Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted in accordance to any guideline/s and GLP and was conducted under NIEHS contract No.: NO1-ES-3-2102

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Fertility of male and female rats and male rabbits was assessed following 10 weeks exposure to ECH. In addition reversibility of any fertility effect following exposure to ECH was also examined.
GLP compliance:
no
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Production grade epichlorohydrin supplied by The Dow Chemical Company, Freeport, Texas, was used for this study. The test material was identified as Lot No. TB 09157-3. Analytical specifications and results of analysis of Lot No. TB 09157-3 for impurities are as follows:

GAS CHROMATOGRAPHIC ANALYSIS:
Epichlorohydrin, Assay 98.8% wt.
Propylene Dichloride 0.03% wt
Cis 1,3 Dichloropropene 0.08% wt.
2,3 Dichloropropene 0.07% wt.
Beta chloroallyl alcohol 0.01% wt.

.

Test animals

Species:
other: rats and rabbits
Strain:
other: Sprague-Dawley and New Zealand white
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Groups of 10 male rabbits, 30 male rats, and 30 female rats were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor. Exposures continued for 6 hours/day, 5 days/week (Monday through Friday) for 10 consecutive weeks to encompass the length of the spermatogenesis cycle in the rat and rabbit (Asdell, 1964, Swierstra and Foote, 1965). The semen of rabbits was evaluated on a weekly basis during the 10-week exposure period. The fertility of male rats was evaluated by mating trials. The exposed female rats were mated to unexposed male rats at the end of the 10-week exposure period and were allowed to deliver a litter. In order to assess the fertility of the exposed rabbits, each male was allowed to mate with an unexposed female rabbit during the 10th week of exposure. At the end of the 10-week exposure period, animals were held for an additional 10 weeks to determine whether any of the observed effects were reversible.

Asdell, S. A. (1964). Patterns of Mammalian ~eproduction, 2nd Edition. Cornell University Press, Ithica, New York.

Swierstra, E. E. and Foote, R. H. (1965). Duration of spermatogenesis and spermatozoan transport in the rabbit based on cytotogical changes, DNA synthesis and labeling with tritiated thymidine. Am. J. Anat. 116, 401-412.
Frequency of treatment:
5 days/week (Monday through Friday) for 10 weeks
Duration of test:
Exposures were for 10 weeks followed by a 10 week recovery period
No. of animals per sex per dose:
Groups of 10 male rabbits, 30 male rats, and 30 female rats, were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day, 5 days/week for 10 weeks, and held for a 10-week recovery period.

Results and discussion

Observed effects

SPRAGUE-DAWLEY RATS
General Health and Demeanor: Body Weiqhts. No deaths occurred among male rats exposed to epichlorohydrin. During the recovery period following exposure, one female rat from the 5 ppm group and one from the 50 ppm group died during the delivery of their litters; upon gross necropsy, death was attributed to loss of blood in these animals. One control female rat died during the recovery period; death was due to overgrowth of the lower incisor teeth resulting in starvation of this animal.

No overt signs of toxicity which could be related to exposure were observed among the rats of either sex. The mean body weight of male rats exposed to 50 ppm of epichlorohydrin vapor was statistically significantly lower than the control value during the 9th week of exposure. The male rats in this group gained significantly less weight than control rats during the 10-week exposure period. The mean body weights of male rats exposed to 5 or 25 pprn of epichlorohydrin were comparable to those of the control rats throughout both the exposure and the recovery periods. The mean body weight of the female rats exposed to 50 pprn of epichlorohydrin was statistically significantly lower than the control value during the 2nd week of exposure. The female rats exposed to 50 pprn of epichlorohydrin also gained less weight than controls during the 10-week exposure period. No discernible effects on body weight were observed among the female rats exposed to 5 or 25 pprn of epichlorohydrin.

Reproductive Parameters - Male Rats. Exposure to 50 pprn of epichlorohydrin vapor resulted in a marked decrease in the number of fertile male rats at all of the 4 matings (2nd, 4th, 7th, and 10th weeks) conducted during the 10-week exposure period. The reduction of fertility was observed in the first mating trial of these male rats to unexposed females during the second week of exposure, suggesting a rapid onset of this effect in the male rats.
Recovery of fertility was observed as early as the first mating in the recovery period, the 12th week of the study (second week of the recovery period). The fertility indices of male rats exposed to 5 or 25 pprn of epichlorohydrin were not statistically significantly different from the control indices for any of the matings conducted either during the exposure period or during the recovery period. Vaginal plugs were observed with approximately equal frequency beneath the cages of the control and of the exposed male rats suggesting that mating had occurred in all groups. Among female rats bred to both the 25 and the 50 ppm males, the average number of implantations was statistically significantly lower than the control value for the 4 matings conducted during the exposure period. The average number of corpora lutea was lower than the controls among the females bred to the 50 ppm males during these mating trials. However, only 2 to 4 females were pregnant as a result of these matings and the mean number of corpora lutea was calculated from this small group size. Since these females were not exposed to the test compound, the toxicologic significance of the reduced number of corpora lutea is not known. These effects were not observed in the 3 matings conducted during the recovery period (weeks 12, 15, and 20).
The average number of corpora lutea was statistically significantly higher than the control value among female rats in this group during the 20th week mating. (the last mating of the recovery period). Among female rats bred to males exposed to 25 ppm of epichlorohydrin, the average number of corpora lutea was statistically significantly lower than the controls during the 2nd week mating, but not during any of the successive matings. The average number of resorptions in the pregnant female rats bred to male rats exposed to epichlorohydrin was comparable to the control value for the 4 matings conducted during the exposure period. During the 12th week mating, the first mating conducted in the recovery period, unexposed female rats bred to the 50 ppm exposed males had fewer resorptions per litter than the controls. A statistically significant increase in the average preimplantation loss was observed in female rats bred to males exposed to 25 or 50 ppm of epichlorohydrin during the exposure period. The pre-implantation loss was observed for all matings during the exposure period (weeks 2, 4, 7, and 10) but was not observed for the matings during the recovery period (weeks 12, 15, and 20). During the 10th week mating, the average pre-implantation loss among females bred to the 5 ppm exposed males was statistically significantly higher than the control value, however the control value of 4 for the tenth week mating was unusually low, and the increase in the 5 ppm group is not considered to be a significant effect of treatment. During the recovery period, a statistically significant increase in the average pre-implantation loss was observed during the 15th week mating of unexposed females to males exposed to 50 ppm of epichlorohydrin vs. a value of 4 in the controls. This value is, however, within the range of control values for pre-implantation loss observed in the several matings throughout the study. During the matings conducted during the exposure period, the average resorption rate was higher than the control value among females bred to the 50 ppm males; the difference was statistically different for the 10th week data. Since these data were obtained from only those few females which were pregnant and which also showed an extremely small number of implantations, the significance of the resorption rate data is not clear. Female rats bred to 50 ppm exposed males showed a significant decrease in resorption rate during the 12th week mating during the second week of the recovery period.

Reproductive Parameters - Female Rats. The female rats exposed to epichlorohydrin were mated to unexposed male rats during the 10 days immediately following exposure. Daily vaginal smears showed that most females were cycling normally through estrus and mated at some point during the period of co-habitation. Eight of the 25 females at 50 ppm, and four control females did not show cyclic changes in the vaginal epithelium, however, the appearance of mucus and leukocytes in 6 of the 50 ppm females indicated that mating had already occurred although sperm were not noticed in the vaginal smear. The percentage of female rats which became pregnant was not affected by exposure to epichlorohydrin. One-female in the 5 ppm group and one in the 50 ppm group died during delivery; upon gross necropsy death was attributed to loss of blood. No effect on the length of the gestation period, the litter size at birth, the survival indices of the neonates, or the sex ratio of liveborn pups was observed. Among litters from rats exposed to 5 ppm of epichlorohydrin, one neonate exhibited a hypoplastic tail. Subcutaneous hemorrhages or hematomas were observed among litters from both the control and exposed rats. None of the alterations was observed at an incidence which was statistically different from the control incidence.

Hematology and Clinical Chemistry Determinations. The results of the hematologic evaluation for male and female rats are presented in Table 8. The mean white blood cell counts were higher than normal for both sexes at all exposure levels for the pre-exposure determination. This observation is consistent with the onset of sialodacryoadenitis during the latter part of the first week of exposure. During the 10th week of exposure, male rats exposed to 50 ppm of epichlorohydrin showed a slight decrease in the red blood cell count when compared to controls; the difference was statistically significant. No effect on hematologic parameters was observed in female rats during the 10th week of exposure; the white blood cell counts were within the normal range for both sexes at this time. The BUN, SGPT, AP, SGOT, and glucose values for male and female rats exposed to epichlorohydrin were comparable to the control values.

Organ Weiqhts and Pathologic Findings
Interim Sacrifice: Male and female rats exposed to 50 ppm of epichlorohydrin showed a statistically significant increase, as compared to controls, in the weight of the kidneys on both an absolute and a relative to body weight basis. Kidney weights were slightly higher than controls in the rats exposed to the two lower levels of epichlorohydrin as well. The livers of male rats exposed to all levels of epichlorohydrin and of females exposed to 50 ppm were slightly, but not statistically significantly higher than the control weights. The mean weights of the brain and heart of the exposed rats were comparable to the control value for both sexes. No effect on the mean weight of the testes or the epididymldes was observed in male rats exposed to epichlorohydrin by inhalation in spite of the fact that the 50 ppm exposed rats showed transient infertility. In both male and female rats from the 50 ppm group there were gross pathologic changes in the kidneys characterized by a lighter color and increased size. These gross observations in conjunction with the increase in the weight of the kidneys suggest a treatment-related effect. Among male rats exposed to 50 ppm of epichlorohydrin the livers of 3 of the 5 animals examined were lighter in color than normal. Although some male and female rats exposed to epichlorohydrin showed a decrease in the amount of intraabdominal adipose tissue, this effect was not reflected by a decrease in body weight. The increased weight of the kidneys and livers in these animals may have been sufficient to negate the effect of decreased adipose tissue when evaluating the body weight.

In the male and female rats there were treatment-related histopathologic changes in the nasal turbinates at the 25 and 50 ppm epichlorohydrin exposure levels. These histopathologic changes in the nasal turbinates were considered to be a result of the irritation caused by the test material. The microscopic changes were degenerative in nature and characterized by inflammation, focal erosions, hyperplasia, and metaplasia with a squamous appearance to the turbinate mucosa. The effect was observed primarily in the respiratory epithelial portion of the nasal turbinates with a less severe involvement of the olfactory epithelium. The kidneys of male and female rats from the interim sacrifice showed dilated tubules in the 50 ppm group. In addition, male rats in the 25 and 50 ppm groups showed a slightly increased incidence of focal tubular change. The focal tubular changes were characterized by a variety of alterations which included dilatation with eosinophilic staining casts and altered staining affinity of the epithelial cells with occasional tubules having a collapsed and atrophied appearance. These changes occured in the control rat kidneys; however, they were observed with a greater frequency in the 25 and 50 ppn male groups only. There were no other treatment-related changes detected in any of the other tissues examined. The male and female reproductive organs did not show any histopathologic changes considered treatment related. There were no histopathologic changes observed in the 5 ppm group of rats which were considered treatment related.

Final Sacrifice: The weights of the kidneys and of the livers of male and female rats from the 50 ppm group were slightly higher than the control values at the end of the 10-week recovery period, however, the differences were not statistically significant. The weights of the other organs were comparable to the control weights. No treatmentrelated changes were observed in the surviving rats after the recovery period. One 50 ppm female and one 25 ppm.male exhibited a grossly-recognized subcutaneous mass. These masses were not considered treatment-related, but were examined microscopically.

Following the 10-week recovery period the histopathologic lesions in the nasal turbinates observed at the interim sacrifice were no longer detectable indicating that they were reversible. Similarly, the dilated renal tubules and other kidney changes noted in male and female rats in the groups at the interim sacrifice were not observed at the final sacrifice. There were no other microscopic findings which were considered treatment related. A single female rat in the 5 ppm group contained a microscopic endometrial polyp while another female rat in the 50 ppm group contained a single mammary gland adenofibroma. The grossly recognized subcutaneous mass in a 25 ppm male rat was diagnosed as an undifferentiated sarcoma without metastasis. None of these observations was considered treatment related. The male and female reproductive organs did not show any histopathologic changes which appeared to be related to exposure to epichlorohydr in vapor.

New Zealand White Rabbits
General. Health and: Demeanor: Body Weights. In male rabbits, exposure to 50 ppm of epichlorohydrin produced toxicity as evidenced by excessive nasal exudation in these animals starting in the 6th week of exposure. One rabbit at this dose level died spontaneously during the 6th week of exposure. Gross pathologic examination of this animal showed suppurative rhinitis, diffuse pneumonia, and a malformed kidney (unilaterally). A second rabbit from the 50 ppm group was sacrificed during the exposed period due to disequilibrium suggestive of an inner ear infection. This animal also showed suppurative rhinitis and pleuritis upon gross examination. Among rabbits exposed to 25 ppm of epichlorohydrin, one animal died spontaneously during the recovery period. Gross pathologic examination of this animal revealed a pulmonary abscess extensively filling the thoracic cavity with subsequent inanition. A second rabbit from this group was sacrificed during the recovery period due to an inner ear infection and disequilibrium; no other significant gross findings were observed in this animal. One rabbit exposed to 5 ppm died spontaneously during the recovery period; gross examination showed evidence of suppurative rhinitis, external otitis, and mucoid enteritis. None of the control rabbits died spontaneously or were sacrificed due to a moribund condition during the exposure or the recovery period. Male rabbits exposed to 50 ppm of epichlorohydrin showed a statistically significant decrease in body weight as compared to controls during the 4th, Sth, and 6th weeks of exposure. These rabbits gained significantly less weight than controls during the 10-week exposure period. The body weights of rabbits exposed to 5 or 25 ppm of epichlorohydrin were not significantly different from the control weights during the exposure or the recovery periods.

Semen Evaluation - Male Rabbits. No effects which are considered to be related to treatment were observed in either of these parameters. During the 10th week of exposure, a statistically significant increase in the percentage of non-motile sperm and concurrent decrease in the percentage of non-progressively motile sperm were observed among semen samples from rabbits exposed to 25 ppm of epichlorohydrin. The percentage of progressively motile sperm was comparable to controls among these rabbits. No statistically significant changes in the percentage of motile sperm were observed among rabbits in the 50 ppm group during the exposure period. During the recovery period, low sperm motility was observed in the 18th week among the semen from 25 ppm rabbits, however, the motility of the sperm from these rabbits and from those exposed to 50 ppm was statistically significantly higher than the controls during the 16th week. Considerable variation in the motility of sperm was observed among all groups as well as in individual animals throughout the study. The occasional differences which were statistically significant are therefore not considered to be related to
exposure to epichlorohydrin vapor. Likewise, no effects on the viability of sperm were considered to be treatmentrelated. No statistically significant differences in the percentage of live sperm were observed among the exposed rabbits as compared to controls. No statistically significant differences in the percentage of normal sperm were observed between the control and 50 ppm exposed groups. The percentages of sperm which exhibited each type of abnormality were comparable for both groups during both the week prior to exposure and during the last week of exposure. During the week prior to exposure, the mean percentage of intact sperm in the 50 ppm exposed rabbits was significantly lower than that of the controls, however, the percentages of intact sperm were comparable in both, groups in the 10th week of exposure.

Reproductive Parameters - Male Rabbits. During the 10th week of exposure, each male rabbit was allowed to mate with a single, unexposed female rabbit. No significant effects on the average number of implantations, corpora lutea, or resorptions were observed among the female rabbits bred to
males exposed to epichlorohydrin. One fetus from a doe bred to a male rabbit exposed to 25 ppm exhibited multiple malformations including an extra rear limb originating, from the caudal end, micrognathia of the upper jaw, anopthalmia, an extra genital papilla, and the occurrence of a prominent facial proboscis. The fertility index of the male rabbits was not affected by exposure to epichlorohydrin; all of the males in the 25 and 50 ppm groups were able to impregnate an unexposed female rabbit. The unexposed female rabbits bred to males exposed to 5 and to 50 ppm of epichlorohydrin showed a higher incidence of pre-implantation loss than the control group . The average pre-implantation loss was 22% and 27% for the 5 and 50 ppm groups, respectively; both groups were statistically significantly different from the control value of 8%. However, both of these values are within the range of percentage of pre-implantation loss observed historically among control rabbits in this laboratory, a range of 9 to 27%. The average pre-implantation loss among female rabbits bred to the 25 ppm exposed males was only 12%.

Hematology and Clinical Chemistry Determinations. No effects were discerned for any of these parameters which were monitored.

Organ Weights and Pathologic Findings
Interim Sacrifice: Among rabbits exposed to 25 or 50 ppm of epichlorohydrin, a statistically significant decrease in the mean weight of the brain was
observed. The brain weight relative to body weight ratios, however, were not different from the control value. No other values for the weight of the heart, liver, kidney, testes, or epididymides were statistically significantly different from the controls for the rabbits submitted for interim sacrifice. The majority of the rabbits exposed to 25 or 50 ppm of epichlorohydrin showed evidence of nasal turbinate inflammation. One rabbit from the 50 ppm group showed a decrease in the amount of intraabdominal fat. There were inflammatory changes present in the nasal turbinates, trachea, and lungs from the majority of the control and treated rabbits from the interim sacrifice. These changes are those usually associated with a clinical or subclinical infection of,the bacterial agent Pasteurella multocida. There appeared to be greater numbers of rabbits in the 25 and 50 ppm groups which showed either bilateral suppurative rhinitis, sinusitis, focal erosion, or metaplasia of the epithelium. These changes in all probability were a result of the irritation of the test material and thereby accentuated the spontaneous disease process. There were no other changes detected in the tissues microscopically examined which were considered treatment related. The male reproductive tract did not show any treatment-related histopathologic changes. There were no histopathologic changes observed in the 5 ppm group of rabbits which were considered treatment related.

Final Sacrifice: No treatment-related effects on organ weights were discerned among any of the exposed rabbits. A treatment-related effect was not recognized upon gross examination of the surviving rabbits following the 10-week recovery period. In the rabbits from the 25 and 50 ppm groups,
there was a greater number which-showed evidence of rhinitis and sinusitis than in the control group. This suggests that the inflammatory treatment-related changes in the nasal and sinus epithelium may be due to a persistent bacterial Pasteurella multocida infection. No other treatment-related
changes were observed In the tissues microscopically examined.

Any other information on results incl. tables

The results of this study to date show that exposure to 50 ppm of epichlorohydrin by inhalation for 10 weeks produced transient infertility in male Sprague-Dawley rats during the exposure period but not in male rabbits. Recovery of fertility in rats occurred as early as the second week following termination of exposure. This finding is consistent with earlier reports on the antifertility effects of orally administered epichlorohydrin in rats (Hahn, 1970; Cooper -et -al., 1974). Male rats exposed to 25 ppm of epichlorohydrin were able to impregnate unexposed females, however, a marked pre-implantation loss was observed in these females for all matings conducted during the exposure period. This effect was also reversed by the second week of the recovery period. The incidence of implantations which were resorbed in the unexposed females was not affected by exposure of the male rats to epichlorohydrin. This absence of post-implantation loss together with the rapid onset and recovery from the observed effects on fertility suggest that exposure of up to 50 ppm of epichlorohydrin did not induce dominant lethal effects in rats, but rather had some direct effect on the function of the spermatozoa or the ejaculation process in the males. No discernible effects on the estrus cycle or the ability to become pregnant and deliver a normal litter.were observed in female rats exposed to up to 50 ppm of epichlorohydrin for 10 weeks and mated to unexposed males during the 10-day period immediately following termination of exposures. In contrast to the effects seen in male rats, no discernible effects on the motility, viability, volume, concentration, or morphology of rabbit semen or on the fertility of male rabbits exposed to epichlorohydrin for 10 weeks were observed in this study. The approximate dosage received on a mg/kg basis, calculated on the basis of the respiratory rates, was slightly less for rabbits than for rats exposed to 50 ppm epichlorohydrin by inhalation; approximately 36 versus 58 mg/kg, respectively. Among unexposed female rabbits bred to the 5 ppm and the 50 ppm exposed males, the percentage of pre-implantation loss was significantly higher than the control value. However, both of the values fall into the range of percentage of preimplantation loss which has been observed in control female rabbits in this laboratory - a range of 9 to 27%. Male rabbits exposed to 50 ppm of epichlorohydrin showed evidence of toxicity from the test material. Signs of toxicity in rabbits consisted of increased nasal exudate during exposure and grossly recognizable pathologic changes in the nasal epithelium at the interim sacrifice. In addition, one rabbit from the 50 ppm level died during the exposure period. The most severely affected organ following inhalation exposure to 25 or 50 ppm epichlorohydrin in both rats and rabbits was the nasal turbinates. The lesions present were interpreted to be a result of irritation due to the test material. In the rats there were no other respiratory system effects observed as a result of exposure, while in the rabbits there was an increased incidence of Pasteurella multocida associated rhinitis, sinusitis, and pneumonia. The rats, but not the rabbits, showed minimal histopathologic kidney effects at these exposure levels. Following the recovery, period, it was noted that the histopathologic lesions in the rat nasal turbinates observed at the interim sacrifice were no longer present at any exposure level. Also, there were no differences in the histopathologic findings in the kidneys of exposed male or female rats when compared to the controls among animals examined from the final sacrifice. In the rabbit nasal turbinate and sinus region, there was a slightly increased incidence of the lesions associated with a persistent Pasteurella multocida infection in the 25 and 50 ppm groups. The reproductive system of male and female rats as well as male rabbits did not show any gross or histopathologic changes which were considered treatment related at either the interim or the final sacrifice.

Applicant's summary and conclusion

Conclusions:
No adverse effects were observed among rats and rabbits exposed to 5 ppm of epichlorohydrin for 10 weeks.
Executive summary:

A study was conducted to determine the effects of inhaled epichlorohydrin on the fertility of Sprague-Dawley rats and New Zealand white rabbits. Groups of 10 male rabbits, 30 male rats, and 30 female rats, were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day, 5 days/week for 10 weeks, and held for a 10 -week recovery period. At intervals during both the exposure and the recovery periods, semen from rabbits was evaluated and the exposed male rats were allowed to mate with unexposed females. A t the end of the 10 -week exposure period, the exposed male rabbits were allowed to mate with unexposed females. Also, the exposed female rats were allowed to mate with unexposed male rats; the females were allowed to deliver their litters. The results of this study show that exposure to 50 ppm of epichlorohydrin vapor for 10 weeks produced transient infertility in male Sprague-Dawley rats but not in male rabbits during the exposure period; recovery of fertility in rats occurred as early as the second week following termination of exposure. Male rats exposed to 25 ppm of epichlorohydrin were able to impregnate unexposed females; however, a marked pre-implantation loss was observed in these females for all matings conducted during the exposure period. This effect was also reversed by the second week following termination of exposure. The incidence of implantations which were resorbed in the unexposed female rats was not affected. No discernible effects were observed on the estrus cycle or the ability to become pregnant and deliver a normal litter in female rats exposed to epichlorohydrin for 10 weeks. In contrast to the effects seen in male rats, there were no discernible effects on the motility, viability, volume, or concentration of rabbit semen nor on the fertility of male rabbits exposed to epichlorohydrin for 10 weeks. Animals exposed to 50 ppm of epichlorohydrin showed evidence of toxicity from the test material. Signs of toxicity in rabbits consisted of increased nasal exudate during the exposure period and grossly recognizable.pathologic changes in the nasal epithelium at an interim sacrifice. Histologic examination of tissues from an interim and final sacrifice of the exposed animals indicated that the most severely affected organ following inhalation exposure to 25 or 50 ppm epichlorohydrin in both rats and rabbits was the nasal turbinates. The lesions present were interpreted to be a result of irritation from the test material. No adverse effects were observed among rats or rabbits exposed to 5 ppm of epichlorohydrin for 10 weeks.