Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992-1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECd and EU guidelines and in compliance with GLP principles. Limited information available to verify the composition of the used test substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
1981
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
1984
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): KY-MA
- Physical state: light yellow solid
- Analytical purity: 99%
- Storage condition of test material: at room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BRL Ltd., Basel, Switzerland
- Age at study initiation: approximately 6 weeks
- Housing: 5 animals of same sex in stainless steel cages with wire mesh floors
- Diet: ad libitum standard pelleted laboratory animal diet (Kliba, Switzerland)
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 06 October 1992 To: 03 november 1992

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
specific gravity 1.036
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Daily immediately prior to dosing. Adjusment was made for specific gravity of the vehicle.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of formulations prepared during week 4 were analysed to check stability, homogeneity and accuracy of preparation.
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 7 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 200, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on a 5-day range finding study with 3 rats/sex/group at dose levels of 50, 200 and 1000 mg/kg bw/day, in which no biological significant differences were observed.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly and on the day preceeding termination, prior to overnight fasting

FOOD CONSUMPTION ): weekly

WATER CONSUMPTION: subjective appraisal only

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: last week of treatment

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to post mortem examination
- Anaesthetic used for blood collection: Yes (ether)
- Parameters checked: according to guideline
- Animals fasted: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to post mortem examination
- Animals fasted: Yes
- Parameters checked: according to guideline

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: organ weights of adrenal glands, heart, kidneys, liver, spleen and testes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, according to guideline
HISTOPATHOLOGY: Yes, according to guideline
Statistics:
Body weight, organ weight and clinical data were analysed by means of univariate one-way analysis of variance to assess the significance of intergroup differences. In case a normal distribution could be assumed, the Dunnett-test (many to one t-test) was applied for the comparison of the treated groups and the control group. the Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
All tests were two-sided and in all cases p<0.5 was accepted as the lowest level of significance.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
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):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY : some animals showed excessive salivation (incidence and severity were within the normal biological range), which is considered to be related to oral treatment by gavage

CLINICAL CHEMISTRY: in treated males sodium levels were decreased and potassium levels were increased (compared to controls). The differences were very small and were considered not to represent toxicity. In addition, in females these changes were not observed.

ORGAN WEIGHTS: Statistically changes in absolute kidney weights at 200 and 1000 mg/kg bw (89%) and in relative kidney weights at 1000 mg/kg bw (92%) in treated females were considered to be due to slightly higher control values and do not represent a sign of toxicity.

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: no treatment-related findings

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral gavage of rats to 0, 50, 200 or 1000 mg/kg bw/day during 28 days did not result in treatment releated toxicity. Based on the absence of adverse effects, the NOAEL in this study is 1000 mg/kg bw/day, the highest dose tested.
Executive summary:

Wistar rats, 5/sex/dose, were administered daily KY-MA by gavage at dose levels of 0, 50, 200 or 1000 mg/kg bw/day for 28 days. The study was performed according to OECD guideline 407 (1981) and EC B7 (1984). No toxicologically relevant effects were observed at all dose levels. Based on the absence of adverse effects, the NOAEL in this study is 1000 mg/kg bw/day, the highest dose tested.