3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione;famoxadone (ISO)

Repeated dose toxicity: dermal

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:

1998

Report date:

1998

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: MAFF Japan 59 NohSan No, 4200 Testing Guidelines for Toxicology Studies (1985)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione

EC Number:

603-520-1

Cas Number:

131807-57-3

Molecular formula:

C22H18N2O4

IUPAC Name:

5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione

Test material form:

solid

Specific details on test material used for the study:

Substance ID: Famoxadone Technical (DPX-JE874)
Lot #: JE874-221
Purity: 97.28%

Test animals

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Details on species / strain selection:

Rats are considered an acceptable species suited for conducting dermal absorption studies. Their use is designated as appropriate according to the testing guidelines for toxicological evaluation of pesticides by the dermal route of exposure. The Crl:CD®(SD)IGS BR rat was selected because extensive background information is available from the literature, the supplier, and previous studies conducted at the test facility. This strain is also considered suitable relative to hardiness and low incidence of spontaneous disease.

Sex:

male/female

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

water

Remarks:

deionized

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

approximately 6 hr

Frequency of treatment:

daily for 28 consecutive days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

250 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

There were no test substance-related clinical observations in either males or females at any dosage during the clinical signs inventory conducted at the time of body weight determination or prior to the daily treatment. In addition, there were no test substance-related clinical signs of toxicity observed following the daily applications in males or females at any dosage. There was an increase, albeit not significant, in the incidence of desquamation and neck sores in the 500 and 1000 mg/kg/day male dose groups, and epidermal scaling in the 250, 500, and 1000 mg/kg/day female dose groups. The desquamation observed in males was not dose-responsive in nature, occurred with similar frequency among all female dose groups, and therefore was not considered to be compound related. The neck sores in the 500 and 1000 mg/kg/day male dose groups were attributed to the use of plastic collars and were not considered compound related. The epidermal scaling in females was not dose-responsive in nature, did not occur in the males, and therefore was not considered biologically significant. A variety of other dermal changes was noted following both application of either the vehicle control or the test substance including erythema, scratches, scabs, and sores; however, these occurred with similar frequency among all groups.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

There were no adverse, test substance-related effects on body weight or body weight gain at any dosage in either males or females. Body weight gain of males in the 250 mg/kg/day group was statistically significantly lower for test days 1-4. The lower weight gain value for the 250 mg/kg/day males was not consistent with a dose-response relationship and therefore, is not considered to be compound related. For test days 21-24, a loss in mean body weight for all of the male dose groups was observed. The reason(s) for these decreases is not known, but is not considered to be compound related because all dose groups, including the control, were affected.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significant, but very slight, decreases in red blood cell count (RBC) and hemoglobin (Hb) were present in female rats in the 500 and 1000 mg/kg/day groups. These changes may indicate compound related increased red blood cell turnover (hemolysis), as mild hemolysis was produced in previous studies with the test substance. However, the decreases in RBC and Hb were very small (6-7% decreases relative to controls) and were not of sufficient magnitude to elicit a bone marrow regenerative response (based on the absence of a reticulocytosis in the affected groups). In addition, the decreases were not associated with statistically significant changes in hematocrit (Ht) or with histological evidence of increased red cell turnover. Based on these considerations, the slight changes in RBC and Hb in 500 and 1000 mg/kg/day females, though possibly compound related, were considered not to be biologically adverse.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant increases in alkaline phosphatase (ALP), alanine aminotransferase (ALT), and sorbitol dehydrogenase (SDH) were present in the 500 and 1000 mg/kg/day male groups. The biological significance of these liver enzyme changes is equivocal. In all cases, increases in enzyme activities were small (less than two-fold relative to controls), the increases were not associated with definitive microscopic evidence of hepatotoxicity, and no effects on liver enzymes occurred in female rats.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Liver weight parameters were increased in all treated male and female groups. Means for liver weight relative to body weight in male rats were increased 10%, 12%, and 21% relative to controls for the 250, 500, and 1000 mg/kg/day groups, respectively; in females, increases were11%, 14%, and 9%, respectively. Liver weight increases were statistically significant for all parameters in 1000 mg/kg/day males and for the liver:body weight ratio in 500 mg/kg/day males. In the 500 and 1000 mg/kg/day males and females, these liver weight increases were associated with minimal hepatocellular hypertrophy microscopically.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no test substance-related gross observations. Gross observations occurred in low incidences across groups and were typical of spontaneous lesions seen in rats of this strain and age.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Compound-related microscopic changes were limited to the livers of male and female rats in the 500 and 1000 mg/kg groups. The principal change was minimal hypertrophy of centrilobular hepatocytes, which was consistent with the increase in liver weights noted above. In the 500 and 1000 mg/kg/day male groups, hypertrophy was associated with low incidences of slight apoptosis in the liver. Apoptosis has been reported to occur following administration of compounds that induce liver enzymes, and may occur as a controlled event to eliminate excess cells rather than as a result of primary cytotoxicity. Such is likely the case for the apoptosis observed in conjunction with hypertrophy in the present study, as no overt microscopic evidence of hepatotoxicity, such as zonal or locally extensive necrosis, was present. At any rate, the low incidence and subtle nature of the apoptosis observed in the affected groups likely does not account for the changes in liver enzymes noted in these groups.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical biochemistry

histopathology: non-neoplastic

2

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

haematology

histopathology: non-neoplastic

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

Dermal 28 day NOAEL (Male rat): 250 mg/kg/day
Dermal 28 day NOAEL (Female rat): 1000 mg/kg/day (highest dose tested)

Executive summary:

The objective of this study was to determine the potential toxicity from repeated dermal exposure to the test substance according to the guidelines OECD 410 and EPA 82-2. The test substance was applied to the shaved, intact skin of male and female Crl:CD®(SD)IGS BR rats for 28 consecutive days. Three groups of 10 male and 10 female rats were treated dermally with 250, 500, or 1000 mg/kg/day. A control group of 10 male and 10 female rats was similarly treated with deionized water. Body weights were measured at 3-4 day intervals, and clinical signs were recorded at least once daily. Food consumption was determined weekly. Blood samples were collected prior to sacrifice on test day 29. All rats underwent necropsy for gross and microscopic pathological evaluation.

There were no test substance-related effects on body weight, food consumption, clinical signs of toxicity, or mortality at any dosage in either males or females. There were no test substance related effects on hematology in males at any dosage. Females in the 500 and 1000 mg/kg/day groups had slight decreases in red blood cell count and hemoglobin. In the absence of other hematologic effects, these very small changes were not considered to be biologically significant. There were no test substance-related effects on clinical chemistry parameters in females at any dosage. Statistically significant increases in alkaline phosphatase, alanine aminotransferase, and sorbitol dehydrogenase were present in the 500 and 1000 mg/kg/day male groups. These increases in the aforementioned enzymes were considered to be indicative of minimal hepatocellular toxicity.

Liver weight parameters were increased in all treated male and female groups. Males in the 1000 mg/kg/day group had statistically significant increases in absolute and relative liver weights (relative to body weight and brain weight), while males in the 500 mg/kg/day group had statistically significant increases in relative liver weights (relative to body weight). In the 500 and 1000 mg/kg/day males and females, the liver weight increases were associated with minimal hepatocellular hypertrophy microscopically. Additionally, in the 500 and 1000 mg/kg/day male groups, hypertrophy was associated with low incidences of slight apoptosis in the liver. These changes were considered adaptive, physiologic responses of the liver to administration of the test substance.

The NOAEL for this study was 250 mg/kg/day in males based on the slight increases in liver enzymes suggestive of minimal hepatotoxicity. The NOAEL in females was 1000 mg/kg/day, the highest dose tested.