Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not stated
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

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
selected clinical chemistry tests not performed
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Epichlorohydrin, (CAS No. 106-89-8) 99.9% pure. was obtained from Aldrich Chemical Company, Milwaukee, WI (Lot No. 75020PM) and was shown by capillary gas chromatography/mass spectrometry to contain no detectable impurities.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Male and female cesarean-derived Sprague-Dawley rats (Crl: CD BR), confirmed free of viral antibodies, bacteria, and parasites, were obtained from Charles River Laboratories (Portage, MI). For the 90-day study, 30-31 day old animals were procured, acclimatized for 2 weeks, and started at 45 days of age. At the initiation of treatment, the males ranged from 210.8 - 215.7 g and the females 157.1 to 160.0 g. The test animals were housed in a temperature (70-72F) and humidity (40 - 60%) controlled room on a 12 hour light-dark cycle in elevated wire mesh cages abd individually for the 90-day study. The rats were provided Purina-certified Chow 5002 (Ralston-Purina Co., St. Louis, Missouri) and tap water ad libitum. Animal identification was via ear tags with the rats assigned to vehicle and treatment groups according to a computerized randomization process. All aspects of this study were conducted under guidelines of the American Association for Accreditation of Laboratory Animal Care.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Epichlorohydrin was administered (in distilled water) by daily gavage for either 10 or 90 consecutive days. Four treatment levels of epichlorohydrin were employed in the 10-day study (3, 7, 19, and 46 mg/kg-day), and three levels (1, 5 and 25 mg/kg-day) in the 90-day study. The controls were intubated with distilled water. All treatments were administered at a constant volume (1 ml/kg) and dosages were based on the weekly individual body weight measurements in order to assure delivery of the precise levels.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability tests confirmed that epichlorohydrin was stable in the aqueous dosing preparations for at least 10 days. However, dosing solutions were prepared daily for the 10-day study and weekly for the 90-day study. These preparations were stored at room temperature in amber colored bottles fitted with a teflon-lined, crimp-top cap.
Duration of treatment / exposure:
Four treatment levels of epichlorohydrin were employed in the 10-day study (3, 7, 19, and 46 mg/kg/day), and three levels (1, 5 and 25 mg/kg/day) in the 90-day study.
Frequency of treatment:
Daily for 7 days/week for 10 or 90 consecutive days.
Doses / concentrations
Remarks:
Doses / Concentrations:
10-day study (3, 7, 19, and 46 mg/kg/day) and 90-day study (1, 5 and 25 mg/kg/day).
Basis:
other: actual oral gavage
No. of animals per sex per dose:
Each study group consisted of 10 males and 10 females with epichlorohydrin being administered (in distilled water) by daily gavage for either 10 or 90 consecutive days.
Control animals:
yes, concurrent vehicle
Details on study design:
Cage-side observations; for behavioral changes and for mortality and morbidity were made twice daily. Body weights were recorded prior to randomization, at initiation of dosing, and weekly, thereafter. At each weighing, examinations were made to detect any changes of the skin, eyes, or appearance. Water consumptioll was determined three times per week and food consumption weekly in both studies. Ophthalmoscopic examination of dilated pupils was performed twice in the 90-day study, prior to treatment and during the last week of the study.

The animals were fasted overnight prior to the terminal salcrifice at which time the animals were anesthetized, weighed, and two blood samples were collected via the orbital sinus for hematological and serum clinical chemistry evaluations. Hematological analysis was conducted using a Coulter Counter, Model ZBI (Hileah, FL) for red blood cell count (RBC), white blood cell count [(WBC), hemoglobin, hematocrit, reticulocyte count, platelet count (90-day study only), and mean corpuscular volume (MCV) (10-day study only). A differential WBC analysis was done to obtain the percentage of segmented neutrophils, lymphocytes, monocytes, and eosinophils.

Serum chemistry determinations, perforrned in both the 10- and 90-day studies using diagnostic bits and a Baker Encore Chemistry Analyzer (Allentown, PA), were: blood urea nitrogen (BUN), calcium, creatinine, lactate dehydrogenase (LDH), alkaline phosphatase (ALK-P), aspartate aminotransaminase (AST), and alanine aminotransaminase (ALT). For the 90-day study, additional analysis was conducted for: sodium, potassium, albumin, total protein, and total bilirubin; whereas, cholesterol and glucose were measured only In the 10-day study. Urinalysis was perforedm at the end of the 90-day study using multiple testlng sticks (Ames Division, Elkhart, IN) and consisted of measurements for; pH, glucose, proteln, bilirubin, occult blood, and urobilinogen.

Euthanasia was vla exsanguination, during necropsy, after the animals had been anesthetized using 60 mg/kg of sodlum pentobarbital. The necropsy included gross examination of the total anlmal surface, all orifices, the carcass, the external surface of the brain, cervical tissues, all organs, and the cranial, thoracic, abdominal, and pelvic cavities.

The adrenal glands, brain (including the brain stem), gonads, heart, kidneys, liver, lungs, spleen, and thymus were removed and weighed. In addition, tissues from 35 additional organs as well as any gross lesions, were collected and preserved in 10% neutral buffered formalin. The harvested tissues (and all gross lesions) were trimmed, processed, embedded in paraffin, and sectioned. Slides were prepared, stained with hematoxylin and eosin, and examlned microscopically. During microscopic examination the inflammatory and degenerative leslons were graded according to severity using a scale of one to four (mlnimal, mild, moderate, or marked). In both studies, data were tabulated according to individual anlmal and summarized by group.
Positive control:
No positive control.

Examinations

Observations and examinations performed and frequency:
Cage-side observations; for behavioral changes and for mortality and morbidity were made twice daily. Body weights were recorded prior to randomization, at initiation of dosing, and weekly, thereafter. At each weighing, examinations were made to detect any changes of the skin, eyes, or appearance. Water consumptioll was determined three times per week and food consumption weekly in both studies. Ophthalmoscopic examination of dilated pupils was performed twice in the 90-day study, prior to treatment and during the last week of the study.
Sacrifice and pathology:
Euthanasia was vla exsanguination, during necropsy, after the animals had been anesthetized using 60 mg/kg of sodlum pentobarbital. The necropsy included gross examination of the total anlmal surface, all orifices, the carcass, the external surface of the brain, cervical tissues, all organs, and the cranial, thoracic, abdominal, and pelvic cavities.

The adrenal glands, brain (including the brain stem), gonads, heart, kidneys, liver, lungs, spleen, and thymus were removed and weighed. In addition, tissues from 35 additional organs as well as any gross lesions, were collected and preserved in 10% neutral buffered formalin. The harvested tissues (and all gross lesions) were trimmed, processed, embedded in paraffin, and sectioned. Slides were prepared, stained with hematoxylin and eosin, and examlned microscopically. During microscopic examination the inflammatory and degenerative leslons were graded according to severity using a scale of one to four (mlnimal, mild, moderate, or marked). In both studies, data were tabulated according to individual anlmal and summarized by group.
Other examinations:
The animals were fasted overnight prior to the terminal salcrifice at which time the animals were anesthetized, weighed, and two blood samples were collected via the orbital sinus for hematological and serum clinical chemistry evaluations. Hematological analysis was conducted using a Coulter Counter, Model ZBI (Hileah, FL) for red blood cell count (RBC), white blood cell count [(WBC), hemoglobin, hematocrit, reticulocyte count, platelet count (90-day study only), and mean corpuscular volume (MCV) (10-day study only). A differential WBC analysis was done to obtain the percentage of segmented neutrophils, lymphocytes, monocytes, and eosinophils.

Serum chemistry determinations, perforrned in both the 10- and 90-day studies using diagnostic bits and a Baker Encore Chemistry Analyzer (Allentown, PA), were: blood urea nitrogen (BUN), calcium, creatinine, lactate dehydrogenase (LDH), alkaline phosphatase (ALK-P), aspartate aminotransaminase (AST), and alanine aminotransaminase (ALT). For the 90-day study, additional analysis was conducted for: sodium, potassium, albumin, total protein, and total bilirubin; whereas, cholesterol and glucose were measured only In the 10-day study. Urinalysis was perforedm at the end of the 90-day study using multiple testlng sticks (Ames Division, Elkhart, IN) and consisted of measurements for; pH, glucose, proteln, bilirubin, occult blood, and urobilinogen.
Statistics:
For both studies, a one-factor analysis of variance (ANOVA) was used to test for a dose-related effect of normally-distributed measure. Males and females were considered separately In all statistical analyses and the parameters analyzed were: body weights, absolute organ weights, organ-to-body weight ratlos, water and food consumption, hematology, and serum chemistry measurements. When a treatment effect was observed (p< or = 0.05), the difference between the control and treatment groups was further probed, using a multiple comparison procedure for individual differences (10-
day study-Tukey's, 90-day study-Dunnett's). Due to the high variability of some of the clinical chemistry measures, a nonparametric analysis of variance, the Kruskal-Wallis test, and associated mulltiple comparison tests were employed in the 10-day study to determine differences amongst the dose groups. For the 90-day study, the data transformations (e.g., log, square root, rank) performed were sufficient to meet the assumptions required for validity of the ANOVA procedure.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
10-Dav Toxicity Study
Mortality: No animals died during the study.

Food and Water Consumption: Water consumption was significantly increased, relative to controls, whereas food consumption was significantly decreased in both males and females receiving 46 mg/kg/day. These differences were also significant when the consumption data was calculated on a per gram body weight basis (data not shown).

Body and Organ Weights. Significant decreases in both final mean body weights and total body weight gain were observed for both sexes at the high-dose level. Minimal differences in brain, heart, liver, lung, spleen, thymus and adrenal weights were observed, although a significant (15%) increase in kidney weights was seen in females at the highest dose.

Relative Organ Weights. Significant increases (22-25%) were seen in the relative weights of the kidneys for both sexes at the two highest doses and in the relative weight of the liver at the highest dose in females and at the two highest doses for males. In addition, relative testes weights were increased in males at the highest dose. All other relative organ weights were unchanged relative to controls.

Hematology. Other than slight but significant decreases in RBC's (6.8 +/- 0.2 v. 6.4 +/- 0.3 x 10(6)/ul males and reticulocyte counts (3.6 +/- 0.1 v. 1.7 +/- 0.7 females) in the high-dose groups, the clinical hematological parameters were comparable for treated and control groups.

Serum Chemistry. In males, some statistically significant changes form the control group were seen in several serurn parameters: slight decreases (not dose-related) in creatinine at the three highest doses; decreases in LDH at 7 and 46 mg/kg/day (1 399 +/- 440 vs. 785 +/- 547 & 218 +/- 252 U/L); and a decrease in calcium at 7 and 19 mg/kg/day, but not at the high dose. An apparent dose-related increase in glucose occurred in males with the change reaching significance at the highest dose compared to the control (113.2 +/- 19.4 vs. 154.3 +/- 32.5 mg/dl). No significant changes were seen in serum chemistries of the females.

Histopathology. The nonglandular stomach (forestomach) was clearly affected by the 10- day intubation with epichlorohydrin. The changes consisted of a range of inflammatory and epithelial alterations in both sexes. The most pronounced occurrence was of hyperplasia (acanthosis) and hyperkeratosis of the forestomach mucosa; with the exception of one male, all rats in the two highest dose group had these changes. The incidence of these changes was significantly elevated at all dose levels in the females and at doses greater than 3 mg/kg-day for males. Hyperplasia was characterized by increased thickness of the mucosa; whereas, hyperkeratosis consisted of an increased thickness of the keratin overlying the mucosa. Degeneration of the mucosa (excessive vacuolization) also occurred at the two highest dose level in both sexes. Each lesion was scored on a scale of normal to severe (1 to 4 respectively) and for both sexes the severity closely paralleled the incidence. The forestomach also exhibited inflammatory responses as evident from the infiltration of macrophages, eosinophils, lymphocytes, and plasrna cells at the two highest doses in males and the highest dose in females. These inflammatory changes appeared to be reactions to the cellular damage occurring in conjunction with the mucosal hyperplasia and hyperkeratosis. Five of the ten female rats exposed to 3 mg/kg-day exhibited at least one of these inflammatory changes. All other histopathological changes occurred with no apparent treatment relationship and were present in both treated and control groups in about equal frequency and severity.


90-Day Toxicity Study
Mortality and Clinical Signs. Dosages for the 90-day study were based on the results of the 10-day study. No animals died during the study. Clinical signs, including ophthalmoscopic diagnoses were essentially normal except for excessive salivation which was frequently observed in the high-dose group, beginning at week 2.

Food and Water Consumption. No significant differences between the treated and control groups were found for food or water consumption.

Body and Organ Weights. No significant differences were observed in total body weights; however, kidney and liver weights were increased for both sexes at 5 and 25 mg/kg/day (significant at 25 mg/kg/day). The absolute weights of the other organs in treated animals were not changed relative to those of controls.

Relative Organ Weight::. The organ-to-body (relative) weight ratios were based on the terminal body weights recorded at necropsy. A dose-related increase was seen in two organs, the kidney and liver, in both males and females at 5 and 25 mg/kg/day and these increases had statistical significance at the higher dose. The relative liver weight was increased significantly at 5 mg/kg/day only in the males. The increases in relative liver weights were comparable between the sexes, but the relative kidney weights were increased 43% in males but only 23% in females.

Hermatology. Treatment with 25 mg/kg/day epichlorohydrin for 90-days caused a significant decrease in the RBC count in both sexes. In addition, males at this dose level also presented with decreased hemoglobin and hematocrit levels. No other dose-related effects were observed in the hematological parameters.

Serum Chemistry. Epichlorohydrin treatment produced minimal changes in the measured clinical chemistry parameters. Creatinine levels in females at the 25 mg/kg/day dose were significantly decreased and significant decreases rn serum LDH levels were observed in females at all dose levels.

Urinalvsis. An increase in severity of urine protein grading was observed in high dose males at the termination of the study. Several animals (6/10) registered +2 (100 mg/dL) and +3 (300 mg/dL) while the controls were generally +1 (50 mg/dL) or less.

Gross Pathology. The main treatment-related changes observed at necropsy were marked thickening of the mucosal lining of the forestomach in 5 male and 3 female rats intubated with 25 mg/kg/day epichlorohydrin.

Histopathology. The only treatment-related microscopic changes observed were in the forestomach where hyperkeratosis and hyperplasia (acanthosis) were observed in both sexes receiving 5 and 25 mg/kg/day but not in the 1 mg/kg/day dose group. The incidences of these lesions were comparable between the two sexes and were clearly dose-related. The stomach lesions were characterized by a varying severity of hyperplasia with a down-growth of the mucosa and increased production of the keratin layer. The cells of the germinal layer of the mucosa were hyperchromatic and contained occasional mitotic figures. histopathologic changes observed in other tissues were considered incidental and unrelated to treatment. A variety of commonly observed spontaneous changes were present in the kidneys of male rats in both treated and control groups.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
10 day study
Effect level:
>= 3 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Forestomach pathologic changes noted in the 10 day study.
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEL
Remarks:
10 day
Effect level:
3 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Forestomach pathologic changes noted in the 10 day study.
Dose descriptor:
NOAEL
Remarks:
10 day study
Effect level:
<= 3 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Forestomach pathologic changes noted in the 10 day study at higher dose levels
Dose descriptor:
LOAEL
Remarks:
10 day study
Effect level:
>= 7 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Forestomach pathologic changes noted in the 10 day study.
Dose descriptor:
NOAEL
Remarks:
90-day study
Effect level:
1 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Forestomach pathological effects noted at higher doses.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

10-Dav Toxicity Study

Mortality: No animals died during the study.

Food and Water Consumption: Water consumption was significantly increased, relative to controls, whereas food consumption was significantly decreased in both males and females receiving 46 mg/kg/day. These differences were also significant when the consumption data was calculated on a per gram body weight basis (data not shown).

Body and Organ Weights. Significant decreases in both final mean body weights and total body weight gain were observed for both sexes at the high-dose level. Minimal differences in brain, heart, liver, lung, spleen, thymus and adrenal weights were observed, although a significant (15%) increase in kidney weights was seen in females at the highest dose.

Relative Organ Weights. Significant increases (22-25%) were seen in the relative weights of the kidneys for both sexes at the two highest doses and in the relative weight of the liver at the highest dose in females and at the two highest doses for males. In addition, relative testes weights were increased in males at the highest dose. All other relative organ weights were unchanged relative to controls.

Hematology. Other than slight but significant decreases in RBC's (6.8 + 0.2 v. 6.4 + 0.3 x 106/ul; malesj and reticulocyte counts (3.6 + 0.1 v. 1.7 + 0.7; females) in the high-dose groups, the clinical hematological parameters were comparable for treated and control groups.

Serum Chemistry. In males, some statistically significant changes form the control group were seen in several serurn parameters: slight decreases (not dose-related) in creatinine at the three highest doses; decreases in LDH at 7 and 46 mg/kg/day (1 399 + 440 vs. 785 + 547 & 218 + 252 U/L); and a decrease in calcium at 7 and 19 mg/kg/day, but not at the high dose. An apparent dose-related increase in glucose occurred in males with the change reaching significance at the highest dose compared to the control (113.2 + 19.4 vs. 154.3 + 32.5 mg/dl). No significant changes were seen in serum chemistries of the females.

Histopathology. The nonglandular stomach (forestomach) was clearly affected by the 10- day intubation with epichlorohydrin. The changes consisted of a range of inflammatory and epithelial alterations in both sexes. The most pronounced occurrence was of hyperplasia (acanthosis) and hyperkeratosis of the forestomach mucosa; with the exception of one male, all rats in the two highest dose group had these changes. The incidence of these changes was significantly elevated at all dose levels in the females and at doses greater than 3 mg/kg-day for males. Hyperplasia was characterized by increased thickness of the mucosa; whereas, hyperkeratosis consisted of an increased thickness of the keratin overlying the mucosa. Degeneration of the mucosa (excessive vacuolization) also occurred at the two highest dose level in both sexes. Each lesion was scored on a scale of normal to severe (1 to 4 respectively) and for both sexes the severity closely paralleled the incidence. The forestomach also exhibited inflammatory responses as evident from the infiltration of macrophages, eosinophils, lymphocytes, and plasrna cells at the two highest doses in males and the highest dose in females. These inflammatory changes appeared to be reactions to the cellular damage occurring in conjunction with the mucosal hyperplasia and hyperkeratosis. Five of the ten female rats exposed to 3 mg/kg-day exhibited at least one of these inflammatory changes. All other histopathological changes occurred with no apparent treatment relationship and were present in both treated and control groups in about equal frequency and severity.

90-Day Toxicity Study

Mortality and Clinical Signs. Dosages for the 90-day study were based on the results of the 10-day study. No animals died during the study. Clinical signs, including ophthalmoscopic diagnoses were essentially normal except for excessive salivation which was frequently observed in the high-dose group, beginning at week 2.

Food and Water Consumption. No significant differences between the treated and control groups were found for food or water consumption.

Body and Organ Weights. No significant differences were observed in total body weights; however, kidney and liver weights were increased for both sexes at 5 and 25 mg/kg/day (significant at 25 mg/kg/day). The absolute weights of the other organs in treated animals were not changed relative to those of controls.

Relative Organ Weight::. The organ-to-body (relative) weight ratios were based on the terminal body weights recorded at necropsy. A dose-related increase was seen in two organs, the kidney and liver, in both males and females at 5 and 25 mg/kg/day and these increases had statistical significance at the higher dose. The relative liver weight was increased significantly at 5 mg/kg/day only in the males. The increases in relative liver weights were comparable between the sexes, but the relative kidney weights were increased 43% in males but only 23% in females.

Hermatology. Treatment with 25 mg/kg/day epichlorohydrin for 90-days caused a significant decrease in the RBC count in both sexes. In addition, males at this dose level also presented with decreased hemoglobin and hematocrit levels. No other dose-related effects were observed in the hematological parameters.

Serum Chemistry. Epichlorohydrin treatment produced minimal changes in the measured clinical chemistry parameters. Creatinine levels in females at the 25 mg/kg/day dose were significantly decreased and significant decreases rn serum LDH levels were observed in females at all dose levels.

Urinalvsis. An increase in severity of urine protein grading was observed in high dose males at the termination of the study. Several animals (6/10) registered +2 (100 mg/dL) and +3 (300 mg/dL) while the controls were generally +1 (50 rng/dL) or less.

Gross Pathology. The main treatment-related changes observed at necropsy were marked thickening of the mucosal lining of the forestomach in 5 male and 3 female rats intubated with 25 mg/kg/day epichlorohydrin.

Histopathology. The only treatment-related microscopic changes observed were in the forestomach where hyperkeratosis and hyperplasia (acanthosis) were observed in both sexes receiving 5 and 25 mg/kg/day but not in the 1 mg/kg/day dose group. The incidences of these lesions were comparable between the two sexes and were clearly dose-related. The stomach lesions were characterized by a varying severity of hyperplasia with a down-growth of the mucosa and increased production of the keratin layer. The cells of the germinal layer of the mucosa were hyperchromatic and contained occasional mitotic figures. histopathologic changes observed in other tissues were considered incidental and unrelated to treatment. A variety of commonly observed spontaneous changes were present in the kidneys of male rats in both treated and control groups.

Applicant's summary and conclusion

Conclusions:
Based on the data presented, a lowest observable adverse effect level (LOAEL) for oral exposure of Sprague-Dawley rats to epichlorohydrin is 3 mg/kg/day for 10 days and 1 mg/kg/day is the no observed adverse effect level (NOAEL) for a 90 day oral exposure. These conclusions were the same whether the lesions were analyzed for each sex individually or whether the data in each study was pooled.
Executive summary:

Adult male and female Spragile-Dawley rats received epichlorohydrin via gavage in distilled water for 10 consecutive days at dose levels of 3, 7, 19, and 46 mg/kg/day, and for 90 days at dose levels of 1, 5, and 25 mg/kg/day. Epichlorohydrin did not adversely effect mortality, but toxicity, at the higher doses, was evident by: 1) losses in body weight gain and organ weights, 2) reductions in food and water consumption, and 3) in the hematological and microscopic examinations in both study periods. Significant decreases in erythrocyte count, hemoglobin, and hematocrit levels were found in the high dose level in males after 10 and 90 days. Dose-related increases in kidney and liver weights were observed in both sexes at 25 mg/kg/day in the 90-day study and in various organs for both 19 and 46 mg/kg/day in the 10-day study. Histopathological examination identified the forestomach as the primary target organ for both sexes and in both studies with significant dose-related increases in mucosal hyperplasla (acanthosis) and hyperkeratosis. Based on the data presented, a lowest observable adverse effect level (LOAEL) for oral exposure of Sprague-Dawley rats to epichlorohydrin is 3 mg/kg/day for 10 days and 1 mg/kg/day is the no observed adverse effect level (NOAEL) for a 90 day oral exposure. These conclusions were the same whether the lesions were analyzed for each sex individually or whether the data in each study was pooled.