving animals at the end of the observation period. No rats died during the study, no clinical signs of toxicity were observed, and no local skin irritation was reported. In addition, no test-article related gross organ changes were observed in any animals. The acute dermal LD50 of butanediol diglycidyl ether in rats was greater than 2150 mg/kg body weight. Butanediol diglycidyl ether was not classified as acutely toxic according to CLP criteria.

 

Acute Toxicity:

Inhalation In accordance with column 2 of REACh (Regulation (EC) No 1907/2006) Annex VIII, the acute toxicity by inhalation study (required in section 8.5.2) does not need to be conducted as acute toxicity studies are available for the oral and dermal routes of exposure.


Justification for selection of acute toxicity – oral endpoint
GLP study conducted according to international guidelines.

Justification for classification or non-classification

Acute Toxicity, oral: The notifiable substance has an acute oral LD50 of greater than 300 and less than 2000 mg/kg bw (acute oral LD50 = 1163 mg/kg bw). As a result, the substance meets the criteria for category 4 classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

 

Acute Toxicity, dermal: The notifiable substance has an acute dermal LD50 of greater than 2000 mg/kg bw (>2150 mg/kg bw). As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

 

Acute Toxicity, inhalative: There is no information available concerning inhalative toxicity; not expected, but data is lacking.