Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
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

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1983
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of 30 male rats and 30 female rats were exposed to 0, 5, 25, or 50 ppm of ECH vapor for 6 hr/day, 5 days/week for 10 weeks or roughly one spermatogenic cycle, and subsequently held without exposure for a 10-week post-exposure period. Two endpoints were evaluated: 1) Ability of male rats exposed to ECH to reproduce with non-exposed female rats (evaluated after 2, 4, 7 and 10 weeks of exposure and 2, 5 and 10 weeks after the last exposure to ECH) and 2) Ability of female rats exposed to ECH for 10 weeks to reproduce with non-exposed male rats.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Production grade material obtained from The Dow Chemical Company, Freeport, Texas. 98.8% purity based on gas chromatographic analysis.

Impurities detected (percentage by weight) included
propylene dichloride, 0.03%
cis-1-3,-dichloropropene, 0.08%
2,3dichloropropene, 0.07%
0-chloroallyl alcohol, 0.01%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Adult animals, male (350 to 450 g) and female (225 to 300 g) Sprague-Dawley rats (Spartan Research Animals, Haslett, Mich.) were allowed to acclimate 2 to 3 weeks before being randomized into treatment groups. All animals were maintained on Purina Laboratory Rat Chow and tap water (Municipal water supply) free choice except during the daily exposure period when rats were deprived of feed. Water was supplied to rats by an automatic watering system while exposures were in progress. Female rats were housed two per cage in the chambers both during and between exposures. Male rats were similarly housed, but were removed between exposures to holding rooms as described above during breeding periods.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Exposures were carried out in 14.5 cubic meter chambers. Temperature and relative humidity were maintained at approximately 24C, and 50%, respectively. The means of the daily analytical concentrations achieved were 5.2 +/- 0.4, 24.7 +/- 1.4, and 50.0 +/- 1.8 ppm for the 50 days of exposure. There were no severe excursions in concentrations of test material or temperature observed during the course of the study.

Vapors were generated by metering liquid ECH with a precision pump into a vaporization vessel. The vapors were swept with filtered air into the main chamber airflow at a flow rate of about 1950 to 3000 literslmin or 8 to 12 air changes/hr. The control chamber was supplied with filtered air without the test material. Daily nominal concentrations of ECH vapors in the chambers were calculated as the ratio of the rate at which the liquid was dispensed to the rate of total chamber airflow. Analytical concentrations in each chamber were determined three to four times per day with a Varian Series 2400 gas chromatograph with 1.0 ml gas sampling loops and flame ionization detectors. The target concentrations were 5, 25, and 50 ppm of ECH vapor..
Details on mating procedure:
Groups of 25 exposed female rats were mated to unexposed male rats at the end of the 10-week exposure period. The females were cohoused with the males for 2 consecutive 5-day periods, until the presence of sperm was detected in a vaginal smear. These females were then allowed to carry and deliver their litters in nesting boxes. The day of delivery was noted, and the number of live and dead pups recorded on day 0 (delivery) and days 1 and 2 post-delivery. The pups were examined on day 1 for morphologic alterations and presence of milk in the stomach as an indication of nursing.


Groups of 25 exposed male rats were mated to unexposed female rats during the 2nd, 4th, 7th, and 10th 12th, 15 and 20th weeks of exposure. Males were cohoused for 7 days with 2 females each during the time when exposure was not in progress. The area beneath each males cage was examined for evidence of copulatory plugs as evidence of mating. Twelve days after the last day of cohabitation, the females were sacrificed and their uterine contents examined for number of corpora lutea, implantation sites, and resorption sites.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber air was assayed via GC for vapor concentration 3-4 times during each 6-hour exposure period.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 10 weeks
Details on study schedule:
Groups of 30 male and 30 female rats per dose level were exposed (whole-body) to 0 (chambered control), 5, 25, or 50 ppm epichlorohydrin vapor six hours daily, five days per week, for 10 weeks, then held for a 10-week recovery period.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 5, 25, or 50 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 5.2+/-0.4, 24.7+/-1.4 or 50.0+/-1.8 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
30 male and 30 female rats/dose
Control animals:
yes, sham-exposed
Details on study design:
For the male rats, matings were conducted during exposure weeks 2,4, 7, and 10 and postexposure weeks 2, 5, and 10. When not in the exposure chambers, 25 of the exposed male rats per group were placed with two unexposed females each for the 7-day breeding period. Each morning, the area beneath each cage was observed for copulatory plugs as evidence of mating activity. The females were killed 12 days after the last day of cohabituation, and the uterine contents were examined. The percentage of fertile males and postimplantation loss (resorption rate) was calculated with the male rat as the experimental unit.

To assess fertility in female rats following the 10 weeks of exposure to ECH, 25 females from each group were housed with unexposed male rats for
two consecutive 5-day periods, each with a different male. During the mating period, the estrus cycle of each female was monitored by vaginal smear. Survival of the young was monitored for 2 days postpartum.

Body weights of all animals were recorded weekly throughout the study. An interim termination was conducted on five rats/sex/group at the end of the tenth week of exposure.
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Animals were observed daily for signs of toxicity. Body weights were collected weekly.

An interim termination was conducted on five rats/sex/group and three or four rabbits/group at the end of the tenth week of exposure. Hematologic evaluations (PCV, RBC, Hgb, and differential WBC counts) were conducted on these animals prior to the start of exposures and during the tenth week of exposure. Clinical chemistry deteminations (BUN, AP, SGPT, SCOT, and glucose) were conducted at the interim termination for both species. Urinalysis (specific gravity, pH, glucose, protein, ketones, bilirubin, urobilinogen, and occult blood) was conducted on rats before the interim termination. After the postexposure period, all surviving rats and rabbits were killed. Organ weights (liver, kidney, brain, heart, testes and epididymides) were recorded for all animals at the interim termination and for 10 ratslsex at the final termination. Selected tissues were examined histologically from all animals at the interim termination and approximately 10 rats/sex at the terminal termination. Tissues for histological examination were fixed in 10% buffered fomalin, Zenker's fixative (eyes), or Bouin's solution (testes and epididymides). The fixed tissues were prepared by routine histologic procedures and stained with hematoxylin and eosin for light microscopic examination. An extensive histopathologic evaluation of the nasal turbinates was performed in rats. After decalcification, three to four transverse sectibns were obtained from the region lined primarily by respiratory epithelium, the transitional region containing both respiratory and olfactory epithelium, and the region lined primarily by olfactory epithelium.


Oestrous cyclicity (parental animals):
During the mating period, the estrus cycle of each female was monitored by vaginal smear
Sperm parameters (parental animals):
Histopathologic examination of the testes and epididymides was conducted
Litter observations:
Groups of 25 exposed females- The day of delivery was noted, and the number of live and dead pups recorded on day 0 (delivery) and days 1 and 2 post-delivery. The pups were examined on day 1 for morphologic alterations and presence of milk in the stomach as an indication of nursing.

Groups of 25 exposed males- All of the males used for the experiment were able to sire at least one litter in a pre-exposure mating. The area beneath each males cage was examined for evidence of copulatory plugs as evidence of mating. Twelve days after the last day of cohabitation, the females were sacrificed and their uterine contents examined for number of corpora lutea, implantation sites, and resorption sites.
Postmortem examinations (parental animals):
A complete necropsy examination was conducted on each remaining animal at the end of the 10-week recovery period, during which organ weights for brain, heart, liver, kidneys, testes, and epididymides were recorded. Approximately 40 organs/tissues from five rats/sex/dose level were examined histologically.

Postmortem examinations (offspring):
Offspring of female rats exposed to ECH were examined and the number of live and dead pups recorded on day 0 (delivery) and days 1 and 2 post-delivery. The pups were examined on day 1 for morphologic alterations and presence of milk in the stomach as an indication of nursing.
Statistics:
Body weights, organ weights, clinical chemistry determinations, specific gravity of urine, hematologic parameters, numbers of corpora lutea and implants, and parameters concerning semen evaluations were evaluated by a one-way analysis of variance; differences between experimental means and the controls were examined by Dunnett's test (Steel and Tonie, 1960). Where appropriate after evaluation by Bartlett's test for equality of variances (Winer, 1971), nonparametric analysis of variance and Wilcoxon's test were used to evaluate these parameters. The number of resorptions and resorption rate were analyzed by the Wilcoxon test as modified by Haseman and Hoe1 (1974). The fertility indexes were analyzed by the Fisher's exact probability test (Siegel, 1956). The nominal alpha level used for statistical analysis of all experimental parameters was alpha = 0.05.
Reproductive indices:
Percentage fertile males = Number impregnating one or both females/Number housed with females X 100.

Percentage fertile females = Number females delivering a litter/Number placed with males X 100.
Offspring viability indices:
Survival = percentage of live born neonates which survived to 1 or 2 days postpartum.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

No deaths ocurred among male rats exposed to epichlorohydrin. Three male rats died during the conduct of the study: one in the control group died during the post exposure period and death was attributed to incisor overgrowth; 1 in the 5 ppm and 1 in the 50 ppm group died during delivery of young due to loss of blood. The total amount of weight gained during the 10-week period of exposure was decreased significantly in the 50 ppm group as compared to controls for both sexes.

During weeks 1 and 2 of exposure, rats of both sexes exhibited clinical signs of sialodacryoadenitis (SDA), the severity and duration of which were similar among the control and exposed groups.

No consistent or treatment-related effects on hematologic parameters, urinalysis, or clinical chemistry determinations were observed in rats of either sex.

In the 50 ppm group, the fertility index for male rats was significantly reduced. Males from the 25 or 50 ppm group were able to fertilize untreated female animals, but there was a significantly reduced number of implantations compared with the controls. This effect disappeared 2 weeks following termination of treatment. The NOAEL for reproduction/fertility in males was 5 ppm.

The reproductive capacity of female rats was not adversely affected. The females showed normal estrus patterns during the 2-week mating period following termination of exposures and were able to become pregnant and deliver viable young. There were no adverse effects on the percentage of pregnant females, length of gestation period, litter size, or pup survival through 2 days postpartum in any exposure group. The NOAEL for reproduction/fertility in females was 50 ppm.

In male and female rats there were treatment-related histopathologic changes in the nasal turbinates at the 25 and 50 ppm exposure levels. 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 kidneys of males and females from the interim sacrifice showed dilated tubules in the 50 ppm group. In addition, males in the 25 and 50 ppm groups showed a slightly increased incidence of focal tubular change. These changes occurred in the control rat kidneys; however, they were observed with a greater frequency in the 25 and 50 ppm groups only. There were no other treatment-related changes detected in any other tissues examined. The NOAEL for all other effects in both sexes was 5 ppm.

Reproductive Parameters - Fertility Index of Male Rats Exposed to Epichlorohydrin by Inhalation

Exposure Level, ppm (a)
Week of 0 5 25 50
Study
2 100(25/25)b 100(25/25) 100(25/25) 16(4/25)c
4 100(25/25) 96(24/25) 88(22/25) 8(2/25)c
7 100(25/25) 100(25/25) 92(23/25) 8(2/25)c
10 100(25/25) 100(25/25) 96(24/25) 12(3/25)c
12 100(25/25) 100(25/25) 100(25/25) 96(24/25)
15 100(25/25) 100(25/25) 100(25/25) 100(25/25)
20 100(25/25) 100(25/25) 100(25/25) 100(25/25)

(a) Male rats were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day; 5 days/week for 10 weeks. During the 2nd, 4th, 7th, and 10th weeks of exposure, 25 male rats per exposure level were housed with 2 unexposed female rats each during the period between exposures for 7 days. Matings were also conducted during weeks 12, 15, and 20 of the recovery period.

b Male fertility index = # fertile males/# males housed with females x 100

c Significantly different from the control value by the Fisher's exact probability test, p<0.05.



Reproductive Parameters - Average Number of Implantations, Corpora Lutea, and Resorptions in Unexposed Female Rats Bred to Male Rats Exposed to Epichlorohydrin by Inhalation
Exposure Level, ppm (a)
Week of 0 5 25 50
Study

Week 2 -
Average # 13.7+/- 14.0+/- 7.8+/- 1.0+/-
implantations 1.8b 1.5 3.3c 0.0 c
Average # 14.4+/- 14.6+/- 12.4+/- 8.8+/-
corpora lutea 1.9 1.6 2.4d 3.3 d
Average # 0.8+/- 0.8+/- 0.4+/- 0.5+/-
resorptions 1.0 0.9 0.5 0.6

Week 4 -
Average # 13.1+/- 13.7+/- 8.4+/- 2.0+/-
implantations 1.7 1.6 3.6 c 1.4 c
Average # 13.6+/- 13.8+/- 13.4+/- 8.5+/-
corpora lutea 1.4 1.3 2.0 4.9 d
Average # 0.7+/- 1.1+/- 0.9+/- 0.5+/-
resorptions 0.8 1.8 0.9 0.7

Week 7 -
Average # 13.0+/- 13.6+/- 7.1+/- 1.0+/-
implantations 1.5 2.3 3.8 c 0.0 c
Average # 13.9+/- 14.5+/- 13.2+/- 10.5+/-
corpora lutea 1.0 1.7 1.5 0.7 d
Average # 0.6+/- 0.9+/- 0.5+/- 0.5+/-
resorptions 0.5 1.9 0.6 0.7

Week 10 -
Average # 14.2+/- 13.8+/- 9.1+/- 4.0+/-
implantations 1.1 1.8 4.7c 4.4 c
Average # 14.4+/- 15.0+/- 13.4+/- 11.7+/-
corpora lutea 1.4 1.7 2.3 0.6 d
Average # 0.9+/- 1.0+/- 0.6+/- 2.0+/-
resorptions 0.8 1.0 0.7 1.0

Week 12 -
Average # 13.7+/- 13.3+/- 12.6+/- 13.8+/-
implantations 2.6 1.7 3.1 1.2
Average # 14.2+/- 13.9+/- 14.0+/- 14.3+/-
corpora lutea 1.4 1.5 1.2 1.6 e
Average # 1.0+/- 0.9+/- 1.1+/- 0.4+/-
resorptions 1.2 1.8 1.0 0.5

Week 15 -
Average # 14.2+/- 14.1+/- 14.5+/- 13.7+/-
implantations 1.9 1.5 1.2 2.2
Average # 14.0+/- 14.3+/- 14.5+/- 14.5+/-
corpora lutea 1.5 1.0 1.3 1.5
Average # 0.7+/- 1.2+/- 0.9+/- 1.2+/-
resorptions 0.7 1.7 0.8 1.0

Week 20 -
Average # 14.2+/- 14.4+/- 13.9+/- 15.2+/-
implantations 2.0 1.6 1.6 1.4 d
Average # 13.1+/- 14.1+/- 13.6+/- 14.5+/-
corpora lutea 2.2 1.6 2.1 1.1
Average # 0.8+/- 0.9+/- 0.7+/- 0.5+/-
resorptions 1.0 0.9 1.2 0.4


a Male rats were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day; 5 days/week for 10 weeks. During the 2nd, 4th, 7th, and 10th weeks of exposure, 25 male rats per exposure level were housed during the period between exposures with 2 unexposed female rats each. Matings were also conducted during weeks 12, 15, and 20 of the recovery period.

b Mean +/- S.D. The average number of implantations, corpora lutea, or resorptions for the two female rats bred to each male was calculated. Group means were then calculated from these averaged values.

c Significantly different from the control value by a non-parametric analysis of variance by ranks, using Wilcoxon's test.

d Significantly different from the control value by an analysis of variance and Dunnett's test, p<0.05.

e Significantly different from the control value by a modified Wilcoxon test, p<0.05.


Reproductive Parameters - Average Preimplantation Loss and Average Resorption Rate in Unexposed Female Rats Bred to Male Rats Exposed to Epichlorohydrin by Inhalation
Week on Exposure Level, ppm (a)
Study 0 5 25 50

Average preimplantation loss, percent b
2nd 8 5 42 c 84 c
4th 6 4 38 78
7th 6 8 48 c 90 c
10th 4 9 c 36 c 66 c
12th 7 6 12 5
15th 5 4 3 8 c
20th 9 4 c 6 c 6 d

Average resorp-
tion rate,
percent e 2nd 6 6 4 50 f
4th 5 8 13 50 g
7th 4 7 6 50 g
10th 6 9 14 78 c,h
12th 8 8 10 3 c
15th 7 8 6 11
20th 8 7 5 4


a Male rats were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day, 5 days/week for 10 weeks. During the 2nd, 4th, 7th, and 10th weeks of exposure, 25 male rats per exposure level were housed during the period between exposures with 2 unexposed female rats each. Matings were also conducted during weeks 12, 15, and 20 of the recovery period.

b Preimplantation loss = # corpora lutea minus # implantations / # corpora lutea X 100
The average pre-implantation loss for the 2 females bred to each male rat was calculated. Group means were then calculated from these averaged values.

c Significantly different from the control value by a modified Wilcoxon test, p<0.05.

d p = 0.053, modified Wilcoxon test.

e Resorption rate # resorptions / # implantations x 100
The average resorption rate for the 2 females bred to each male rat was calculated. Group means were then calculated from these averaged values.

f Only 4 of the female rats bred to exposed males were pregnant. Two females each had only one implantation site which was resorbed.

g Only 2 of the female rats bred to exposed males were pregnant. One female had only one implantation site which was resorbed.

h Only 3 of the female rats bred to exposed males were pregnant. One female had only one implantation site which was resorbed; one female had two implantation sites which were both resorbed.



Reproductive Parameters - Fertility Index Survival Indices in Female Rats Exposed to Epichlorohydrin by Inhalation
Exposure Level, ppm a
0 5 25 50

No. Females 25 25 25 25
No. maternal deaths during
delivery 0 1 0 1

Fertility index b 84%(21/25) 92%(23/25) 92%(23/25) 92%(23/25)
Gestation period, days c 22+/-0.6 22+/-0.6 23+/-2.0 22+/-1.0
Litter size at birth c 12+/-4 12+/-5 12+/-4 12+/-3
Gestation survival 97% 97% 96% 98%
index (243/250) (261/269) (268/278) (265/270)
24-Hr survival 99% 100% 99% 98%
index e (240/243) (261/261) (265/268) (259/265)
2-Day survival 98% 100% 98% 97%
index f (238/243) (261/261)g (262/268) (258/265)
Sex ratio on day 1, M:F 52:48 55:45 49:51 49:51


a Female rats were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day, 5 days/week for 10 weeks. Directly following termination of the exposures 25 female rats per exposure level were housed with two different unexposed male rats for a 5-day period with each male.

b No. of females delivering a litter/no. of females placed with males.

c Mean 1 S.D.

d No. of liveborn neonates/total no. of pups.

e Percentage of liveborn neonates which survived for 24 hrs.

f Percentage of liveborn neonates which survived for 2 days.

g Significantly different from the control value by the Fisher's exact probability test, p<0.05.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEC
Effect level:
5 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: Histopathologic effects noted in nasal turbinates
Dose descriptor:
NOAEC
Remarks:
reproduction/fertility
Effect level:
5 ppm (nominal)
Sex:
male
Basis for effect level:
other: based on male fertility following exposure to epichlorohydrin
Dose descriptor:
NOAEC
Remarks:
reproduction/fertility
Effect level:
50 ppm (nominal)
Sex:
female
Basis for effect level:
other: based on reproduction

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

Reproductive Parameters - Fertility Index Survival Indices in Female Rats Exposed to Epichlorohydrin by Inhalation
Exposure Level, ppm a
0 5 25 50

No. Females 25 25 25 25
No. maternal deaths during
delivery 0 1 0 1

Fertility index b 84%(21/25) 92%(23/25) 92%(23/25) 92%(23/25)
Gestation period, days c 22+/-0.6 22+/-0.6 23+/-2.0 22+/-1.0
Litter size at birth c 12+/-4 12+/-5 12+/-4 12+/-3
Gestation survival 97% 97% 96% 98%
index (243/250) (261/269) (268/278) (265/270)
24-Hr survival 99% 100% 99% 98%
index e (240/243) (261/261) (265/268) (259/265)
2-Day survival 98% 100% 98% 97%
index f (238/243) (261/261)g (262/268) (258/265)
Sex ratio on day 1, M:F 52:48 55:45 49:51 49:51


a Female rats were exposed to 0, 5, 25, or 50 ppm of epichlorohydrin vapor for 6 hrs/day, 5 days/week for 10 weeks. Directly following termination of the exposures 25 female rats per exposure level were housed with two different unexposed male rats for a 5-day period with each male.

b No. of females delivering a litter/no. of females placed with males.

c Mean 1 S.D.

d No. of liveborn neonates/total no. of pups.

e Percentage of liveborn neonates which survived for 24 hrs.

f Percentage of liveborn neonates which survived for 2 days.

g Significantly different from the control value by the Fisher's exact probability test, p<0.05.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

No deaths occurred among male rats exposed to ECH by inhalation. Three female rats died during the conduct of the study: one in the control group died during the postexposure period and death was attributed to incisor overgrowth; 1 in the 5 pprn and 1 in the 50 pprn group died during delivery of young due to loss of blood. The mean weekly body weights of male and female rats in the 50 pprn group were slightly lower than for the control group during the 10 weeks of exposure, but the decreases were stastistically significant only during Weeks 1 (males) and 9 (females) of exposure. Group mean body weights were comparable to controls for both male and female rats prior to initiation of exposures. The total amount of weight gained during the 10 week period of exposure was decreased significantly in the 50-ppm group as compared to controls for both sexes. Male rats exposed to 50 pprn of ECH gained, on the average, 74 +/- 21 vs 92 +/- 5 g in controls during the 10 weeks of exposure. Similarly, females exposed to 50 pprn gained 46 +/- 8 vs 52 +/- 10 g in the control group during the 10-week interval. Both values were statistically significantly different from controls by an analysis of variance and Dunnett's test. During Weeks 1 and 2 of exposure, rats of both sexes exhibited clinical signs of sialodacryoadenitis (SDA), the severity and duration of which were similar among the control and exposed groups. No viral serology or additional diagnostic procedures were conducted on the test animals. However, histopathologic examination was conducted on the respiratory tissues, salivary glands, and posterior orbital lacrimal glands of additional rats from the same shipment of animals. These animals, three male rats and three female rats, were killed during the period of time when clinical signs of SDA were noted in the animals. Lesions consistent with the diagnosis of an SDA infection were present.

Exposure to 50 pprn of ECH resulted in a marked decrease in the percentage of male rats that were fertile for the four matings conducted during the period of exposure. Only 16% (4/25) of the males in this group impregnated one or both of the females with which they were housed during the second week of exposure. Fertility in this group remained low for all matings conducted during the 10-week exposure period. Rapid recovery of fertility was evident in these males following cessation of exposures; in the second week postexposure (week 12), 96% of the animals sired at least one litter. Vaginal plugs beneath the cages were observed at approximately equal frequencies in the control and all exposed groups suggesting that mating activity was similar in all test groups. Most of the male rats in the 5- and 25-ppm groups were able to impregnate females in all of the matings. However, females impregnated by males from both the 25- and 50-pprn groups during the exposure period had significantly fewer implants than those bred to control males. The average number of corpora lutea and resorptions per litter were comparable to controls for all exposed groups. Thus, the data indicate that fertility was impaired in both the 25- and the 50-ppm groups. This effect was reversible as the number of implantations per litter returned to the control range within 2 weeks following cessation of exposure to ECH.

The reproductive capacity of female rats following 10 weeks of exposure to ECH was not adversely affected. The females showed normal estrus patterns during the 2-week mating period following termination of exposures and were able to become pregnant and deliver viable young. There were no adverse effects on the percentage of pregnant females, length of gestation period, litter size, or pup survival through 2 days postpartum in any of the ECH-exposed groups.

At the interim termination after 10 weeks of exposure, male and female rats in the 50-ppm group showed a statistically significant increase, as compared to controls, in the absolute and relative kidney weights. Histopathologically, a slight accentuation of spontaneous changes was noted in the kidneys of both males and females in the 50-ppm group. In some of these rats and in some of the 25-ppm group, focal tubular changes which included dilation with eosinophilic staining casts and altered staining affinity were observed. No indication of renal tubular degeneration or necrosis was detected at any level of exposure in either sex. The absence of significant histopathologic effects in the kidneys was further supported by the presence of normal clinical chemistry values for renal function and urinalysis. Data for organ weights, histopathology, and clinical chemistry evaluations are not presented in tabular form.

The most obvious indications of toxicity in both the male and female rats were the exposure-related histopathologic changes in the nasal turbinates in the 25- and 50-ppm groups. The changes were degenerative in nature, characterized by inflammation, focal erosions, hyperplasia, and metaplasia with a squamous appearance to the turbinate mucosa in the respiratory epithelial region, and were considered to be the result of irritation caused by the test material. Generally, the lesions were minimal to moderate in animals from the 25-ppm group, and moderate to severe in the 50-ppm exposed rats. Nasal turbinates of rats exposed to 5 ppm were indistinguishable from controls. Following the 10-week postexposure period, the histopathologic lesions in the nasal turbinates were not detected, indicating that.they were reversible. Similarly, the dilated renal tubules and other changes noted in the kidneys of male and female rats at the interim termination were not observed in rats examined at the end of the postexposure period.

The weights of the male reproductive organs did not show any significant differences from control values, and histopathologic examination did not reveal changes which were considered treatment related either directly - following exposure to ECH or after the postexposure period. No consistent or treatment related effects on hematologic parameters, urinalysis, or clinical chemistry determinations were observed in rats of either sex.

Applicant's summary and conclusion

Conclusions:
In male rats, the reproduction/fertility and parental toxicity NOAEL's are 5 ppm. In female rats, the reproduction/fertility NOAEL is 50 ppm and the parental toxicity NOAEL is 5 ppm.
Executive summary:

The effects of inhaled epichlorohydrin (ECH) on the fertility of Sprague-Dawley rats were studied. Groups of 30 male rats and 30 female rats were exposed to 0, 5, 25, or 50 pprn of ECH vapor for 6 hr/day, 5 days/week for 10 weeks, and were held for a 10-week postexposure period. Exposed male rats were mated with unexposed females at several intervals during and after the exposure period. In addition, female rats which had been exposed for the 10-week period were mated with unexposed males and allowed to deliver their young. Exposure to 50 pprn of ECH vapor for 10 weeks resulted in transient infertility in the male Sprague-Dawley rats; recovery of fertility in rats occurred during the second week after termination of exposure. Male rats exposed to 25 pprn of ECH were able to impregnate unexposed females; however, fewer implantations were observed in these females than in the females mated to control males suggesting that fertility was adversely affected in this group as well. This effect also was reversed by the second week following termination of exposure. The incidence of resorptions in the unexposed female rats which were bred to the exposed males was not adversely affected. Amgng female rats exposed to ECH, no adverse effects were observed on estrus cycle, pregnancy rate, parturition, or the number and viability of the offspring. Histologic examination of tissues from an interim and final termination of the exposed animals indicated that the most severely affeded organ following inhalation exposure to 25 or 50 pprn of epichlorohydrin in both rats was the nasal turbinates. These lesions, interpreted to be a result of irritation from the test material, were no longer present in animals which were held for the 10-week postexposure period. No adverse effects were observed among rats exposed to 5 pprn of ECH for 10 weeks.