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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 based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
09 Jul - 10 Oct 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (no data on test substance purity; only 2 dose groups, open application, limited parameters examined)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
(no data on test substance purity, only 2 dose groups, open application, limited parameters examined)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): [trade name]
- Substance type: polyol ester
- Physical state/appearance: light yellow liquid
- Analytical purity: no data
- Relative density: 1.00

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Lakeview, NJ, USA
- Age at study initiation: approx. 7 weeks
- Housing: individually in hanging, stainless steel cages with wire bottoms and fronts
- Diet: Purina Certified Lab Chow ' 5002 in pellet form; ad libitum
- Water: tap water; ad libitum
- Acclimation period: at least 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 40-60
- 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: no data
- Type of wrap if used: no wrap used, open
- Time intervals for shavings or clipplings: 24 h before the first treatment; at least weekly afterwards
- Application site: back (shaved)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing; wiping off with a gauze pads every saturday (applications on working days)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): undiluted
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (collars), removal during the weekend
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week (65 exposures), 24 hours/day, removal of substance on saturdays (once a week)
Doses / concentrations
Remarks:
Doses / Concentrations:
800 and 2000 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10
(5 additional animals of the control and the high dose group were included for dermal bioavailability experiments only.)
Control animals:
yes, concurrent no treatment
Details on study design:
The test substance was dispensed by volume from a syringe and left uncovered on the shaved skin. The rats were fitted with cardboard Elizabethan collars to minimze ingestion of the test material.
The controls were treated in the same manner except that no material was applied to their skin.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: appearance, behaviour, secretory function and discharges

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly
- Parameters evaluated: erythema and edema according to Draize, chronic deterioration: flaking, thickening, stiffening, cracking and slouthing

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

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

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: red blood cells, white blood cells, and platelets

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: glucose, urea nitrogen, alanine aminotransferase, albumin, phosphorus; only females: lactate dehydrogenase, aspartate aminotransferase

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 5 and 13
- Metabolism cages used for collection of urine: No
- Parameters examined: pH, bilirubin, specific gravity, urobilinogen, blood, protein, glucose, ketones

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: sperm morphology: at termination
- Parameters: percentage normal sperm, abnormal heads, headless, tailless, and curled tail
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; organ weights: kidneys, liver; only males: brain, spleen; only females: thyroids
HISTOPATHOLOGY: Yes (no further information available)
Statistics:
The level of statistical significance was P < 0.05.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
slight erythemal and flaking; slight epidermal hyperplasia and chronic inflammation (both treatment groups)
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced body weight gain in males (800 mg/kg: 7% and 2000 mg/kg: 10%)
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
No treatment-related effects were observed.

BODY WEIGHT AND WEIGHT GAIN
Treated males gained slightly less weight than the controls (800 mg/kg bw: 7%, 2000 mg/kg bw: 10%). As the difference is low, the decrease in body weight was not interpreted as a sign for systemic toxicity.

HAEMATOLOGY
No adverse effects on any haematologic parameters measured were observed.

CLINICAL CHEMISTRY
A few of the serum paramters of the high-dose animals were statistically different from the controls, but the differences were small, not consistent between males and females, and did not present any pattern suggestive of effects on any specific organ (no corresponding histological findings). Thus, the effects were considered not to be of toxicological relevance.
- high-dose males (compared to controls): glucose: -14%, albumin: -3%, and phoshorus: +16%
- high-dose females (compared to controls): lactate dehydrogenase: +45% (low-dose: +22%), and aspartate aminotransferase: +22%

URINALYSIS
No additional data given on Urinalysis in study report.

ORGAN WEIGHTS
Increased thyroid weight in the low-dose (+ 25%) females and decreased spleen weight (- 10%) in the low-dose males were not considered to be toxicologically relevant, as these effects were not observed in the high-dose groups.

GROSS PATHOLOGY
No abnormalities were detected.

HISTOPATHOLOGY:
No abnormalities were detected.

OTHER FINDINGS
- Sperm morphology: No effects on sperm morphology were detected.
- Local effects: Slight erythema and flaking of the skin were observed in the treated groups during the dosing phase. Microscopic examination of the skin indicated trace to slight epidermal hyperplasia and chronic inflammation of the superficial dermis.

SKIN PENETRATION
Skin penetration values of 2 - 6% were obtained.
The results of the in vivo skin penetration study indicate that the 13-week treatment with the test substance does not increase the skin penetration of the test substance (only the value for females was statistically different from the penetration in untreated animals). The skin penetration of untreated rats was less than 2% and the mean value for treated rats was approx. 6%. The recovery of radioactivity was measuered in the urine and faeces as well as the remaining radioactivity in tissue samples.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion