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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 Jan - 7 Feb 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:
adopted 1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,6-dibromo-4-cyanophenyl octanoate
EC Number:
216-885-3
EC Name:
2,6-dibromo-4-cyanophenyl octanoate
Cas Number:
1689-99-2
Molecular formula:
C15H17Br2NO2
IUPAC Name:
2,6-dibromo-4-cyanophenyl octanoate

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products Inc, Michigan, USA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 17 - 18 weeks
- Weight at study initiation: 2.447 - 2.999 kg (males), 2.457 - 2.840 kg (females)
- Fasting period before study: no
- Housing: individually in stainless steel, screen-bottom cages.
- Diet: Certified High Fiber Rabbit Chow5 #5325 (Purina Mills, Inc.), ca 180 g/day and animal
- Water: tap water, ad libitum
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 13 Jan 1992 To: 7 Feb 1992

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Remarks:
the test material was moistened with deionized water (2.0 mL)
Details on exposure:
TEST SITE
- Area of exposure: dorsal trunk
- % coverage: ca. 10%
- Type of wrap if used: gauze patch, fixed with Coban self-adhesive wrap and secured with elastic tape
- Time intervals for shavings or clippings: before initiation of treatment and as needed thereafter

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the test site was wiped with a clean towel moistened with tap water
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): the appropriate amount of the test material was spread on a gauze patch, moistened with 2.0 mL of deionized water and applied to the skin
- For solids, paste formed: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (flexible plastic collar)
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Dose analysis was not done because the test material was applied neat. Homogeneity, stability, and dose confirmation analyses were the responsibility of the Sponsor.
Duration of treatment / exposure:
6 h per treatment
The treatment period was 3 weeks
Frequency of treatment:
daily, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for mortality and moribundity twice daily. Once daily, the animals were removed from the cage and examined for signs of toxicity.

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION: Yes
- Time schedule for examinations: immediately before each application of the test or control material (except on Day 1) and on the day of necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of treatment (Day 1), weekly thereafter, and at necropsy.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

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: prior to study start (Week -2) and before scheduled necropsy (Week 4)
- Anesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all animals of all dose groups
- Parameters checked: Red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, differential blood cell count and blood cell morphology.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pre study and before scheduled necropsy
- Animals fasted: No
- How many animals:
- Parameters checked: Glucose, urea nitrogen, creatinine, total protein, albumin, globulin, total bilirubin, cholesterol, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, calcium, inorganic phosphorous, sodium, potassium and chloride.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
After 3 weeks of treatment, all animals were anesthetized with sodium pentobarbital, weighed, exsanguinated, and necropsied.

GROSS PATHOLOGY: Yes
The necropsy of all animals included macroscopic examination of the external surface of the body; all orifices; the cranial cavity; the external surfaces of the brain and spinal cord; the nasal cavity and paranasal sinuses; and the abdominal, thoracic, and pelvic cavities and viscera. Cut surfaces of the brain and spinal cord were examined when tissues were trimmed.
Organs weighed (paired organs weighed separatly): Adrenals, brain, kidneys, liver, ovaries, and testes.

HISTOPATHOLOGY: Yes
- fixed tissues: adrenals, aorta, brain, cecum, colon, duodenum, epididymides, esophagus, eyes, femur with bone marrow (with articular surface), gall bladder, heart, ileum, jejunum, kidneys, lacrimal gland, lesions, liver, lungs, lymph nodes (mesenteric), mammary gland, muscle (thigh), ovaries, pancreas, pituitary, prostate, rectum, salivary gland (submandibular), sciatic nerve, seminal vesicle, skin (treated and untreated), spinal cord (cervical, thoracic and lumbar regions), spleen, sternum with bone marrow, stomach, testes, thymus, thyroids (and parathyroids), trachea, urinary bladder and uterus.
Tissues were fixed in 10% phosphate-buffered formalin. The eyes were preserved in Zenker's solution.
- embedding media: paraffin wax
- staining: hematoxylin and eosin
- animals investigated: control and high-dose animals
Other examinations:
Bone marrow smears were taken from the sternum at scheduled sacrifice but not examined.
Statistics:
Levene's test was done to test for variance homogeneity. In the case of heterogeneity of variance at p ≤ 0.05, transformations were used to stabilize the variance.
Analysis of variance (ANOVA) was done on the homogeneous or transformed data. If the ANOVA was significant, Dunnett's t-test was used for pairwise comparisons between treated and control groups.
One-way ANOVA was used to analyze initial body weights, cumulative body weight gains, food consumption, clinical chemistry and hematology values (except red blood cell morphology), organ weights, organ-to-body weight percentages, and organ-to-brain weight ratios.
One-way analysis of covariance (ANCOVA) was used to analyze body weights, with initial body weights as the covariate. Although Levene's test for variance homogeneity was done (see above), no transformations were used because covariance adjustment removes extraneous heterogeneity. If the ANCOVA was significant, Dunnett's t-test was used for pairwise comparisons between treated and control groups.
Group comparisons were evaluated at the 5.0% two-tailed probability level.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no test material-related observations during the study period.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
- 0 mg/kg bw/day: slight erythema (2/10 males, 1/10 females)
- 30 mg/kg bw/day: slight erythema (5/10 males, 1/10 females)
- 300 mg/kg bw/day: slight (10/10 males, 8/10 females) to moderate erythema (1/10 males) and slight desquamation (4/10 males, 4/10 females) and edema (1/10 females)
- 1000 mg/kg bw/day: slight (9/10 males, 10/10 females) to moderate erythema (1/10 males, 1/10 females), slight desquamation (8/10 males, 6/10 females), moderate desquamation (1/10 males), slight fissuring (5/10 males, 3/10 females), moderate fissuring (1/10 males), slight edema (1/10 males, 4/10 females), moderate edema (1/10 males, 2/10 females) and slight atonia (1/10 males)

The observations did not increase in severity during treatment.

Summarized results can be found in Attachment 1 in the attached background material.
Mortality:
no mortality observed
Description (incidence):
All animals survived to scheduled sacrifice.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No differences were observed regarding body weight and cumulative body weight gains between control and treatment groups.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There were no statistically significant differences in food consumption for females. A significant increase in food consumption was present in Week 3 for males given 30 mg/kg bw/day; however, this difference was not considered to be toxicologically significant, since there was no dose dependency.

Summarized results can be found in Attachment 2 in the attached background material.
Food efficiency:
not examined
Description (incidence and severity):
not applicable
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
not applicable
Ophthalmological findings:
not examined
Description (incidence and severity):
not applicable
Haematological findings:
no effects observed
Description (incidence and severity):
No toxicologically relevant differences were observed regarding hematology between control and treatment groups.

Statistically significant differences for red blood cell count and urea nitrogen were considered normal biological variation. The difference for red blood cell count was small; the differences for urea nitrogen were small, occurred in intermediate-dose males only, and were similar to findings observed before treatment was initiated.

Summarized results can be found in Attachment 3 in the attached background material.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No differences were observed regarding clinical chemistry between control and treatment groups.
Endocrine findings:
not examined
Description (incidence and severity):
not applicable
Urinalysis findings:
not examined
Description (incidence and severity):
not applicable
Behaviour (functional findings):
not examined
Description (incidence and severity):
not applicable
Immunological findings:
not examined
Description (incidence and severity):
not applicable
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No toxicologically relevant differences were observed regarding organ weights between control and treatment groups.

Females of the 1000 mg/kg bw/day group showed increased absolute and relative kidney weights (< 15%), but these fell within the biological variation. Additionally, there were no macroscopic or microscopic findings in the kidneys of these animals correlating with the higher organ weights.

Summarized results can be found in Attachment 4 in the attached background material.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No toxicologically relevant differences were observed at necropsy between control and treatment groups.
Neuropathological findings:
not examined
Description (incidence and severity):
not applicable
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No toxicologically relevant differences were observed regarding histopathology between control and treatment groups.
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
not applicable
Other effects:
not examined
Description (incidence and severity):
not applicable

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
30 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The dermal irritation at this dose level was comparable to the vehicle control.
Key result
Dose descriptor:
LOAEL
Remarks:
local
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed up to the highest dose level.

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

The codes and abbreviations used in the tables are explained in Attachment 5 in the attached background material. 

Applicant's summary and conclusion

Conclusions:
The study was conducted similar to OECD guideline 410 (1981) and under GLP. Under the conditions of the test, the test substance caused dermal irritation when applied dermally for three weeks to the intact skin of male and female New Zealand White rabbits, starting at 300 mg/kg bw/day. No systemic toxicity was observed. Thus, 30 mg/kg bw/day is regarded as the NOAEL for local skin effects and the NOAEL for systemic effects is 1000 mg/kg bw/day for males and females.