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Diss Factsheets

Administrative data

Description of key information

Using the GHS classification system, epichlorohydrin is a Category 3 following oral, dermal and inhalation exposure.

KJB 05/10/2018. The acute inhalation classification was corrected from category 2 to category 3 in 7.2.2 in Applicants summary and conclusion section.

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:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Not GLP, study was conducted in accordance with Guidelines and sufficient data is available for the interpretation of results.
Qualifier:
according to guideline
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
Remarks:
Not specified in report
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Fischer 344 and Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Fischer 344 rats: Charles River Breeding Laboratories, Portage, MI; Sprague-Dawley rats: Spartan Research Animals, Inc., Haslett, MI

Age: 7-8 weeks

Mean Weight at Study Initiation: male Fischer 344 rats: 103-185 g female Fischer 344 rats: 80-132 g; male Sprague-Dawley rats: 262-325 g; female Sprague-Dawley rats: 192-208 g
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Doses per time period: Single-dose oral gavage

Maximum volume administered: Fischer 344 rats: 2.8 ml; Sprague-Dawley rats: 4.7 ml

Post-Dose Observation Period: 2 weeks
Doses:
25, 50, 100, 200, 210, 225, 252, 398, 795 mg/kg for male and female Fischer 344 rats

24, 50, 100, 200, 398 and 795 mg/kg for male and female Sprague-Dawley rats.
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
Examinations: Clinical observations, gross pathological examination
Statistics:
Statistics: The acute oral median lethal dose and approximate slope of the dose-response curve for both strains were calculated by the moving average method of Thompson and Weil (Biometrics 8: 51-54, 1952).
Preliminary study:
not applicable
Sex:
male
Dose descriptor:
LD50
Effect level:
282 mg/kg bw
95% CL:
117 - 448
Remarks on result:
other: Sprague-Dawley rat calculated using moving average method
Sex:
female
Dose descriptor:
LD50
Effect level:
175 mg/kg bw
95% CL:
116 - 306
Remarks on result:
other: Sprague-Dawley rat calculated using moving average method
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 218 mg/kg bw
Remarks on result:
other: Fischer 344 rat calculated using moving average method
Sex:
female
Dose descriptor:
LD50
Effect level:
210 mg/kg bw
95% CL:
203 - 216
Remarks on result:
other: Fischer 344 rat calculated using moving average method
Mortality:
MORTALITY:

# Dead/# Treated
Dose Male Female Male Female
(mg/kg) S-D S-D CDF CDF
25 0/5 0/5 0/5 0/5
50 0/5 0/5 0/5 0/5
100 0/5 0/5 0/5 0/5
200 1/5 2/5 0/5 0/5
210 --- --- 0/5 3/5
225 --- --- 5/5 5/5
252 --- --- 5/5 5/5
398 4/5 5/5 5/5 5/5
795 5/5 5/5 5/5 5/5

---: not tested

Time to death not available.
Clinical signs:
other: CLINICAL SIGNS: # Affected/# Treated Dose Sign Male Female Male Female (mg/kg) S-D S-D CDF CDF 25 0/5 0/5 0/5 0/5 50 0/5 0/5 0/5 0/5 100 0/5
Gross pathology:
GROSS PATHOLOGY:
Roughening and thickening of the squamous epithelium of the non-glandular stomach was observed in rats given 100-210 mg/kg with Sprague-Dawley rats exhibiting an increased incidence compared to Fischer 344 rats. Other findings were non-specific and not considered treatment-related.

Other findings:
POTENTIAL TARGET ORGANS: None identified.

SEX-SPECIFIC DIFFERENCES: No significant differences observed.

The LD50 results were very similar between both strains and sexes with individual values ranging from 175 -282 mg/kg..

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 was calculated in male and female Sprague-Dawley and Fischer 344 rats. The LD50 ranged from 175-282 mg/kg.
Executive summary:

The LD50 was calculated in male and female Sprague-Dawley and Fischer 344 rats for a number of compounds. The LD50 for epichlorohydrin ranged from 175-282 mg/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
175 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
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted in accordance with GLP guideline(DOT) and sufficient data is available for the interpretation of study results.
Qualifier:
according to guideline
Guideline:
other: DOT guidelines
Deviations:
no
Principles of method if other than guideline:
The 1 hour LC50 was determined for Epichlorohydrin in male and female rats
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Charles River Breeding Laboratories, Kingston, NY
Age: 6-8 weeks
Weight at study initiation: males: 177-266 g; females: 126-148 g
Number of animals: 6/sex/exposure concentration
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
ADMINISTRATION:
Type of Exposure: whole-body vapor exposures
Concentrations:
Target 500 1000 2000 2800 3350 4000
Nominal 599 1133 2329 3306 3866 4609
Analyt. 552 1008 1970 2865 3275 3995
Males only were exposed to analytical concentrations of 2865 and 3275 ppm.

Exposur es occurred in 2.6 cubic meter Rochester-type inhalation chambers. Atmospheres were generated by passing heated compressed air through a J-tube assembly as the test material entered the J-tube assembly. Chamber airflow was maintained at 400-500 liters/hour. Chamber concentrations were monitored 7 times/hour using gas chromatography.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatography
Duration of exposure:
1 h
Concentrations:
Target 500 1000 2000 2800 3350 4000
Nominal 599 1133 2329 3306 3866 4609
Analyt. 552 1008 1970 2865 3275 3995
Males only were exposed to analytical concentrations of 2865 and 3275 ppm.
No. of animals per sex per dose:
6/sex/exposure concentration
Control animals:
no
Details on study design:
Animals were observed for signs of toxicity during exposure and for 14 days post-exposure. Animals were weighed at study initiation, and surviving rats were weighed on study days 2, 4, 8, 11, and 15. All animals were submitted for pathological examination of major organ systems either at death or at study termination. In addition, nasal cavities were split longitudinally for examination of the turbinate area.
Statistics:
The LC50 for females was calculated as a function of the time-weighted average analytical exposure concentrations by the moving-average method (Thompson and Weil, 1952). The LC50 for males was estimated by calculating the geometric man between exposure levels that resulted in 0 and 100% mortality among males, as implemented in a computer program furnished by Dr. Charles E. Stephan, USEPA Environmental Research Laboratory, Duluth, MN.

Based on the mortality observed in this study, a LC50 value for male
rats could not be calculated using the moving average method because there were no partial kills (Thompson and Weil, 1952). As an alternative, the LC50 for males was estimated by calculating the geometric mean between exposure levels that resulted in 0 and 100% mortality among male rats (i.e., 3275 and 3995 ppm, respectively), as implemented in a computer program furnished by Dr. Charles E. Stephan, USEPA Environmental Research Laboratory, Duluth, MN.
Preliminary study:
not applicable
Sex:
male
Dose descriptor:
LC50
Effect level:
ca. 3 617 ppm
Exp. duration:
1 h
Remarks on result:
other: no mortality observed at 3275 ppm and all rats died at 3995 ppm
Sex:
female
Dose descriptor:
LC50
Effect level:
2 165 ppm
Exp. duration:
1 h
Mortality:
MORTALITY:

# Dead/# Treated Time to Death
Dose Male Female Male Female
(PPM) CDF CDF CDF CDF
552 0/6 0/6 --- ---
1008 0/6 0/6 --- ---
1970 0/6 2/6 --- 1@2 days
1@3 days
2865 0/6 --- --- ---
3275 0/6 --- --- ---
3995 6/6 6/6 3@1 day 6@1 day
1@2 days
1@3 days
1@4 days

---: not tested
Clinical signs:
other: Signs of toxicity were predominantly noted at exposure concentrations of 1970 ppm and above, although all rats exposed to 1008 or 552 ppm spent most of their exposure time huddled in their cages with eyes completely shut. Signs of eye and nasal irritation
Body weight:
Body weights were essentially unaffected following exposure to 552 ppm with animals gaining weight. At higher concentrations, rats lost weight immediately following exposure but survivors gained weight thereafter.
Gross pathology:
The most frequent observation noted at necropsy among male rats surviving the 2-week observation period was bilaterial corneal cloudiness at 1970 ppm (1/6), 2865 (5/6), or 3275 (6/6). No other observations noted were considered to be treatment-related.
Other findings:
POTENTIAL TARGET ORGANS: Eye.

SEX-SPECIFIC DIFFERENCES: None other than differing LC50's

Six rats/sex/exposure level were exposed to time-weighted average (TWA) analytical concentrations of 552, 1008, 1970 or 3995 ppm (2.088, 3.814, 7.453 or 15.114 mg/l, respectively) ECH vapors for l-hr. Two additional groups of 6 male rats were also exposed to TWA concentrations of 2865 or 3275 ppm (10.839 or 12.390 mg/l, respectively). The l-h r LC50 for male rats was estimated to be 3617 ppm. For females, a l-h r LC50 of 2165 ppm was calculated by the moving average method of analysis. Eye and nasal irritation, respiratory difficulty and secretion of a reddish, porphyrin-like material on the facial area were noted among rats exposed to 1970, 2865, 3275 or 3995 ppm, Hyperactivity, followed by lethargy and a cyanotic appearance were also noted in rats exposed to 3275 or 3995 ppm, Although a temporary body weight loss was evident in almost all exposure groups, all rats that survived a 2 -week observation period steadily gained weight. Bilateral corneal cloudiness was the only exposure-related lesion noted among animals (males only) surviving to scheduled necropsy.

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Based on the results of the study the 1 hour LC50 values of ECH in male and female Fischer-344 rats were not only greater than 1000 ppm ppm but
also greater than 1/10th of maximum saturated vapor concentration of ECH at 20c which is calculated to be 17,100 ppm.
Executive summary:

The purpose of this study was to determine the single-exposure 1-hr LC50 of epichlorohydrin (ECH) in Fischer-344 rats. These data were requested in response to recently proposed Department of Transportation (DOT) guidelines that would require additional labeling for the transportation of any liquid whose 1 -hr LC50 values in male and female rats are: 1) less than or equal to1000 ppm; and 2) less than or equal to 1/10th of the liquid's theoretical saturated vapor concentration at 20°C.

Six rats/sex/exposure level were exposed to time-weighted average (TWA) analytical concentrations of 552, 1008, 1970 or 3995 ppm (2.088, 3.814, 7.453 or 15.114 mg/l, respectively) ECH vapors for 1 -hr. Two additional groups of 6 male rats each were also exposed to TWA concentrations of 2865 or 3275 ppm (10.839 or 12.390 mg/l, respectively). The 1-hr LC50 for male rats was estimated to be 3617 ppm. As calculated by the moving average method of analysis, the LC50 for females was 2165 ppm.

Based on the results of this study, ECH does not meet the proposed DOT criteria that would require additional labeling for transportation. The 1-hr LC50 values of ECH were not only greater than 1000 ppm, but also greater than 1/10 of the maximum saturated vapor concentration of ECH at 20°C (calculated to be 17,100 ppm).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
4 114 mg/m³ air

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:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted according to guideline/s and GLP but the report contains sufficient data for interpretation of study results. Study does not meet guideline requirements for minimum number of animals/dose level. .
Qualifier:
no guideline followed
Principles of method if other than guideline:
The dermal LD50 was examined using epichlorohydrin, neat, or diluted with propylene chloride with rabbits. Animals were observed until they died or regained pre-treatment weight.
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:
Weight at Study Initiation: 2.43-3.50 kg
Type of coverage:
occlusive
Vehicle:
other: Dosed undiluted and as a 20% solution in propylene glycol
Details on dermal exposure:
Single dose

Area Covered: Unknown

Occlusion: Impervious cuff held in place with cloth bandage taped to hair

Removal of Test Material: Washing with soap and water 24 hours post-dosing

Maximum Volume Administered: 2.38 ml

Post-Dose Observation Period: 2 weeks

Duration of exposure:
24 hours
Doses:
Undiluted: 100, 200, 465, 795 mg/kg
20% solution in propylene glycol: 252, 500, 630 or 795 mg/kg
No. of animals per sex per dose:
2/sex/dose
Control animals:
no
Details on study design:
Approximately 24 hours prior to dosing, the hair was removed from the trunk of 2 laboratory white rabbits/dose level with electric clippers. The test material was applied at 100, 200, 465, or 795 mg/kg body weight under an impervious cuff held in place with a cloth bandage taped to the hair.
Following application the animals were returned to holding cages and allowed to eat and drink ad libitum. Following a 24-hour exposure period, the cuffs were removed and the skins washed with soap and water. The animals were observed during and after exposure and weighed at intervals up to two weeks post-application. The animals were then submitted for necropsy examination at death or at scheduled study termination.
Statistics:
LD50 calculation method not specified
Preliminary study:
not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
515 mg/kg bw
Remarks on result:
other: Undiluted
Sex:
male/female
Dose descriptor:
LD50
Effect level:
250 - 500 mg/kg bw
Remarks on result:
other: 20% solution in propylene glycol
Mortality:
Undiluted

# Dead/# Treated
Dose Male Female
(mg/kg)
100 0/2 0/2
200 0/2 0/2
465 1/2 0/2 Found dead 24 hours post-dosing
795 2/2 2/2 Found dead 24 hours post-dosing

20% solution in propylene glycol

# Dead/# Treated
Dose Male Female
(mg/kg)
252 0/2 0/2
500 2/2 2/2 Found dead 24-48 hours post-dosing
630 - 2/2 Found dead 24 hours post-dosing
795 - 2/2 Found dead 24 hours post-dosing
Clinical signs:
other: Severe redness and swelling and slight necrosis were observed when the cuffs were removed after the 24-hour exposure to either test material.
Gross pathology:
no data
Other findings:
no additional information available

Two male and two female rabbits per dose level were exposed to undiluted epichlorohydrin or a 20% solution of epichlorohydrin in propylene glycol in acute percutaneous absorption tests. The LD50 for undiluted epichlorohydrin was 515 mg/kg and for the 20% solution in propylene glycol was between 250 and 500 mg/kg epichlorohydrin. Propylene glycol may enhance the toxicity of epichlorohydrin by this route as in the previous Dow Test.

Survivors dosed at 200 mg/kg and higher of either solution required 3 to 6 weeks to regain pre-treatment weight; animals dosed at 100 mg/kg required 2 to 3 weeks to regain pre-treatment weight. Severe redness and swelling and slight necrosis were observed when the cuffs were removed after the 24-hour exposure to either test material.

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Based on the results of the study LD50 for undiluted epichlorohydrin was 515 mg/kg and for the 20% solution in propylene glycol was between 250 and 500 mg/kg.
Executive summary:

Two male and two female rabbits per dose level were exposed to undiluted epichlorohydrin or a 20% solution of epichlorohydrin in propylene glycol in acute percutaneous absorption tests. The LD50 for undiluted epichlorohydrin was 515 mg/kg and for the 20% solution in propylene glycol was between 250 and 500 mg/kg epichlorohydrin. Propylene glycol may enhance the toxicity of epichlorohydrin by this route as in the previous Dow Test.

Survivors dosed at 200 mg/kg and higher of either solution required 3 to 6 weeks to regain pre-treatment weight; animals dosed at 100 mg/kg required 2 to 3 weeks to regain pre-treatment weight. Severe redness and swelling and slight necrosis were observed when the cuffs were removed after the 24-hour exposure to either test material.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
515 mg/kg bw

Additional information

Legislation has placed epichlorohydrin in a Category 3 in the GHS classification system.

Justification for classification or non-classification

Epichlorohydrin was moderate to high in toxicity based on oral, dermal and inhalation exposure and thus meets the definition of a Category 3 in the GHS classification system.