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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:
7th June 1989 to 29th June 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
no
Principles of method if other than guideline:
During the study, one animal was overdosed by 12.5 % and another underdosed by 11.1 % for one day of the study due to error in assigning animals to treatment cages.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Propargite
EC Number:
219-006-1
EC Name:
Propargite
Cas Number:
2312-35-8
Molecular formula:
C19H26O4S
IUPAC Name:
propargite
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report): Omite® Technical

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Animals, Inc., Denver, Pennsylvania, USA
- Age at study initiation: approximately 3 months old
- Fasting period before study: yes
- Housing: individually in stainless steel cages
- Diet: Certified Rabbit Chow® #5322, Ralston Purina ad libitum
- Water: ad libitum
- Acclimation period: 38 days

ENVIRONMENTAL CONDITIONS
- Temperature: 69 ± 2.1 ºC
- Humidity: 60 ± 5.5 %
- Photoperiod: 12 hours light/12 hours dark

Administration / exposure

Type of coverage:
not specified
Vehicle:
not specified
Details on exposure:
TEST SITE
- Area of exposure: 2.1 mg/cm2 (0.1 mg/kg); 4.5 mg/cm2 (1.0 mg/kg); 12.5 mg/cm2 (10 mg/kg); 28 mg/cm2 (100 mg/kg)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours
Frequency of treatment:
Once daily; 5 days/week for 3 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
0.1 other: mg/kg nominal per unit area
Dose / conc.:
1 other: mg/kg nominal per unit area
Dose / conc.:
10 other: mg/kg nominal per unit area
Dose / conc.:
100 other: mg/kg nominal per unit area
No. of animals per sex per dose:
Five
Control animals:
no

Examinations

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

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

BODY WEIGHT: Yes
- Time schedule for examinations: pretest, weekly and at terminal necropsy

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest and on day 21
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked: erythrocyte count, haematocrit, haemoglobin, mean corpuscular volume/haemoglobin/haemoglobin concentration, total and differential leukocyte count, platelet count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pretest and on day 21
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked: aspartate aminotransferase, alanine aminotransferase, glucose, urea nitrogen, total bilirubin, total cholesterol, albumin, globulin, total protein, creatinine, sodium potassium, chloride, calcium, inorganic phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Parameters checked: absolute and relative weights of liver, kidneys and testes.

HISTOPATHOLOGY: Yes
- Parameters checked: treated skin (3 sections), untreated skin (3 sections), liver, kidneys, all gross lesions.
Statistics:
Body weight, food consumption, organ weight and clinical pathology parameters analysed using analysis of variance and Bartlett's test. Treatment and control groups compared by sex using appropriate t-statistic (equal or unequal variance) and Dunnett's multiple comparison tables. Nonparametric procedures by rank transformation.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment related signs of toxicity.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Dermal irritation was seen in all treated animals, with erythema, oedema, eschar, exfoliation, atonia, desquamation, fissuring, blanching and/or coriaceousness observed at all dose levels, the severity depending on the dose.
Mortality:
no mortality observed
Description (incidence):
There were no mortalities during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weight of all treated male groups and the high dose female group was slightly reduced compared to the control, while the mean body weight of the remaining females was slightly higher than the controls. However, none of these differences were statistically significant and weight gain was normal in all animals over the course of the study.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption was slightly reduced at some doses/time points, with statistical significance in the 0.1, 1.0 and 10 mg/kg female groups at week 2, in the 100 mg/kg females at week 1 and at test termination in the 0.1 and 1.0 mg/kg males (see Table 1).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological data indicate that there was a statistically significant increase in segmented neutrophil values in males dosed with 100 mg/kg bw. There were no other treatment related haematological effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no treatment related biochemical effects.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment related organ weight changes were observed at any dose level.
Gross pathological findings:
no effects observed
Description (incidence and severity):
On necropsy, aside from skin damage associated with dermal irritation, there were no treatment related systemic macroscopic or microscopic observations.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Test material related microscopic pathology changes were observed on the treated skin of animals for all treatment groups. These changes included acanthosis, hyperkeratosis, dermal inflammation, necrosis (epidermis and dermis) and abscess (epidermal/dermal). While hyperkeratosis and acanthosis showed a dose-related pattern, the incidence and severity of dermal inflammation was similar for all treated groups. No other test material related microscopic findings were observed.
Histopathological findings: neoplastic:
not specified

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
> 100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Other than dermal irritation, the only systemic treatment related effect was an increase in segmented neutrophils in the 100 mg/kg bw males. Since this is an isolated finding, it is considered to have no biological significance.

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1: Summary of food consumption values (g/animal/day)

 Week  0 mg/kg  0.1 mg/kg  1.0 mg/kg  10 mg/kg  100 mg/kg
 Males               
 1  179.2 ± 23.59 147.1 ± 8.38   160.2 ± 22.04 151.1 ± 19.75   157.5 ± 24.79
 2  173.4 ± 21.75  145.6 ± 13.07  155.8 ± 22.39 153.2 ± 22.53  155.2 ± 16.99
 3  172.3 ± 19.80  143.6 ± 18.59  145.3 ± 18.49 150.2 ± 18.77  154.0 ± 22.83 
 Females               
 1  187.0 ± 18.88  177.1 ± 15.56 175.7 ± 9.58   165.9 ± 3.92  157.3* ± 17.97
 2  188.8 ± 8.51  172.9* ± 3.94 167.6** ± 8.11   173.1* ± 5.33 178.8 ± 28.29 
 3 176.9 ± 24.18   187.6 ± 12.75 177.3 ± 9.56   182.3 ± 6.15 165.1 ± 31.06 

*significantly different from control (p<0.05)

**significantly different from control (p<0.01)

Applicant's summary and conclusion

Conclusions:
Under the conditions of the test, the test material was irritating to skin (as expected). However, the only systemic treatment related effect was an increase in segmented neutrophils in the 100 mg/kg bw males. Since this is an isolated finding, it is considered to have no biological significance. Therefore, the NOEL in this study is >100 mg/kg bw. Since the dose was applied daily, 5 days per week, for a 3 week period, this is equivalent to 100 mg/kg body weight/day.
Executive summary:

In a GLP compliant repeated dose toxicity (dermal) study conducted in accordance with standardised guideline EPA OPP 82-2, the repeat dose dermal toxicity of the test material was determined over 21 days. Under the conditions of the test, the NOEL of the substance was determined to be >100 mg/kg bw.