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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
Study period:
30 October 1978 - 21 November 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was not conducted under GLP, but was performed according to methods similar to OECD guideline 410.
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
10 animals/sex/dose group
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sancticizer-154
- Physical state: liquid
- Lot/batch No.: confidential
- Storage condition of test material: room temperature

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Marland Breeding Farms, Inc., Hewitt, New Jersey 07421, USA
- Age at study initiation: no data
- Weight at study initiation: Males: 3.08 - 2.08 kg - Mean: 2.41 kg; Females: 2.93 - 2.13 kg – Mean: 2.42 kg
- Fasting period before study: no data
- Housing: Individually in elevated stainless steel cages
- Diet: Fisher Rabbit pellets, ad libitum. Fresh food presented as required
- Water: ad libitum, by automated water system (Elizabethtown Water Company)
- Acclimation period: 24 days

ENVIRONMENTAL CONDITIONS
Temperature and humidity monitored twice daily
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: An area equal to approx. 25% of the total body surface area was carefully and closely clipped on the dorsal surface of all animals, approximately 10 cm. wide and extending from the suprascapula area to the hind quarters.
- % coverage: clipping area 25%
- Type of wrap if used: a paper towel folded to the approx. dimensions of 6.5 x 5.0 cm was held over the left suprascapula dorsal surface
- Time intervals for shavings or clipplings: all rabbits were reclipped on Sunday and Thursday throughout the study. The skin of the first 5 rabbits of each sex in each group was abraded twice weekly on Sunday and Thursday.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the backs of all rabbits were gently wiped with paper towels to remove excessive test material.
- Time after start of exposure: approx. 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10, 100, and 1000 mg/kg
- Constant volume or concentration used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (collar)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours, 5 days/week, for 23 days
Frequency of treatment:
daily (5 days/week)
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 100, and 1000 mg/kg
Basis:
analytical per unit body weight
No. of animals per sex per dose:
10
Control animals:
other: yes: concurrent distilled water
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): Rabbits were randomly distributed into three dose groups and 1 control group.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations: mortality and gross signs of toxicologic or pharmacologic effects

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes, erythema, edema, atonia, desquamation, fissuring, eschar formation, and exfoliation.
- Time schedule for examinations: Graded 6 hours after the first application of test material and immediately prior to each application thereafter; daily, seven days per week

BODY WEIGHT: Yes
- Time schedule for examinations: Twice pretest, weekly during treatment, and terminally (after fasting).

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: Pretest and Termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: All
- Parameters checked: haemoglobin, hematocrit, erythrocytes, leukocyte count (total and differential), and erythrocyte morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Pretest and Termination
- Animals fasted: Yes
- How many animals: All
- Parameters checked; serum glutamic pyruvic transaminase, alkaline phosphatase, blood urea nitrogen, fasting glucose, total protein, albumin, calcium, inorganic phosphorus

URINALYSIS: No

NEUROTOXICITY: Yes
Cholinesterase activity was measured: RBC and Plasma Cholinesterase: weeks -1 and 3
Brain Cholinesterase: week 3
Sacrifice and pathology:
GROSS PATHOLOGY: Complete gross postmortem examinations were performed on all survivors at 3 weeks as well as on all animals either dying spontaneously or killed in extremis during the course of the study.

ORGAN WEIGHTS: Adrenals, ovaries/testes, spleen, thyroid/parathyroids, kidneys, liver (Organs were not weighed from animals dying spontaneously or killed in extremis).

HISTOPATHOLOGY: Adrenal (2), bone marrow (R Costochondral Junction), brain (Cerebrum, Cerebellum and Pons), eye (2), gall bladder, heart, intestine, duodenum, ileum, jejunum, cecum, colon, kidney (2), liver, lung, lymph node (Mesenteric and Cervical), Muscle (R Biceps Femoris), Nerve (R Sciatic), ovaries/testes, pancreas, pituitary, prostate/uterus. Skin (treated (R Suprascapular), and untreated (L Suprascapular)), spinal cord (Cervical), spleen, stomach, thymus, thyroid, parathyroids, trachea, urinary bladder, any unusual lesions or tissue masses.
Microscopic examinations were performed for all rabbits in the control and high-dose groups.
Other examinations:
Not relevant
Statistics:
Body weight, hematology and clinical chemistry parameters, organ weights and organ/body weight ratios were analyzed. Mean values of the treated groups were compared to their respective control at each time interval (Groups II, III and IV to Group I, distilled water control).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
effects observed, treatment-related
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: One Santicizer-154 control male died spontaneously during the course of the study. One Santicizer-154 high-dose male was killed in extremis on Day 4 of test substance administration. From the nature of the gross postmortem findings and the group distribution of these deaths, there did not appear to be a treatment related effect in the deaths of these animals.

DERMAL IRRITATION: Edema was exhibited by some of the Santicizer-154 high-dose males during Weeks 2 and 3 and some of the Santicizer-154 low-, mid- and high-dose females during Week 3. Atonia was observed in some of the Santicizer-154 low-dose males at Week 3 and some of the Santicizer-154 mid- and high-dose males and females during Weeks 2 and 3. Rabbits treated with Santicizer-154 also displayed a higher incidence of desquamation, (mid- and high-dose males, low-, mid- and high-dose females during Week 2; low-, mid- and high-dose males and females during Week 3) and Fissuring (high-dose males and females, Week 2; high-dose males and mid- and high-dose females during Week 3), than did control animals.

CLINICAL CHEMISTRY: The mean terminal blood urea nitrogen values of the Santicizer-154 high-dose males and females were significantly greater (approximately 40%) than control values. Mean plasma cholinesterase values of the Santicizer-154 low- dose males and females were comparable to control values at the termination of the study. All other mean terminal cholinesterase values of the Santicizer-l54 low , mid- and high-dose males and females were depressed compared to their respective control values, significant in mid and high dose. This depression, slight to marked, occurred in a dose-related pattern and is considered indicative of a treatment related effect.

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 10 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Not relevant

Applicant's summary and conclusion

Conclusions:
Based on the evident dose response depression of terminal cholinesterase in the Santicizer-l54 treated males and females, which was significant in the mid and high dose, a NOAEL of 10 mg/kg bw/day was derived.
Executive summary:

A three week repeated dose dermal toxicity study, comparable to OECD Guideline 410, was performed to determine the toxicological potential of Santicizer-154. New Zealand White rabbits were randomly distributed into four groups of 10 animals/sex/group. The test material Santicizer-154, at dose levels of 10, 100 and 1000 mg/kg/day, was applied to the clipped dorsal surface of New Zealand White rabbits daily, 5 days per week for three weeks. Group I (distilled water, 1 ml/kg) served as the control group for the Santicizer-154 low-, mid- and high-dose groups (Groups II, III and IV). The skin of the first 5 rabbits of each sex in each group was abraded twice weekly. Skin reponses (erythema, edema, atonia, desquamation, fissuring, eschar formation, and exfoliation) were graded daily, seven days per week. Hematology and clinical chemistry studies were performed on all animals pretest and at the termination of the study. Cholinesterase determinations were also performed on all rabbits pretest (RBC and plasma) and at termination (RBC, plasma and brain). Complete gross postmortem examinations were performed on all animals dying spontaneously, killed in extremis and killed at the termination of the study. Microscopic examinations of selected tissues were performed on all rabbits in the Santicizer-l54 control and high-dose groups. One rabbit died spontaneously and one was killed in extremis during the course of the study. There did not appear to be a treatment related effect in the deaths of these animals. A higher incidence of edema, atonia, desquamation and fissuring was observed in the Santicizer-154 treated males and females than was observed in their respective controls. Mean terminal blood urea nitrogen values of the Santicizer-154 high-dose males and females were significantly greater than control values. A dose response depression of RBC and brain cholinesterase was evident in the Santicizer-l54 treated males and females, which was significant in the mid and high dose. All other parameters evaluated (daily physical observations, body weights, hematology and clinical chemistry data, organ weights and organ/body weight ratios) were considered either comparable to control values or unremarkable. Gross postmortem examinations of all animals in all groups did not reveal any gross changes attributable to the administration of Santicizer-154. There were no apparent microscopic changes in the tissues evaluated which were considered to be related to treatment with high-dose Santicizer-154.

Based on the evident dose response depression of terminal cholinesterase in the Santicizer-l54 treated males and females, which was significant in the mid and high dose, a NOAEL of 10 mg/kg bw/day was derived.