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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1984-11-06 to 1985-03-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report equivalent or similar to OECD guideline 411.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Stock 509

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: 6-7 weeks old
- Housing: individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Two weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: back
- Type of wrap if used: open
- Time intervals for shavings or clippings: as needed but at least weekly


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
once daily. 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 800, 2000 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
30 animals/dose group (15males and 15 females)
Control animals:
yes, concurrent no treatment

Examinations

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



DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data:No data


WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: before treatment, weeks 5, 9, and 13
- Anaesthetic used for blood collection: Yes (diethyl ether)
- Animals fasted: Yes
- How many animals: 30 animals before study began (15 males; 15 females); all animals after treatment (30/dose group)
- Parameters examined. hematocrit, hemoglobin, RBC count, WBC count and differential, RBC morphology


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before treatment, weeks 5, 9, and 13
- Animals fasted: Yes
- How many animals: 0 animals before study began (15 males; 15 females); all animals after treatment (30/dose group)
- Parameters examined. glucose, alanine aminotransferase, aspartate aminotransferase, total protein, albumin, globulin, A/G ratio, alkaline phosphatase, urea nitrogen, uric acid, creatinine, bilirubin, sodium, potassium, chloride, phosphorous, calcium, cholesterol, triglycerides, iron, total iron-binding capacity, lactate dehydrogenase


URINALYSIS: Yes
- Time schedule for collection of urine: end of study
- Parameters examined. pH, specific gravity, blood, protein, bilirubin, urobilinogen, glucose, ketones


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Other examinations:
sperm morphology was assessed.
Statistics:
Body weight data were analyzed for normality and homogeneity of variances, and then by analysis of variance and Duncan’s Multiple Range Test. Differences between groups were considered statistically significant when the probability of the differences being due to chance was less than 5%.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
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:
no effects observed
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
Most clinical signs observed were due to local effects from the collars (lesions around the neck, reddish nasal discharge, chromodacryorrhea) or the ocular bleedings (corneal opacities). No signs of systemic toxicity were observed.

Two animals (a male from low dose group, and one female from high dose group) died during blood collections in week 5, presumably from anesthetic overdoses. No gross abnormalities were found in either animal at necropsy

BODY WEIGHT AND WEIGHT GAIN
Both groups of treated males gained weight more slowly than the control group during the study. The reduced rate of weight gain in the high-dose group began soon after dosing started, and persisted throughout the study. Differences between the mean weights of the high-dose and control groups were statistically significant at each weighing period from Day 37 to the end of the study, except for Day 50. However, at no time was the mean weight of the high-dose groups ever less than 90% of that of the controls. In the low-dose group, the absolute and percent differences from control were smaller than in the high-dose group, and no statistically significant differences occurred.

No treatment related differences in weight gain occurred in the females


HAEMATOLOGY
No changes were seen.

CLINICAL CHEMISTRY


URINALYSIS
No differences in urinalysis.


ORGAN WEIGHTS
No statistical differences


GROSS PATHOLOGY
No statistical differences

OTHER FINDINGS
No differences in the percentages of abnormal sperm heads or abnormal general sperm morphology were observed.

Effect levels

Dose descriptor:
NOAEL
Remarks:
limit dose
Effect level:
>= 2 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Repeated dermal applications of Stock 509 at 800mg/kg/day and 2000mg/kg/day resulted in no significant treatment related effects. The NOAEL was determined to be greater than or equal to 2000mg/kg/day.
Executive summary:

Stock 509 was administered dermally to rats (15 males and 15 females per group) at concentrations of 0, 800, and 2000 mg/kg, five days per week for 13 weeks to evaluate the subchronic toxicity. Only a very slight effect on the skin at the site of application was seen during the study.  No effects on hematology, serum chemistry, unrinalysis, organ weights or histopathology were observed.  A statistically significant decrease in body weight compared to controls was seen in males treated with 2000mg/kg/day from Day 37 until the end of the study (with one exception).  However the mean weights were within 10% of those of controls, and no effect was observed in females at this dose.  Based on these findings, the NOAEL was determined to be greater than or equal to 2000mg/kg/day.