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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally acceptable scientific standards with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1967
Report date:
1967

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 9-icosyl-9-phosphabicyclo[3.3.1]nonane and 9-icosyl-9-phosphabicyclo[4.2.1]nonane
EC Number:
915-206-4
Molecular formula:
C28H55P
IUPAC Name:
Reaction mass of 9-icosyl-9-phosphabicyclo[3.3.1]nonane and 9-icosyl-9-phosphabicyclo[4.2.1]nonane
Details on test material:
- Name of test material (as cited in study report): RM-17
- Physical state:No data
- Analytical purity: No data
- Impurities (identity and concentrations): No data
- Lot/batch No.: No data
- Stability under test conditions: Not stated
- Storage condition of test material: Not stated

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not stated.
- Age at study initiation: young, culled from a larger population after examination of each animal for general health and adequacy for test purposes.
- Weight at study initiation: 99 to 115 grams
- Fasting period before study: No
- Housing: The animals were divided as to sex and housed individually in standard laboratory rodent cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Administration / exposure

Type of coverage:
open
Vehicle:
other: Dowanol DPM
Details on exposure:
Dermal applications were scheduled to be made upon either clipped and intact skin or to clipped and abraded normal skin of the backs of the animals. Clipping was done 24 hours prior to the start of the study and on the seventh, fourteenth, twenty-first and twenty-eighth days thereafter. Abrading was done three times per week just prior to the applications. All animals were clipped on this schedule while abrading was done only upon half of the animals in each group.

Clipping was performed with special electric animal clippers which permitted close shaving of the skin. An area immediately behind the neck of each animal was clipped free of hair to expose approximately two square centimeters of surface on rats and approximately one square centimeter on mice. This site was selected to prevent the animals from being able to remove the test material with their paws.

Abrading was performed with a pronged metal instrument drawn across the skin of the back with mild pressure to produce a series of parallel longitudinal abrasions. These were sufficient to penetrate the stratum corneum but were not deep enough to cause bleeding.


Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
30 consecutive days.
Frequency of treatment:
Applications to the skin were made daily. Measured doses were delivered via syringe onto the prepared intact and abraded skin sites of the animals. After dosing, each animal was returned to its cage until a subsequent application was made.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500
Basis:
other: mg/kg/day
Remarks:
Doses / Concentrations:
1000
Basis:
other: mg/kg/day
Remarks:
Doses / Concentrations:
2000
Basis:
other: mg/kg/day
No. of animals per sex per dose:
Four male and four female per dose.
Control animals:
yes, concurrent vehicle
Details on study design:
The 32 rats were each equally divided into four groups corresponding to the schedule outlined in Table 1 (please see further information on methods and materials). Within each group the animals were subdivided into four animals of each sex. As indicated in the table, these four groups corresponded to a treated control group and three experimental groups. The two variables studies among the latter were dosage (three levels) and skin condition (intact skin and abraded skin).

Examinations

Observations and examinations performed and frequency:
Parameters Evaluated
Survival
Ascertained daily during the 30-day dosing period and the 14-day recovery period.

Signs and Symptoms of Toxicity
Ascertained daily by observation.

Body Weight Gains
Determined by direct weighing on Day Number 0 (the first test day), on Day Number 7, Day Number 14, Day Number 21, Day Number 28, and on Day Number 30 of the dosing period, and on Day Number 7 and Day Number 14 of the recovery period.

Food Intake·
Ascertained daily by observation.
Sacrifice and pathology:
Gross Pathology
Arrangements were made to subject any animals which might die during the test period to a complete gross pathologic examination and to secure representative tissues and organs for possible future reference.
At the end of the dosing period, selected animals from all groups were sacrificed. The remaining animals were allowed to undergo a 14-day recovery period (no further contact with test material) and were then sacrificed. The sacrifice schedule is shown in Table II for both rats and mice. Gross pathologic examinations were conducted upon all of the animals at the time of sacrifice and sections of the following tissues and organs were preserved in 10 per cent aqueous formaldehyde solutions:

Heart, Lungs, Pancreas, Lymph Nodes, Gonads, Uterus, Thyroid Gland, Spinal Cord, Skeletal Muscle, Aorta, Liver, Gastro-Intestinal Tract, Kidneys, Prostate,
Salivary Glands, Pituitary Gland, Peripheral Nerves, Treated Skin, Trachea, Spleen, Urinary Bladder, Seminal Vesicles, Adrenal Glands, Brain, Sternum, Femur

In addition, differential cell counts were conducted on bone marrow obtained from sections of rat femur.

Microscopic Pathalogical studies
Histopathologic studies were conducted on bone marrow sections (sternum) obtained from all animals.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One male rat died on day 27. The death was believed to be related to the daily dosing of the test material.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Please see "details on results" section below for details.
Mortality:
mortality observed, treatment-related
Description (incidence):
One male rat died on day 27. The death was believed to be related to the daily dosing of the test material.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Please see "details on results" section below for details.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Please see "details on results" section below for details.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Please see "details on results" section below for details.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Please see "details on results" section below for details.
Histopathological findings: neoplastic:
not examined
Details on results:
DERMAL IRRITATION
Moderate to severe skin alterations were observed at the application site in all animals subjected to daily contact with the test material. These alterations consisted of erythema, edema and ulceration, followed by fissuring and ultimate loss of the outermost layers. This sequence or cyclic pattern was in general observed twice during the 30-day dosing period.

BODY WEIGHT AND WEIGHT GAIN
Severe anorexia and cachexia were noted among the rats dosed at the two highest levels. Slight bodyweight losses were noted in two rats from the 2000 mg/kg/day level.

FOOD CONSUMPTION
Bodyweight and growth effects were associated with consistently poor food consumption which was believed to be principally related to the repeated dermal application of the test material.

GROSS PATHOLOGY
The only significant pathologic findings at autopsy which could be attributed to the test material were those associated with the treated skin. These consisted of erythema, edema, scab formation and thickening and/or drying of the skin.
Examination of the bone marrow sections (sternum) revealed no significant pathological changes.

HISTOPATHOLOGY: NON-NEOPLASTIC
With the exception of one animal from the high dose level group which showed a slight increase in myeloid elements, bone marrow differential cell counts were within normal limits and myeloid-erythroid elements were considered normal. The slight change in this animal may be attributable to the test material, but this cannot be definitely determined.

OTHER FINDINGS
A distinct growth depression was observed among rats at all three test levels which was not evident in the adult mice.

Effect levels

open allclose all
Dose descriptor:
dose level: 500 mg/kg/bw
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; food consumption; gross pathology; histopathology
Dose descriptor:
dose level: 1000 mg/kg/bw
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; food consumption; gross pathology; histopathology
Dose descriptor:
dose level: 2000 mg/kg/bw
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs;body weight; food consumption; gross pathology; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The results of the study concluded that the test material has systemic action and cumulative toxicity in rats above 500 mg/kg/bw.