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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: effects on reproductive organs
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study with acceptable restrictions. Report does not contain all study details. Female fertility data are identical in rats and mice, indicating a transcription error.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992

Materials and methods

Principles of method if other than guideline:
Within a 90 day oral feeding study performed equivalent to OECD guideline 408 with Castor oil, male and female fertility parameters were analyzed in rats and mice. No matings were performed.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Castor oil
EC Number:
232-293-8
EC Name:
Castor oil
Cas Number:
8001-79-4
Details on test material:
- Name of test material (as cited in study report): Castor Oil
- Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid
- Composition of test material, percentage of components: Triglyceride of fatty acids. Fatty acid composition is approximately 87% ricinoleic,
7% oleic, 3% linoleic, 2% palmitic, 1% stearic, and trace amounts of dihydroxystearic.
- Analytical grade: USP AA grade
- Source: Cas Chemical, Inc. (Bayonne, NJ, USA)
- Stability: The stability of the study material during the toxicology studies was monitored by determination of peroxide content and by high performance liquid chromatography. No deterioration of the castor oil study material was observed over the course of the studies.

Test animals

Species:
other: rats and mice
Strain:
other: F344/N and B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA, USA)
- Age at study initiation: 6 weeks
- Weight at study initiation: male rats: 126 - 132 g; female rats: 107- 110 g, male mice: 22.6 - 23.0 g, female mice: 17.2 - 17.7 g
- Fasting period before study:
- Housing: rats: 5 per cage, mice individually in Polycarbonate cages lined with heat-treated hardwood chips, covered with polyester filter sheets.
- Diet: Control feed (NIH 07) or diet formulations of castor oil were available ad libitum; feeders were changed twice per week throughout the study.
- Water: automatic watering system, ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-76
- Humidity (%): 42-72
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulated diets were prepared by blending the appropriate amount of castor oil with a small quantity of feed to prepare a premix. The premix then was layered between the required amount of feed in a twin-shell blender and blended for 15 minutes to achieve a uniform mix. The homogeneity of castor oil in feed at 10% (100 mg/g) was determined by gravimetric analysis, and blends at 0.5% (5 mg/g) were determined by HPLC analysis. These concentrations of chemical in feed were found to be homogeneously distributed by this mixing procedure. The stability of the 0.5% dose level was determined using HPLC; it was found to be stable for at least 21 days when stored in the dark at 5°C and for 3 days when stored open to air and light in a rodent cage. During the studies, formulated diets were stored for no longer than 3 weeks at 5°C; feed hoppers in the animal cages were changed twice weekly.
Details on mating procedure:
no matings performed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The results of the analyses for all dose mixtures given to the animals ranged from 97% to 106% of the target concentrations.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily ad libitum feeding
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 2.50, 5.00, 10.0 % (w/w)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 1583, 3067 and 5835 mg/kg bw/day
Basis:
other: actual ingested: male rats
Remarks:
Doses / Concentrations:
0, 1569, 3045, 5725 mg/kg bw/day
Basis:
other: actual ingested: female rats
Remarks:
Doses / Concentrations:
0, 3800, 7823, 15017 mg/kg bw/day
Basis:
other: actual ingested: male mice
Remarks:
Doses / Concentrations:
0, 5009, 9627, 16786 mg/kg bw/day
Basis:
other: actual ingested: female mice
No. of animals per sex per dose:
10
Control animals:
yes, plain diet

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS/ CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day

BODY WEIGHT: Yes
- Time schedule for examinations: initially and 1 x wk thereafter.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


Oestrous cyclicity (parental animals):
Proestrus, Estrous, Metestrous, Diestrous, Cycle Length (days)
Sperm parameters (parental animals):
Caudal weight, epididymal weight, testis weight, Sperm countig testis, Sperm motility (%)
Litter observations:
not performed
Postmortem examinations (parental animals):
Complete histopathology examinations were conducted on all rats and mice from the control and 10% dose groups. Livers were examined from male rats in all other dose groups; histologic sections of gross lesions were examined from all rats. Organ weights were determined to the nearest milligram for the liver, right kidney, right testicle, heart, thymus, and lungs. All tissues were preserved in 10% neutral buffered formalin.

The following tissues were routinely processed for preparation of histologic sections and microscopic examination: adrenal glands, brain, cecum, colon, duodenum, epididymis/seminal vesicles/prostate/testes or ovaries/uterus, esophagus, eyes (if grossly abnormal), femur (including marrow), heart, ileum, jejunum, kidneys, liver, lungs and mainstem bronchi, mammary gland, mandibular and mesenteric lymph nodes, nasal cavity and turbinates, pancreas, parathyroid glands, pituitary gland, preputial or clitoral glands, rectum, salivary glands, skin, spinal cord and sciatic nerve (if neurologic signs present), spleen, forestomach and glandular stomach, thymus, thyroid gland, trachea, urinary bladder, zymbal glands, and all gross lesions and tissue masses including regional lymph nodes. A complete histopathologic examination was conducted on all rats and mice from the control and 10% dose groups. Liver was examined from male rats in all other dose groups, and histologic sections of gross lesions were examined from all rats.
Postmortem examinations (offspring):
not performed
Statistics:
Dunn's test; Shirley's test.

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:
no effects observed
Reproductive performance:
not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY
No effects

BODY WEIGHT AND WEIGHT GAIN
Group mean body weights of rats receiving diets containing castor oil did not differ significantly from controls. Mean body weights of exposed female rats were slightly lower than the mean body weights of controls but the differences were not dose-related.
Mean body weights of exposed male mice generally were lower than controls, while mean body weights of exposed females generally were higher. There were no obvious indications that these differences were related to dietary concentrations of castor oil, except that mean body weights of male mice receiving the 10% castor oil diet were consistently lower than those of control mice from week 3 through the end of the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No significant differences in average food consumption among each sex were observed, although food consumption of male and female rats receiving diets containing 10% castor oil was slightly lower than that of controls. Similarly, food consumption by female mice receiving diets containing 10% castor oil was slightly lower than controls.

ORGAN WEIGHTS
In male rats, there was a slight decrease in epididymal weight (6-7%) which occurred in the middle- and high-dose groups, but this was not dose-related. There were no effects on any other male rat reproductive endpoint, or on any female rat reproductive endpoint. Although there was some variation in epididymal weights, their small magnitude and the absence of changes in other endpoints suggested that there was little or no evidence of any reproductive toxicity associated with castor oil exposure. Histopathologic examination revealed an absence of compound-related lesions in any organ or tissue of rats exposed to castor oil in the diet.

Castor oil exposure produced no adverse effects on any male (testes weight, epididymal sperm motility, density, or testicular spermatid head count) or female (estrual cycle length, or time spent in each phase of the cycle) reproductive parameter among mice. The low value for sperm motility
in control mice was attributed to poor preparative technique.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
parental fertility parameters
Effect level:
ca. 5 000 mg/kg bw/day (actual dose received)
Based on:
other: calculated test material intake based on food consumption and body weight
Sex:
male/female
Basis for effect level:
other: for rats based on oestrus stage and cycle length and sperm characterization.
Dose descriptor:
NOAEL
Remarks:
parental fertility parameters
Effect level:
ca. 15 000 mg/kg bw/day (actual dose received)
Based on:
other: calculated test material intake based on food consumption and body weight
Sex:
male/female
Basis for effect level:
other: for mice based on oestrus stage and cycle length and sperm characterization.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
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)

not examined

Effect levels (F1)

Dose descriptor:
NOAEL
Remarks on result:
not measured/tested
Remarks:
No matings were performed.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1: Reproductive System Data for F344/N Rats in the 13-Week Feed Studies

of Castor Oil

 

 

Percent in Feed

 

0

2.5

5

10

Malea

Left caudal weight (mg)

151

153

145

153

Left epididymal weight (mg)

502

498

464*

476

Left testis (mg)

1539

1550

1463

1492

Sperm count (x106)/g testis

72.8

65.9

71.7

77.5

Sperm motility (%)

73.6

65.9

72.1

69.8

Femaleb

Estrous stage (%)

Proestrus

12.5

14.2

15.8

16.7

Estrous

28.3

32.5

25.8

25.8

Metestrous

18.3

19.2

18.3

19.2

Diestrous

40.8

34.2

39.2

38.3

Not clear or no cells observed

0.0

0.0

0.8

0.0

Cycle Length (days)

5.0

5.1

5.2

5.1

aMean for groups of 10 animals; no significant difference vs. the controls by Dunn's test

bMean for groups of 10 animals unless otherwise specified

* Significantly different from control groups by Shirley's test ; p < 0.05.

 

Table 2: Reproductive System Data for B6C3F1 Mice in the 13-Week Feed Studies

of Castor Oil

 

 

Percent in Feed

 

0

2.5

5

10

Malea

Left caudal weight (mg)

15

13

16

16

Left epididymal weight (mg)

45

46

46

44

Left testis (mg)

121

120

121

119

Sperm count (x106)/g testis

179.2

162.4

170.1

158.3

Sperm motility (%)

39.2

53.7

45.4

52.2

Femaleb

Estrous stage (%)

Proestrus

12.5

14.2

15.8

16.7

Estrous

28.3

32.5

25.8

25.8

Metestrous

18.3

19.2

18.3

19.2

Diestrous

40.8

34.2

39.2

38.3

Not clear or no cells observed

0.0

0.0

0.8

0.0

Cycle Length (days)

5.0

5.1

5.2

5.1

aMean for groups of 10 animals; no significant difference vs. the controls by Dunn's test

bMean for groups of 10 animals unless otherwise specified

 

Applicant's summary and conclusion