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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Chlorpyrifos
EC Number:
220-864-4
EC Name:
Chlorpyrifos
Cas Number:
2921-88-2
Molecular formula:
C9H11Cl3NO3PS
IUPAC Name:
O,O-diethyl O-3,5,6-trichloropyridin-2-yl phosphorothioate
Test material form:
solid
Specific details on test material used for the study:
Chlorpyrifos (DURSBAN R)
Lot AGR 219646
Purity: 99.98%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
female

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
21 days
Frequency of treatment:
6 hours/day
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
0.1 mg/kg bw/day (nominal)
Dose / conc.:
0.5 mg/kg bw/day (nominal)
Dose / conc.:
1 mg/kg bw/day (nominal)
Dose / conc.:
5 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
Clinical signs, Functional Observational Battery, Cholinesterase (CHE) activity in plasma, red blood cell (RBC), and brain homogenate.

Hematology (hematocrit (HCT), hemoglobin concentration (HGB), erythocyte count (RBC), total leukocyte count (WBC), and platelet count (PLAT). Differential leukocyte counts were obtained from stained blood smears of all rats.

Clinical chemistry: alanine aminotransferase activity (ALT), aspartate aminotransferase activity (AST), urea nitrogen (UN), alkaline phosphatase activity (AP), glucose (GLUC), creatinine activity (CREAT), total protein (TP), albumin (ALB), globulin (GLOB), cholesterol (CHOL), triglycerides (TRIG), calcium (CALC) and phosphorous (PHOS). Sodium (Na), potassium (K) and chloride (Cl) were also measured.

Urinalysis: bil irubin, glucose, ketones, blood, pH, protein, and urobilinogen. In addition, the color and appearance of the urine were noted and determinations of specific gravity and microsediment were conducted (determinations of specific gravity were done on individual samples; microsediment was done on pooled urine samples from each dose group).
Sacrifice and pathology:
All surviving animals were sacrificed the day following the last application; rats were fasted prior to the sacrifice. Each animal was weighed, anesthetized, the trachea was clamped and the animal was decapitated. Weights of adrena1s, brain, liver, kidneys and testes were recorded for each animal at the scheduled sacrifice. All animals were examined for gross pathological alterations by a veterinary pathologist. The necropsy included in situ examination of the eyes by a glass-slide technique with fluorescent illumination. A complete set of tissues was collected from each animal and preserved in neutral, phosphate-buffered 10% formalin. The brain was bissected longitudinally and one half was utilized for cholinesterase determination. The lungs were infused with buffered formalin to their approximate normal inspiratory volume and the nasal cavity was flushed with formalin via the pharyngeal duct to ensure rapid fixation of the tissue. The adrenals, brain, kidneys, liver, peripheral nerve (sciatic), skin (from the treated portion of the back and an untreated site from the dorsal portion of the neck), spinal cord (cervical, thoracic, and lumbar areas), and a few selected tissues which had gross pathologic observations were prepared for histopathological examination by standard methods from all controls and rats treated with 5 mg/kg/day. The tissues were stained with hematoxylin and eosin and examined microscopically by a veterinary pathologist. Although tissues weresimilarly prepared from rats treated with 0.1, 0.5 or 1 mg/kg/day, they were not examined microscopically due to a lack of lesions at the highest dose level.
Statistics:
The statistical analysis outlined below was conducted on parameters measured during the 21-day study; no statistical analysis was conducted on data from the 4-day probe. Descriptive statistics (mean and standard deviation) were calculated for white blood cell differential counts and feed consumption data. Body weights,absolute and relative organ weights, cholinesterase activity, clinical chemistry data, urinary gravity and hematology data (except white blood cell differential counts) were evaluated by Bartlett's test for equality of variances followed by a parametric analysis of variance (ANOVA) and Dunnett's test. Statistical outliers were identified by a sequential outlier test. Only feed consumption outliers were routinely excluded from analysis.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Red-brown exudate (staining) around the eyes was noted for most female rats (including controls) throughout the course of the study; a few male rats (including controls) exhibited this red-brown stain around eyes on days 2 and 21 of the study. No other clinical observations were noted.
Dermal irritation:
no effects observed
Description (incidence and severity):
There were no indications of skin irritation based on dermal scores.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
All groups of rats lost weight (2-4%) during the first week of the study. During the second week, however, all groups recovered the lost weight and continued to gain until study termination. Mean body weights were comparable between dose groups ,throughout the course of the study. The initial weight loss was probably the result of stress from the increased handling associated with the bandaging technique.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Mean feed consumption values were comparable between groups over the study period. Feed consumption was lower for all groups during the first week of the study but increased during the last 2 weeks of the study supporting the theory of initial stress associated with acclimation to the application technique.
Haematological findings:
no effects observed
Description (incidence and severity):
There were no toxicologically significant effects observed in routine hematology parameters.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no toxicologically significant effects observed in routine clinical chemistry parameters.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinalysis values for chlorpyrifos treated groups of animals were comparable to controls.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Results of the functional observational battery indicate no appreciable difference between dose groups and control groups. Observations of decreased muscle tone noted for two female rats of the 5 mg/kg/day dose group and increased fecal staining for one male rat of the 0.5 mg/kg/day group were considered incidental findings since no treatment-related effects were observed in other parameters (specifically cholinesterase data).
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no indications of systemic toxicity based on terminal body weight or organ weight data.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No indication of toxicity was observed during gross pathologic examination of animals treated dermally with chlorpyrifos for 21 days. Likewise, histopathologic examination did not reveal evidence of toxicity. Each of the few observations made at necropsy was present only in a single rat and all observations were considered to be spontaneous changes unrelated ·to treatment. In addition, all histopathologic observations (except for one control female rat) were of a minimal nature and were considered to be typical spontaneous changes normally present in rats of this strain and age. One female control rat had ureteral and urinary bladder calculi with associated hyperplasia and inflammation of the associated tissues and kidney.
Other effects:
no effects observed
Description (incidence and severity):
There were no statistically identified differences in mean values of brain, plasma, or RBC cholinesterase activity for any group treated with chlorpyrifos. While values for 5.0 mg/kg/day male plasma and RBC cholinesterase and female plasma cholinesterase activities were 7, 11 and 17% lower, respectively, than their concurrent control groups, these values were within the range observed for recent historical controls in this laboratory.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no adverse effects noted after 21 day dermal exposure at highest level tested

Applicant's summary and conclusion

Conclusions:
21-day dermal NOEL (female rat) > 5 mg/kg/day
However, application of 10 mg chlorpyrifos/kg body weight/day for 4 days, produced decreases in plasma (45%) and RBC (16%) cholinesterase activity without evidence of toxicity.
Executive summary:

In a probe study, female Fischer 344 rats {4/dose group) were exposed dermally to chlorpyrifos in corn oil solution at dose levels of 0 (corn oil), 1, 10, 100 or 500 mg/kg body weigh~/day, approximately 6 hours/day, for 4 consecutive days. Clinical observations were recorded daily, body weights were recorded on days 1 and 4, plasma and red blood cell (RBC) cholinesterase activities were measured and a gross necropsy conducted on day 5. There were substantial dose-related decreases relative to control in plasma cholinesterase activities (45, 91, or 98%) for animals that received 10, 100 or 500 mg/kg/day, respectively; RBC cholinesterase activities were also decreased in these groups (16, 49 or 75%, respectively). Animals that received 1 mg/kg/day were unaffected by treatment. Decreases in plasma cholinesterase activity as high as 98%

were not asociated with any changes in body weight, in-life clinical signs, or gross

pathologic alterations.

 

Based on the results of the probe study, 5 rats/sex/exposure group were subsequently exposed to a (corn oil), 0.1, 0.5, 1 or 5 mg chlorpyrifos/kg body weight/day in corn oil solution for approximately 6 hours/day, 5 days/week for 3 consecutive weeks. Body weight, feed consumption, in-life clinical observations, clinical laboratory studies, gross pathology and histopathology were evaluated and found to be unaffected. Plasma, RBC and brain cholinesterase activities measured at necropsy were comparable in treated and control groups. In addition, nothing remarkable was observed in a functional observational battery conducted immediately prior to necropsy.

 

Daily dermal application of up to 5 mg chlorpyrifos/kg body weight/day over 21 days (15

applications) was well tolerated by rats with no indication of systemic toxicity and no decrease in cholinesterase activity, the most sensitive indicator of exposure. However, application of 10 mg chlorpyrifos/kg body weight/day for 4 days, produced decreases in plasma (45%) and RBC (16%) cholinesterase activity without evidence of toxicity.