Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
testing was conducted between the 16th September and 30th September 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Dermal repeated dose range finding study for 14 days using treatment similar to guideline study and conducted in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
The study was conducted for 14 days and only gross repeated dose parameters were evaluated
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
Identity: Salicynalva
Appearance: Clear yellow liquid
Storage condition of test substance: Ambient temperature (21°C) in the dark.
Storage conditions: Ambient temperature (21°C)
Date received: 28 September 1994

Test animals

Species:
rat
Strain:
other: albino
Sex:
male/female

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 hours a day for 14 days.
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
140 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
400 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 males and 5 females were tested at each dose group
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Males at 1000 mg/kg bw showed slight centrilobular hepatocyte hypertrophy at 1000 mg/kg bw
Details on results:
The mean concentrations of Salicynalva in test formulations analysed during the study were within 6 % of nominal concentrations confirming the accuracy of formulation.

Mortality:
One control male (no.1) was sacrificed on Day 12 due to eye damage which occurred accidentally during the blood sample procedure on Day 7. There were no other unscheduled deaths during the study.

Clinical signs:
One male receiving 50 mg/kg/day, one female receiving 140 mg/kg/day, one male and two females receiving 400 mg/kg/day and one female receiving 1000 mg/kg/day all showed slight to barely perceptible erythema, the female receiving 1000 mg/kg/day also showing well-defined erythema for a short period. The earliest time of occurrence was Day 4, for the affected females at 400 and 1000 mg/kg/day, but no animal showed this sign after Day 10.

Exfoliation was seen for females only. One control female, one female receiving 140 mg/kg/day, three females receiving 400 mg/kg/day and one female receiving 1000 mg/kg/day were affected generally between Days 4 and Day 10.

Scabbing was seen in one male at 0, 140 and 1000 mg/kg/day, one female at 0, 140 and 1000 mg/kg/day and three females at 400 mg/kg/day.

In the absence of any dose-related trend in incidence or degree of effect of erythema, exfoliation and scabbing, relationship of these signs to administration of Salicynalva is not likely.

Bodyweight:
No statistically significant differences were notified

Food Consumption:
Food consumption for treated groups was comparable to controls.

Organ Weights:
There were no differences in the liver and prostate between treated and control rats

Macroscopic Pathology:
The macroscopic examinations performed revealed no changes attributable to treatment with Salicynalva.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The dermal route of administration was well tolerated at dosages up to 1000 mg/kg/day, with no treatment-related effects at the site of administration. There were no treatment-related effects on bodyweight gain, food consumption, liver and prostate weights or macroscopic findings at any dosage. Males receiving 1000 mg/kg/day showed slight centrilobular hepatocyte hypertrophy although a similar effect was not seen in females and no associated increase in liver weight was noted in males. The No Observed Adverse Effect Level (NOAEL) was 1000 mg/kg/day for males and females.
Executive summary:

This 14 -day dietary range finding study was perfomed to assess the systemic toxic potential of Salicynalva, to the rat, in order to assess the suitability of the dermal route of administration. The protocol of the OECD TG 410 was used. The test substance was administered dermally (occlusive dressing over the treatment area for 6 hours per day) to groups of five male and five female rats at 50, 140, 400 or 1000 mg/kg/day (at a dosage volume of 2 ml/kg/day) in corn oil. A further group of five male and five female rats received the vehicle (corn oil) alone, at the same dose volume as control. The study started initially for a period of seven days, though this was extended to fourteen days by the Sponsor, since the initial seven days of treatment did not reveal any clear adverse effects of treatment. All animals were killed on Day 15. Clinical signs including examination of the dermal test site of each animal, bodyweight, food consumption, liver and prostate weights, macroscopic and microscopic examinations were recorded for the study. The dermal route of administration was well tolerated at dosages up to 1000 mg/kg/day, with no treatment-related effects at the site of administration. There were no treatment-related effects on bodyweight gain, food consumption, liver and prostate weights or macroscopic findings at any dosage. Males receiving 1000 mg/kg/day showed slight centrilobular hepatocyte hypertrophy although a similar effect was not seen in females and no associated increase in liver weight was noted in males. The No Observed Adverse Effect Level (NOAEL) was 1000 mg/kg/day for males and females.