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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:
2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF 12 NohSan No. 8147, Guideline 2-1-10
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Test material:
IR5878
Batch number: G 009/02
Purity: 98.56 ± 0.19 %

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test animals:
Species and Strain: Male and Female Crl:CD (SD)IGS BR rats
Age: 62 to 69 days
Body weight: 321 ÷ 367 g (males) and 213 ÷ 238 g (females)
Housing: one animal per cage of polycarbonate body with a stainless mesh lid.
Feed: free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet from Special Diets Services Ltd., Witham, Essex, England), except overnight before routine blood sampling. Potable water was freely available.

Environmental conditions:
Temperature and humidity measured during the study were 19 ÷ 23°C and 40 ÷ 70%, respectively.
Light: 12 hours of continuous light and 12 hours of continuous dark.

Administration / exposure

Type of coverage:
semiocclusive
Details on exposure:
One group of 10 male and 10 female Crl:CD (SD)IGS BR rats received IR5878 topically, by means of a 6-hour period of semi-occluded application, at a dosage of 1000 mg/kg/day for 4 consecutive weeks.
At the end of the daily treatment period the dressing was carefully removed and the exposed area was cleansed with saline and dabbed- dry with a disposable towel to avoid the oral ingestion during grooming.
The application site remained non-occluded until the next administration.
A similarly constituted control group received the vehicle (purified water) obtained by reverse osmosis, at the same volume-dosage (2 mL/kg bw) and at the same period of occlusion.
Duration of treatment / exposure:
One group of 10 male and 10 female Crl:CD (SD)IGS BR rats received IR5878 topically, by means of a 6-hour period of semi-occluded application, at a dosage of 1000 mg/kg/day for 4 consecutive weeks. At the end of the daily treatment period the dressing was carefully removed and the exposed area was cleansed with saline and dabbed- dry with a disposable towel to avoid the oral ingestion during grooming. The application site remained non-occluded until the next administration. A similarly constituted control group received the vehicle (purified water) obtained by reverse osmosis, at the same volume-dosage (2 mL/kg bw) and at the same period of occlusion.
Frequency of treatment:
One group of 10 male and 10 female Crl:CD (SD)IGS BR rats received IR5878 topically, by means of a 6-hour period of semi-occluded application, at a dosage of 1000 mg/kg/day for 4 consecutive weeks.
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
One group of 10 male and 10 female Crl:CD (SD)IGS BR rats received IR5878 topically, by means of a 6-hour period of semi-occluded application, at a dosage of 1000 mg/kg/day for 4 consecutive weeks
Control animals:
yes
Details on study design:
. A similarly constituted control group received the vehicle (purified water) obtained by reverse osmosis, at the same volume-dosage (2 mL/kg bw) and at the same period of occlusion.

Examinations

Observations and examinations performed and frequency:
Clinical condition and dermal responses particularly in the application site were performed daily; bodyweight and food consumption were recoreded at day 0, weekly during the treatment and before necrospsy; ophthalmic examination was carried out before treatment commenced anf during week 4; haematology, blood chemistry, organ weight, macroscopic and microscopic pathology investigations were carried out according to the guideline indications.

Sacrifice and pathology:
Organ weights
Bodyweight-relative spleen weights were slightly increased for treated males. Females were not affected.


Macroscopic pathology
Macroscopic examination revealed an increased incidence of pale areas on the livers in treated males.

Microscopic pathology
There were no microscopic findings that were attributable to the administration of IR5878.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related systemic signs associated with dosing and no animals died prematurely. Changes at the dermal application site (slight to well-defined erythema, eschar-formation and exfoliation) occurred on occasion in a few treated animals, but it was not clearly attributable to treatment.
Dermal irritation:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related systemic signs associated with dosing and no animals died prematurely. Changes at the dermal application site (slight to well-defined erythema, eschar-formation and exfoliation) occurred on occasion in a few treated animals, but it was not clearly attributable to treatment.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Overall bodyweight gain was slightly increased for treated females, when compared to that of the control. Males were unaffected.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Overall food conversion efficiency was slightly increased for treated females, when compared to that of the controls. This is attributed to the increased bodyweight gain in these animals. Males were unaffected.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Organ weights
Bodyweight-relative spleen weights were slightly increased for treated males. Females were not affected.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Macroscopic examination revealed an increased incidence of pale areas on the livers in treated males.
Histopathological findings: non-neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
body weight and weight gain
dermal irritation
food consumption and compound intake
food efficiency
haematology
mortality
ophthalmological examination
organ weights and organ / body weight ratios

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
A daily 6-hour semi-occluded dermal application of IR5878 to CD rats for 4 weeks was well-tolerated, producing no toxicologically significant change or any clear response at the dermal application site.
The NOAEL (No Observed Adverse Effect Level) in this study was considered to be 1000 mg/kg/day.
Executive summary:

In order to assess the systemic toxic potential of IR5878 following dermal application (semi-occlusive 6 hours/day) to rats for four weeks, one group of 10 male and 10 female Crl:CD (SD)IGS BR rats received IR5878 topically, by means of a 6-hour period of semi-occluded application, at a dosage of 1000 mg/kg/day for 4 consecutive weeks. A similarly constituted control group received the vehicle (purified water) obtained by reverse osmosis, at the same volume-dosage (2 mL/kg bw) and at the same period of occlusion.

IR5878 was well-tolerated, producing no toxicologically significant change or any clear response at the dermal application site. The NOAEL in this study was considered to be 1000 mg/kg/day.