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Description of key information

In a multi-dose acute percutaneous study with rabbits, the dermal LD50 was found to be greater than 4.5 mL/kg (equivalent to 4000 mg/kg).
In an acute oral study with rats, no deaths occurred in the control group and test groups treated with 17.8 mL/kg, 23.7 mL/kg and 27.4 mL/kg.
16 out of 20 rats died in the highest treated group (31.6 mL/kg) during the course of the study. Oral LD50 was calculated to be 30.1 mL/kg.
The exposure of 4 albino rats to the saturated atmosphere (nominal concentration = 0.15 mg/l) for 7 hours at room temperature resulted in 100% survival.

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:
1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: comparable to guideline study with acceptable restriction
Qualifier:
no guideline available
Principles of method if other than guideline:
Four groups each of 10 male rats and one group of 20 male rats were treated with the undiluted substance. The application volume was 17.8 mL/kg, 23.7 mL/kg, 27.4 mL/kg and 31.6 mL/kg, respectively. One control group with 10 male rats was treated with demineralized water at 31.6 mL/kg.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Willi Gassner (WIGA) SPF breeding CH-8741 Sulzfeld Switzerland
- Weight at study initiation: between 110 g and 178 g (mean 133 g)
- Fasting period before study: overnight
- Housing: in groups of 10 or 20 animals in Makrolon (55x33x20) cages during acclimatization and in groups of 5 animals in Makrolon cages (38x22x15) after treatment and during observation.
- Diet: ad libitum except overnight before treatment
- Water: ad libitum
- Acclimation period: 3 to 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 22°C
- Humidity (%): approx. 57%



Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 31.6 mL /kg
Doses:
control group: 31.6 mL/ kg demineralized water
Test group 1: 17.8 mL/kg
Test group 2: 23.7 mL/kg
Test group 3: 27.4 mL/kg
Test group 4: 31.6 mL/kg
No. of animals per sex per dose:
Control group: 10 males
Test group 1: 10 males
Test group 2: 10 males
Test group 3: 10 males
Test group 4: 20 males
Control animals:
yes
Details on study design:
Four groups each of 10 male rats and one group of 20 male rats were treated with the undiluted substance. The single-application volume was 17.8 mL/kg, 23.7 mL/kg, 27.4 mL/kg and 31.6 mL/kg, respectively. One control group with 10 male rats was treated with demineralized water at 31.6 mL/kg.
All animals were examined for mortality and clinical signs at 10, 18 and 33 minutes, 1, 1.8, 3.3, 6 and 24 hours after treatment and at least once daily up to day 14, the end of the observation period. Body weights were recorded on the day of treatment prior to application and on days 7 and 14. All animals that died spontaneously during the course of the study were necropsied and examined as soon as they were found dead.
Preliminary study:
none
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 30.1 mL/kg bw
Mortality:
No deaths occurred in the control group and test group treated with 17.8 mL/kg, 23.7 mL/kg and 27.4 mL/kg.
16 out of 20 rats died in the highest treated group (31.6 mL/kg) during the course of the study. All animals died between day 3 and 8.
Clinical signs:
Systemic toxicity was observed in all test item treated groups. All clinical signs disapeared in the lowest treated group (17.8 mL/kg) after day 4 where where as the animals treated with 23.7 mL/kg, 27.4 mL/kg and the surviving animals treated with 31.6 mL/kg still showed clinical signs at the end of the observation period.
Decrease spontaneous activity and reactivity to stimuli, hunched posture with ruffled fur and atxia as well as half-closed eyes was noted within 24 hours after treatment in all 17.8 mL/kg treated animals. Hypothermia was also noted in the same group at the 24-hour observation. Hunched posture with ruffled fur and high-legged walk persisted up to day 4.
Decrease spontaneous activity and reactivity to stimuli as well as ruffled fur appeared in some animals treated at 23.7 mL/kg within 6 hours after treatment. Hunched posture with high-legged walk, half-closed to closed eyes, ruffled fur, tachypnea, alopecia as well as ataxia were noted at the 24-hour reading, persisting until day 2 for ataxia or day 9 for hunched posture with high-legged walk, half-closed to closed eyes and tachypnea. Alopecia, increaed reactivity to stimuli, ruffled fur were still ovserved at the end of the observation period in all animals.
Reduced spontaneous activity, hunched posture with high-legged walk, ruffled fur, tachypnea as well as soft feces were observed within 24 hours after treatement and persisted except for soft feces until the end of the observation period, additionally alopecia, ataxia, increased reactivity to stimuli appeared after the 24-hour reading and persisted up to day 14.
In the high dose level group (31.6 mL/kg), reduced spontaneous activity, hunched posture with high-legged walk, ruffled fur, tachypnea or bradypnea, increased reactivity to stimuli followed by a decrease, ataxia, half-closed eyes and soft feces were noted. High-legged walk, ruffled fur, alopecia persisted in the surviving animals.
Body weight:
Loss of body weight was noted in the 31.6 mL/kg treated group during the first week of observation but the surviving animals did not recover completly at the end of the observation period compared with the control animals. Body weight increased in the other treated groups was comparable to the control group.
Gross pathology:
For the 31.6 mL/kg treated animals, red discoloration of the stomach with hemmorhage was noted at the unscheduled necropsy in 12 out of 16 animals. Blood in the stomach was observed in 5 animals. Red discoloration of the small intestine with hemmorhage was observed in 10 animals and blood in the small intestine was seen in 12 animals.
Interpretation of results:
relatively harmless
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Oral LD50 male rats > 27.4 and < 31.6 ml/kg
Oral LD50 male rats = 30.1 ml/kg (26.8 g/kg)
density = 0.89g/cm3
Executive summary:

Four groups each of 10 male rats and one group of 20 male rats were treated with the undiluted substance. The single-application volume was 17.8 mL/kg, 23.7 mL/kg, 27.4 mL/kg and 31.6 mL/kg, respectively. One control group with 10 male rats was treated with demineralized water at 31.6 mL/kg.

Mortality and clinical signs were observed during 14 days after treatment.

No deaths occurred in the control group and test groups treated with 17.8 mL/kg, 23.7 mL/kg and 27.4 mL/kg.

16 out of 20 rats died in the highest treated group (31.6 mL/kg) during the course of the study.

Systemic toxicity was observed in all test item treated groups. All clinical signs disapeared in the lowest treated group (17.8 mL/kg) after day 4 where where as the animals treated with 23.7 mL/kg, 27.4 mL/kg and the surviving animals treated with 31.6 mL/kg still showed clinical signs at the end of the observation period.

Loss of body weight was noted in the 31.6 mL/kg treated group during the first week of observation but the surviving animals did not recover completly at the end of the observation period compared with the control animals. Body weight increased in the other treated groups was comparable to the control group.

For the 31.6 mL/kg treated animals, red discoloration of the stomach with hemmorhage was noted at the unscheduled necropsy in 12 out of 16 animals. Blood in the stomach was observed in 5 animals. Red discoloration of the small intestine with hemmorhage was observed in 10 animals and blood in the small intestine was seen in 12 animals.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
26 800 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets National standards method with acceptable restrictions
Principles of method if other than guideline:
Four albino rats were exposed to a saturated atmosphere (nominal concentration: 0.15 mg/l) for 7 hours at room temperature.
GLP compliance:
no
Test type:
fixed concentration procedure
Species:
rat
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
air
Concentrations:
saturated atmosphere (nominal concentration: 0.15 mg/l)
No. of animals per sex per dose:
4
Sex:
not specified
Dose descriptor:
LC0
Effect level:
0.15 mg/L air
Based on:
test mat.
Exp. duration:
7 h
Remarks on result:
other: limited data
Mortality:
0%
Clinical signs:
other: Moderate eye and nasal irritation was observed in all animals during the exposure
Body weight:
No adverse body weight changes
Conclusions:
The 7 hour LC 50 > 0.15mg/l (a saturated atmosphere).
Executive summary:

The exposure of 4 albino rats to the saturated atmosphere (nominal concentration (0.15 mg/l) for 7 hours at room temperature resulted in 100% survival. Moderate eye and nasal irritation was observed in all animals during the exposure.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Exposure concentrations were not measured. Limited documentation.
Principles of method if other than guideline:
The test material was sprayed undiluted for fifteen seconds into an inhalation chamber containing four rabbits and ten rats. The
chamber was sealed and flushed with air under reduced pressure for one hour. This procedure was repeated three times daily for
two days for the test material.
Necropsies were performed on each group of animals the morning following the last treatment. Blood and tissues were taken
for examination.
GLP compliance:
no
Test type:
fixed concentration procedure
Species:
rat
Strain:
CD-1
Details on test animals and environmental conditions:
Ten (10)Charles River CD Rats and four (4) New Zealand Albino Rabbits
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
The test material was sprayed undiluted for fifteen seconds into an inhalation chamber containing four rabbits and ten rats. The
chamber was sealed and flushed with air under reduced pressure for one hour. This procedure was repeated three times daily for
two days for the test material.
Analytical verification of test atmosphere concentrations:
no
No. of animals per sex per dose:
10 rats and 4 rabbits
Remarks on result:
other: No changes were found which related to the test treatment
Mortality:
No deaths
Clinical signs:
other: No symptoms noted
Body weight:
Average body weights were normal
Gross pathology:
No lesions were noted grossly in either species exposed to Epoxide No.8.
Other findings:
Microscopic examination of tissues showed no unusual changes except myocarditis in all four rabbits. The myocarditis was considered
unrelated to test treatment since the population of rabbits being used had a higher than normal incidence of myocarditis.
Average blood values and organ/body weight-ratios were normal.
Interpretation of results:
relatively harmless
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Epoxide No. 8 does not pose any apparent
inhalation problem since it has a low toxicity and vapor pressure.
Executive summary:

The test material was sprayed undiluted for fifteen seconds into an inhalation chamber containing four rabbits and ten rats. The chamber was sealed and flushed with air under reduced pressure for one hour. This procedure was repeated three times daily for two days for the test. material. Necropsies were performed on each group of animals the morning following the last treatment. Blood and tissues were taken for examination.

No lesions were noted grossly in either species exposed to Epoxide No.8. Microscopic examination of tissues showed no unusual changes except myocarditis in all four rabbits. The myocarditis was considered unrelated to test treatment since the population of rabbits being used had a higher than normal incidence of myocarditis. Average blood values and organ/body weight-ratios were normal.

Epoxide No. 8 does not pose any apparent inhalation problem since it has a low toxicity and vapor pressure.

Endpoint conclusion
Dose descriptor:
discriminating conc.
Value:
150 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 1980 to April 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed under GLP conditions with only 3 days observation.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
The procedure involved the application of undiluted test material (at three dose levels) to the intact skin of sexually mature male rabbits. Ten animals, randomly selected, were used in each group. A fourth group of rabbits served as the sham control. Animals were exposed to the test material (0.5, 1.5 and 4.5 mL/kg bw) for 24 hours. They were sacrificed 72 hrs after initial application. Tissues that were collected during necropsy were evaluated histologically on a blind basis. Complete blood count was determined and evalated statistically.
GLP compliance:
yes (incl. certificate)
Test type:
other: Multi-dose acute percutaneous toxicity in rabbits
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
The animal maintenance was according to DHEW Standards in a USDA registered, AAALAC accredited facility.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The appropriate amount of test material was applied to a pre-cut patch (pad with Blenderm backing) and placed on the clipped back of each rabbit. dental dam was placed over the entire test site and held in place by several wrappings of Elastoplast tape. The animals were placed in Newmann harness and returned to their cages for 24 hours. After 24 hours , the harness and wrapping were removed. The test site were rinsed off under a sink with tepid water for 25-30 seconds and were blotted with paper towels. Approximately 30 minutes after the test sites were dry, teh test sites were evaluated for skin irritation.
Duration of exposure:
24 hopurs
Doses:
Group I: Control
Group II: 4.5 mL/kg
Group III: 1.5 mL/kg
Group IV: 0.5 mL/kg
No. of animals per sex per dose:
10 male animals per test group
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 3 days after dosing
- Frequency of observations: Skins were graded 30 minutes aftre removal of the patches and again 3 days aftre dosing. Body weight at start and end of the study.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, skin reaction, hematology
Statistics:
Where appropriate, the results were compared statistically using the method of analysis of variance at <= 0.05 (G.W. Snedecor and W.G. Cochran in statistical Methods, P.258, Iowa State U. Press, 1978).
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 4.5 mL/kg bw
Based on:
test mat.
Mortality:
No mortality occured during the course of the study.
Clinical signs:
No test article related changes in normal behavior or physiological processes were observed during the study.
Body weight:
The body weights of the animals in the four groups were not significantly different either before the study started or at the 3-day weighing.
Gross pathology:
No test article related gross lesions were observed at necropsy.
Other findings:
Only slight irritation was observed at 24 hours, and moderate irritation was reported after 72 hours in all treated groups. Immediately prior to sacrifice, blood was collected from the vena cava of each animal and checked for Hgb, Hct, WBC, RBC, and differential leukocyte counts. Organ weights were determined for testes with and without epididymis, and for liver, heart, kidneys and brain. The testes, epididymis, ductus deferens, seminal vesicles, prostate and heart were further subjected to histopathological examination. There were no compoundrelated effects on body weight, organ weights, and blood morphology, and no adverse effects observed at gross necropsy or histopathological examinations
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Based on the sudy results, the dermal LD50 in rabbits is considered to be greater than 4.5 mL/kg (equivalent to 4000 mg/kg)
Executive summary:

Sexually mature male New Zealand albino rabbits were exposed dermally to doses of alkyl (Cl2-C14) glycidyl ether, ranging from 0.5 to 4.5 ml/kg (equivalent to 4 g/kg). The test material was applied undiluted. There was no mortality. Only slight irritation was observed at 24 hours, and moderate irritation was reported after 72 hours in all treated groups. Immediately prior to sacrifice, blood was collected from the vena cava of each animal and checked for Hgb, Hct, WBC, RBC, and differential leukocyte counts. Organ weights were determined for testes with and without epididymis, and for liver, heart, kidneys and brain. The testes, epididymis, ductus deferens, seminal vesicles, prostate and heart were further subjected to histopathological examination. There were no compoundrelated effects on body weight, organ weights, and blood morphology, and no adverse effects observed at gross necropsy or histopathological examinations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 000 mg/kg bw

Additional information

In a multi-dose acute percutaneous study with rabbits, the dermal LD50 was found to be greater than 4.5 mL/kg (equivalent to 4000 mg/kg).

In an acute oral study with rats, no deaths occurred in the control group and test groups treated with 17.8 mL/kg, 23.7 mL/kg and 27.4 mL/kg. Sixteen (16) out of 20 rats died in the highest treated group (31.6 mL/kg) during the course of the study. Oral LD50 was calculated to be 30.1 mL/kg.

The exposure of 4 albino rats to the saturated atmosphere (nominal concentration = 0.15 mg/l) for 7 hours at room temperature resulted in 100% survival.

Justification for classification or non-classification

The Oral LD50 is greater than 2000 mg/kg. The dermal LD50 is greater than 4000 mg/kg. Saturated atmosphere caused no death, therefore data are insufficient for inhalation classification.