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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity 98.6%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 150, 500 mg/kg bw/d
Basis:
no data

Examinations

Parental animals: Observations and examinations:
Clinical observation performed and frequency: General condition was
observed once a day, body weights were determined at days 1 (before
dosing),8,15,22,29,36,43 and 49 of treatment for males and at days 1, 8
and 15 of treatment and at days 0,7,14,and 20 of gestation period and at
days 0 and 4 of lactation period and at autopsy for females, food
consumption was determined at days 1,8,15,22,29,36,43 and 48 of
treatment for males and at days 1,8 and 15 of treatment and at days 0,
7,14 and 20 of gestation period and at days 0 and 4 of lactation for
females. but food consumption were not determined during mating period
for males and females.
For 5 males per group, urinalysis was carried out at 43-48 days of administration period. For all males and all females after childbirth per group, hematology and biochemistry were carried out at time of necropsy
after 49 days for males and at 5 days after delivery for females.
Postmortem examinations (parental animals):
Organs
examined at necropsy.
Organ weight: Brain, liver, kidney, spleen, adrenal, thymus, testis and
epididymis
Microscopic examination: Brain, pituitary, thymus, thyroid, parathyroid,
adrenal, spleen, heart, thoracic aorta, tongue, esophagus, stomach, liver,
pancreas, duodenum, jejunum, ileum, cecum, colon, rectum, larynx,
trachea, lung, kidney, urinary bladder, testis, epididymis, prostate, seminal
vesicle, ovary, uterus, vagina, eye, harderian gland, mammary gland, skin,
sternum, femur, spinal cord, skeletal muscle, mesentery lymph node,
mandibular lymph node, submandibular gland, sublingual gland, parotid
gland, ischiadic nerve, bone marrow.
Statistics:
Dunnett's test for continuous data and Steel test for quantal data.
Reproductive indices:
No.of pairs with successful
copulation, No. of pregnant females, copulation index (No. of pairs with
successful copulation/No. of pairs mated x 100), fertility index (No. of
pregnant animals/No.of animals with successful copulation x 100), estrous
cycle, No. of dams delivered live pups, duration of gestation, No. of total
corpora lutea, No. of total implants, No. of total pups born, No. of total live
pups born, sex ratio, No. of total dead pups, No. of total cannibalism,
gestation index (No. of females with live pups/No. of pregnant females x
100), implantation index (No. of implants/No.of corpora lutea x 100),
Offspring viability indices:
delivery index (No. of pups born/No. of implants x 100), live birth index (No.
of live pups born/No. of pups born x 100), and viability index on day 4 (No.
of live pups on day 4 after birth/No. of live pups born x 100).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

Mortality: There was no mortality related to the test substance treatment.
Clinical signs: Salivation was apparent in three animals of 150 mg/kg bw group and in twelve animals of 500 mg/kg bw group for males and in two
animals of 150 mg/kg bw group and twelve animals of 500 mg/kg bw group for females. Although the grades of salivation were not reported, the sign was observed for about 5 minutes after dosing at 150 mg/kg bw , and for 30 minutes to 5 hours after dosing at 500 mg/kg bw during treatment
period. In addition, lacrimation was observed in two animals of 500 mg/kg bw group for males and in one animal each of 150 and 500 mg/kg bw
groups for females. The onsets and grades of lacrimation were not reported.

Body weight: No statistically significant changes for males and females.
Food consumption: No effects for males and females.
Urinalysis: No statistically significant changes.
Hematology: No effects for males and females
Blood biochemistry:
Males: Decreases in triglyceride in 150 and 500 mg/kg bw groups, increases in total bilirubin in 500 mg/kg bw group, and total bile acid in 150 and 500 mg/kg bw.
Females: Increase in total bile acid in 50, 150, and 500mg/kg bw.
Necropsy and histopathology: No adverse effects for males and females.
Organ weights:
Males: Increase in a relative kidney weight in 500 mg/kg bw group.
Females: No statistically changes.
Histopathology: No changes related to test substance.
Reproductive and developmental parameters: No effects observed on reproductive performance in males and females given each dose, and developmental performance of the newborns.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
> 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

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 specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Summary of reproductive performance in rats treated orally with cyclohexene in the combined repeat dose and reproductive/developmental toxicity screening test

Dose level (mg/kg)

0

50

150

500

No, of pairs mated

12

12

12

12

No. of pairs copulated

12

11

12

12

No. of pregnant females

11

10

10

10

Copulation index (%)a

100.0

91.7

100.0

100.0

Fertility index (%)b

91.7

90.9

83.3

83.3

Estrous cycle

 

 

 

 

No. of animals examined

12

12

12

12

Mean estrous cycle (days, Mean t S.D.)

4.1 ± 0.1

4.1 ± 0.3

4.2 ± 0.4 (11)

4.1 ± 0.3

Irregular cyclec(%)d

0(0.0)

0(0.0)

1(8.3)

2 (16.7)

a)  (No, of animals with successful copulatiun/no. of animals mated)x100

b)  (No. of pregnant animals/nm. of animals with successful copulation) x100 c) (No. of unimals having irregular estrous cycle

d) (No. of animals having irregular estrous cycle/no.of animals examined) X100 Values in parentheses are expresser" no. of animals observed

 

Findings of delivery in dams treated orally with cyclohexene and observations an their pups(F1)in thecombined repeat dose and reproductive/developmental toxicity screening test

Dose level (mg/kg)

0

50

150

500

No. of dams observed

11

10

10

10

No. of dams delivered live pups

11

10

10

10

Duration of gestation (Mean ± SD)

22.5 ± 0.5

22.2 -± 0.4

22.3 ± 0.5

22.5 ± 0.5

No. of total corpora lutea (Mean ± SD)

211(19.2 ± 2,6)

174 (17.4 ± 3.3)

184(18.4 ± 3.2)

201(20.1 ± 3.8)

No. of total implants (Mean ± SD)

151 (13.7 ± 3.0)

144 (14.4 ± 1.6)

143 (14.3 ± 1.5)

143(142 ±1.6)

Ne. of total pups bora (Mean ± SD)

144(13.1 ± 3.5)

135 (13.5 ± 1.6)

139(13.9 ± 1.4)

128(12.8 ± 1.5)

No. of total live pups born (Mean ± SD)

141 (12.8 ± 3.5)

134 (13.4 ± 1.6)

135(13.5 ± 2,1)

125(12.5 ± 2.2)

Male

62( 5.6 ± 1.9)

72 ( 72 ± 2.0)

67 (0.7 ± 2.6)

51(5.1 ± 1.9)

Female

79( 7.2 ± 2.3)

62( 6.2 ± 1.9)

68 (6.8 ± 2.3)

74( 7.4 ± 2.4)

Sex ratio(Male/ Female, (Mean ± SD)

0.80 ± 0,23

1.32 ± 0.68

1.14 ± 1.60

0.81 ± 0.56

No. of total live pups on day 4 (Mean ±SD)

 

 

 

 

Male

51( 5.5 ± 2,2)

69( 69±2.1)

67( 6.7 ± 2.6)

59( 5.0±2.1)

Female

75( 6.8 ± 2,8)

62( 6,2 ± 1.9)

67( 6.7 ± 2.4)

72( 7.2±2.0)

No. of total dead pups (Mean ± SD)

3( 0.3 ± 0.6)

1( 0.1 ± 0.3)

1( 0.1 ± 0.3)

3( 0.3 ± 0.9)

No. of total cannibalism (Mean ± SD)

0( 0.0 ± 0.0)f

0( 0.0 ± 0.0)f

3( 0.3 ± 0.9)f

0( 0.0 ± 0.0)f

Gestation index(%)a

100.0

100.0

100.0

100.0

Implantation index (%, Mean SD)b

73.2 ± 202

84.1 ± 93

79.0 ± 10.6

72.9 ± 13,1

Delivery Index (%, Mean±SD)c

93.2 ± 11.9

93.8 ± 6.1

97.3 ± 4.7

90.0 ± 10.3

Live birth index (%, Mean ± SD)d

98.0 ± 4.7

99.3 ± 2,3

96.9 ± 9.7

97.0± 9.5

Viability index on day 4 (%, Mean ± S.D.)e

 

 

 

 

Male

90.9 ± 30.2f

95.3 ± 10.0f

100.0 ± 0.0f

96.7 ± 10.5f

Fernale

88.6 ± 29.8f

100.0 ± 0.0f

98.3 ± 5.3f

98.3 ± 5.3f

Applicant's summary and conclusion

Conclusions:
No adverse effects regarding fertility or development. The NOAEL was 500 mg/kg bw/day regarding reproductive endpoints.
Executive summary:

The study was conducted according to the OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test guideline [TG 422].

Cyclohexene was administered to SD(Crj:CD)IGS rats by gavage at doses of 0, 50, 150 and 500 mg/kg b.w./day for 48 days from 14 days prior to mating in males and for 42-53 days from 14 days prior to mating to day 4 of lactation throughout the mating and pregnancy period in females.

Regarding the reproductive ability of parent animals, no effects were detected on the estrus cycle, copulation index, fertility index, gestation length, numbers of corpora lutea and implantations, implantation index, gestation index, delivery index, parturition or maternal behavior. And regarding the developmental parameters, no effects were detected on viability, body weight, general

appearance or autopsy findings of offspring. The NOAEL for reproduction/developmental toxicity was considered to be 500 mg/kg bw/day, the highest dose tested.