Chlorimuron ethyl

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

The tissue slides will be retained at the Haskell Laboratory for Toxicology and Industrial Medicine (Newark, Delaware) rather than at WIL. This protocol deviation has no effect on the study.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

ethyl 2-({[(4-chloro-6-methoxypyrimidin-2-yl)carbamoyl]amino}sulfonyl)benzoate

EC Number:

618-690-2

Cas Number:

90982-32-4

Molecular formula:

C15H15ClN4O6S

IUPAC Name:

ethyl 2-({[(4-chloro-6-methoxypyrimidin-2-yl)carbamoyl]amino}sulfonyl)benzoate

Test material form:

solid: particulate/powder

Details on test material:

Purity: 96.7%

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals: Source: Covance Research Products, Inc., Denver, Pennsylvania;
Age at study initiation: Approximately 15 weeks old;
Weight at study initiation: 2.3-2.7 kg (males) and 2.3-2.6 kg (females);
Housing: Animals were housed individually in clean, wire-mesh cages suspended above ground corn cob bedding (Bed-O'Cobs®);
Diet: PMI Feeds, Inc. Certified Rabbit LabDiet® 5322;
Water: Reverse osmosis-treated municipal water ad libitum;
Acclimation period: 9 Days;
Environmental conditions: Temperature: 68 ± 4°F and a relative humidity of approximately 30-70%; Photoperiod: 12-hour light/12-hour dark

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

water

Details on exposure:

6 hours a day for 21 consecutive days

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

21 days

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

400 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day

No. of animals per sex per dose:

5 males and 5 females

Control animals:

yes, concurrent vehicle

Positive control:

No

Examinations

Observations and examinations performed and frequency:

The animals were observed for signs of overt toxicity, dermal irritation and effects on body weight, food consumption and clinical pathologic (hematology and serum chemistry) parameters. Complete necropsies were performed on all animals. Selected organs were weighed. A microscopic examination was conducted on selected tissues from all animals in the control and 1000 mg/kg/day groups. In addition, the skin (treated and untreated), liver, lungs and kidneys from all animals in the 100 and 400 mg/kg/day groups were examined microscopically.

Sacrifice and pathology:

A complete necropsy was conducted on all animals. All animals were euthanized by an intravenous injection of sodium pentobarbital followed by exsanguination. The necropsies included, but were not limited to, examination of the external surface, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, and the thoracic, abdominal and pelvic cavities including viscera. The following tissues and organs were collected and placed in 10% neutral buffered formalin, except for eyes with optic nerve in Davidson's solution, and testes with epididymides in Bouin's solution: Adrenals (2), Aorta (thoracic), Bone with marrow (stemebrae), Brain (forebrain, mid-brain, hindbrain) Eyes with optic nerve (2), Gallbladder, Gastrointestinal tract, Esophagus, Stomach, Duodenum, Jejunum, Ileum, Cecum, Colon, Rectum, Heart, Kidneys (2), Liver (sections of two lobes), Lungs [including bronchi, fixed by inflation with fixative (2)], Lymph node (mesenteric and mandibular), Ovaries with oviducts (2), Pancreas, Parathyroids (if present), Peripheral nerve (sciatic), Pituitary, Prostate, Salivary gland [submaxillary (2)], Skeletal muscle (vastus medialis), Skin, dorsal (treated and untreated), Spinal cord (cervical, midthoracic and lumbar), Spleen, Testes with epididymides (2), Thymus, Thyroids, Trachea, Urinary bladder, Uterus with vagina, and All gross lesions.

Statistics:

All analyses were conducted using two-tailed tests for significance levels of 5% and 1% comparing the treatment groups to the vehicle control group by sex. All means are presented with standard deviations (S.D.) and the number of sampling units (N) used to calculate the means. All statistical tests were performed by a Digital® MicroVAX® 3400 computer with appropriate programming. Body weights, body weight changes, food consumption, clinical laboratory values and absolute and relative organ weights were analyzed by a one-way analysis of variance followed by Dunnett's Test. Clinical laboratory values for cell types that occur at a low incidence (i.e., monocytes, eosinophils and basophils) were not subjected to statistical analysis. The statistics for the microscopic evaluation were conducted by Haskell Laboratory, E. I. du Pont de Nemours and Company.

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No test substance-related clinical findings were noted at any dose level. Clinical signs observed in the treated groups (such as soft feces, wet or dried yellow or brown material in the urogenital region, red ocular discharge, etc.) were observed at low incidence, were not present in a dose-related manner and/or were not uncommon findings in laboratory rabbits. Occasional red or yellow material observed around the mouth of some animals was noted in conjunction with the Elizabethan restraint collar found caught in the animal's mouth.

Dermal irritation:

effects observed, non-treatment-related

Description (incidence and severity):

No test substance-related dermal irritation was observed in any treatment groups. Very slight erythema was occasionally noted for 1, 1, 5 and 4 males and 2, 3, 1 and 2 females in the control, 100, 400 and 1000 mg/kg/day groups, respectively. On single occasions, one 400 mg/kg/day group male (no. 22330) exhibited slight erythema and one 1000 mg/kg/day group female (no. 22339) exhibited very slight erythema with very slight edema. This female and one control group female (no. 22357) also had single occurrences of desquamation. The limited occurrence of the dermal findings in all groups, including the control, suggests that the irritation was probably a result of the procedures used to remove the test substance rather than a test substance-related effect.

Mortality:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test substance-related effects on mean body weights or body weight gains were observed. Values in the treated groups were comparable to the control group values throughout the study.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test substance-related effects on food consumption were observed. Food consumption in the treated groups was similar to the control group throughout the study.

Food efficiency:

no effects observed

Description (incidence and severity):

Food efficiency reflected body weight values throughout the study.

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, non-treatment-related

Description (incidence and severity):

Alkaline phosphatase was increased in the 100 mg/kg/day group males. Albumin was decreased in the 400 mg/kg/day group females and aspartate aminotransferase was decreased in the 100 mg/kg/day group females and in the 400 mg/kg/day group males and females. These changes were not considered to be compound related as the differences were not large, were not observed in a dose-related manner and/or treatment period values were similar to pretest values.

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Organ weights (absolute and relative to final body weight) were unaffected by treatment. Mean absolute adrenal gland weights and adrenal gland weights relative to final body weight ratios were increased in the 400 and 1000 mg/kg/day group females at the scheduled necropsy. The differences from the control group were statistically significant at p<0.01 and p<0.05, respectively. However, these increases were not considered to be test substance-related as the differences from control group values did not occur in a dose-related manner and similar changes were not observed in the males.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no test substance-related gross lesions, noted at the macroscopic examination. Findings present in the treated groups (dark red lungs, reddened thyroid glands or trachea, cystic oviducts, accessory spleens) occurred similarly in the control group, were limited to single animals and/or were findings commonly observed in laboratory rabbits.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination revealed no test substance-related changes. Fatty change and regeneration of renal tubules, noted for one female from the 1000 mg/kg day group (no. 22343), were the result of protozoan infection. All other findings were considered incidental (dermal, pulmonary, cardiac or liver inflammation, liver necrosis, thyroid hyperplasia, etc.) or findings commonly noted in laboratory rabbits (accessory spleen, cystic oviducts, testicular atrophy, etc.)

Histopathological findings: neoplastic:

not examined

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a 21-day dermal study in rabbits, there were no test substance effects at the highest dose tested, 1000 mg/kg/day.

Executive summary:

OECD Test Guideline 410 - The test substance was applied seven days per week for three consecutive weeks to the shaved intact dorsal skin of each rabbit for a minimum of 21 applications. The application sites were wrapped for six hours with a gauze dressing, which was covered with impervious plastic wrap and secured with Dennifonn® tape. Each of the three test substance-treated groups consisted of five males and five females. Dosage levels of 100, 400 and 1000 mg/kg/day were selected for the study. A concurrent control group of identical design received 5.0 mL/animal/day of deionized water on a comparable regimen. All animals, wore Elizabethan collars during the six-hour exposure period. Residual test substance was removed from the application sites with Ivory® soap, warm tap water and wet paper towels following the six-hour exposure period. The animals were observed for signs of overt toxicity, dermal irritation and effects on body weight, food consumption and clinical pathologic (hematology and serum chemistry) parameters. Complete necropsies were performed on all animals. Selected organs were weighed. A microscopic examination was conducted on selected tissues from all animals in the control and 1000 mg/kg/day groups. In addition, the skin (treated and untreated), liver, lungs and kidneys from all animals in the 100 and 400 mg/kg/day groups were examined microscopically.

 

There were no test substance-related effects on the clinical condition of the rabbits. Food consumption, food efficiency and body weight data were unaffected by treatment with the test substance. Test substance administration had no effect on hematology and serum chemistry parameters or organ weight data. There were no test substance-related lesions noted at the macroscopic or microscopic examinations. Under the conditions of this study, the no-observed-effect level (NOEL) is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalet to the NOEL as defined by the U.S. EPA and the no-observed-adverse-effect-level (NOAEL) as defined by the European Union. The NOEL for toxicity for this study was 1000 mg/kg/day, the highest dose tested for both male and female rabbits.