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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, guideline study available as unpublished report, no restrictions, fully adequate for assessment.
Cross-reference
Reason / purpose:
reference to same study

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,3 Pentadiene (MRD-91-935)
- Physical state: pale yellow liquid
- Analytical purity: 98% (assumed 100% for dosing)
- Lot/batch No.: 1
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston Facility, Stone Ridge, New York, USA
- Age at study initiation: 69 days (males), 76 days (females)
- Weight at study initiation: 345-407 g (males), 223-262 g (females)
- Housing: Single housed during the test period, except during mating and post-parturition, in suspended stainless steel and wire mesh cages.
- Diet: Purina Certified Rodent Chow (5002 Meal), ad libitum. Manufacturer: Purina Mills, Inc., Richmond, Indiana, USA.
- Water: Mains water ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature: 68-76°F
- Humidity: 40-70%
- Air changes (per hr): Not reported
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: From: 16 September 1991 To: 12 November 1991

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The undiluted test material was thoroughly mixed with corn oil at the following concentrations to ensure a 5 mL/kg dose volume at all dose levels:
30 mg/kg = 0.6% (w/v); 100 mg/kg =2.0% (w/v); 1000 mg/kg = 20.0% (w/v). Dosing solutions were prepared every 2-5 days during the first 3 weeks of the study and weekly thereafter.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of MRD-91-935 in corn oil were analysed for stability, uniformity and achieved concentration by gas chromatography at intervals during the study and were found to be satisfactory.
Duration of treatment / exposure:
P1 animals were dosed daily for 2 weeks prior to mating and throughout the mating period for the F1 litter. P1 females additionally were dosed during gestation and until the day prior to euthanasia on or after postpartum Day (PPD) 4.
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 100, 1000 mg/kg day
Basis:
other: nominal in corn oil
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In a range-finding study rats were dosed with 0, 50, 500, and 1000 mg/kg. Treatment-related body weight gain suppression was seen. Therefore, the following dose levels were used: 30 mg/kg (anticipated to be the NOAEL), 100 and 1000 mg/kg.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

BODY WEIGHT: Yes
- Time schedule: Males - prior to prior to P1 selection, on the first day of dosing, and at least weekly thereafter until euthanasia. Females - prior to P1 selection, on the first day of dosing and at least weekly thereafter until mating was confirmed, then on GD 0, 7, 14, and 21 and on PPD 0 and 4.

FOOD CONSUMPTION: Yes
- Time schedule: P1 male on the first day of dosing and at least weekly thereafter, except during mating, until euthanized. Food consumption of P1 females on test Day 0 and at least weekly thereafter, except during mating, then on GD 0, 7, 14 and 21 and on PPD 0 and 4.

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At post mortem examination
- Animals fasted: Yes
- How many animals: All surviving P1 males
- Parameters examined: haematocrit, haemaglobin, erythrocyte count, leukocyte count (total and differential), platelet count, reticulocyte count (slides prepared but examined only if other RBC parameters abnormal), mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At post mortem examination
- Animals fasted: Yes
- How many animals: All surviving P1 males
- Parameters examined: albumin, alkaline phosphatase, urea nitrogen, calcium, cholesterol, creatinine, electrolytes (Na+, Cl-, K+, CO2), gamma glutamyl transferase, glucose, phosphorus, alanine aminotransferase, aspartate aminotransferase, total protein, total bilirubin, triglycerides

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All adult animals, including those that died spontaneously. Body weights were recorded on the day of necropsy. The uterus of each female which failed to deliver a litter was examined for evidence of implantations. The number of implantation sites and corpora lutea were recorded at the time of necropsy for all dams with litters.

The following organs and tissues of all adult animals euthanized at study termination were weighed prior to fixation: liver, testes, thymus, kidneys, epididymides. Organ:body weight ratios were calculated.

All Fl pups which died were subjected to an external examination, including the palate. All live Fl pups were sexed and examined externally and weighed on the day of euthanasia. Offspring were discarded without further examination.

HISTOPATHOLOGY: Yes
The following tissues were examined from the controls and high dose animals only: brain, heart, spleen, kidneys, liver, adrenals, testes/epididymides, abnormal tissues. In addition, ovaries and thymus were fixed but not routinely processed. Ovaries from females which failed to complete pregnancy were examined histopathologically.


Statistics:
mean body weights, food consumption, organ weights, relative organ weights and clinical laboratory findings: Bartlett's test of homogeneity of variance, followed by a standard one-way analysis of variance. If the ANOVA was significant, Dunnett's test was performed to determine which treated groups differed from the control. A linear regression to test for a dose response also was performed and tested for lack of fit to the regression. If the variances were not equivalent, then a Kruskal-Wallis (non-parametric) test was performed to determine if the treatment effects were equivalent. If there was a difference, Dunn's Summed Rank Test was used to determine which treatment groups differed from the control. Jonckheere's test for ordered response also was performed.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no apparent trends in male or female in-life observations which were associated with treatment with the
test material. Mortality was limited to three high dose females which died spontaneously prior to mating; one of these deaths was due to a gavage accident

BODY WEIGHT AND WEIGHT GAIN: There were no biologically meaningful differences in mean body weights for either sex in treated groups when compared with controls at any interval during the study, including gestation and the postpartum period.

FOOD CONSUMPTION: A statistically significant decrease in mean food consumption was observed in high dose females on test Day 7 compared with that in controls.

HAEMATOLOGY: No remarkable differences observed between treated and control males.

CLINICAL CHEMISTRY: No remarkable differences observed between treated and control males.

ORGAN WEIGHTS: Mean absolute and relative organ weights in treated groups of both sexes were comparable with controls.

GROSS PATHOLOGY: Postmortem abnormalities were limited to incidental findings which were considered unrelated to treatment with the test material

HISTOPATHOLOGY: There were no treatment-related microscopic changes observed.

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: transient decrease in food consumption in high dose (1000 mg/kg/day) females. No other treatment-related effects in parents or offspring

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Treatment-related parental toxicity was limited to a transient decrease in food consumption in high dose (1000 mg/kg day) females. No other treatment-related effects were observed in parents or their offspring. The NOAEL for MRD-91-935 (1,3-pentadiene) was 100 mg/kg/day.
Executive summary:

In a combined repeat dose and reproductive/developmental toxicity screening study with MRD-91-935 (1,3-pentadiene) in rats effects were limited to a transient decrease in food consumption in high dose (1000 mg/kg day) females. No other treatment-related effects were observed in parents or their offspring. The NOAEL (repeat dosing) for MRD-91-935 (1,3-pentadiene) was 100 mg/kg/day.