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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26th December 1996 - 6 May 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline No. 407 "Repeated Dose 28-day Oral Toxicity Study in Rodents".
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: OFA
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA Credo
- Age at study initiation: 8 weeks
- Weight at study initiation: males 249-334 g; females: 177-232 g
- Fasting period before study: did not
- Housing: wire meshed bottom stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): free assess to tap water
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22+-2C
- Humidity (%):40-70
- Air changes (per hr):10-11
- Photoperiod (hrs dark / hrs light):12/24

IN-LIFE DATES: From: December 26 To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: suspension of 0.6% methylcellulose aqueous solution
Details on oral exposure:
Method of administration:
Gavage
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Test duration: 35 days.

also 2 week reversibility study conducted from day 36 to day51
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
62.5 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
250 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
other: gavage
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 62.5 mg/kg bw/day
Male: 5 animals at 250 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 62.5 mg/kg bw/day
Female: 5 animals at 250 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random):random
-
A 2 week reversibility study was conducted from days D36 to D51 where 5 males and 5 females from the control and high dose groups were observed.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice daily on treatment days

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: prior to exposure and then once a week

BODY WEIGHT: Yes
- Time schedule for examinations: prior to treatment and then weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: D30 and day 50
- Anaesthetic used for blood collection: Yes (identity)
- Animals fasted: Yes for 16+2 hours
- How many animals:all animals
- Parameters checked in table [No.?] were examined. yes

URINALYSIS: Yes
- Time schedule for collection of urine: day 30 and day 50
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes 18 hours
- Parameters checked : voluem.color and clearness and multi-reagent strips

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: day 26 males, day 27 females, motor activity day 28
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / other: all

OTHER: blood chemistry and coagulation, mortality
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
macroscpic, organ weight and microscopic-standard organs and tissues
HISTOPATHOLOGY: Yes
--organs and tissues - microscopic, bone marrow smear
Statistics:
parametric methods:
step 1: homogeneity of intergroup vairance
step 2: equality of intergroup means
step 3: pair wise comparison of means between the treated groupd and the control groups

non-parametric methods:
1). equality of intergroup means
2). pair wise comparison of means between the treated groupd and the control groups

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS pyylism at >= 62.5 one female, solied urogenital area( only one female at 250 mg/kg

AND MORTALITY:

BODY WEIGHT AND WEIGHT GAIN : low body weight gain during first week of treatment

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not studied

FOOD EFFICIENCY: not studied

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not studied

OPHTHALMOSCOPIC EXAMINATION:not studied
HAEMATOLOGY:at 250 mg/kg slightly increased PCV, MCHC and MCV; at 1000 slightly increased hemoglobin levels in females

CLINICAL CHEMISTRY: coagulation no treatment effects; >=62.5 slightly increased potassium levels (females); >= 250 mg/kg slight increased ALAT activity females; at 1000 mg/kg slightly increased creatinine levels(males), total cholestrol(females) & calcium levels (females )

URINALYSIS: at >-250 mg/kg slightly increased specifc gravity ( males) at 1000 mg/kg slightly decreased pH, slightly increased urinary volume and presence of leukocytes and proteins( males)

NEUROBEHAVIOUR: at 1000 mg/kg decreased spontaneous activity in females on day 12,19,26 and 40; and decreased motor activity in females

ORGAN WEIGHTS at >- 62.5 increased absolute relative liver weight(females only); >- 250 increased relative kidney weight in males

GROSS PATHOLOGY: no treatment related changes

HISTOPATHOLOGY: at >- 62.5 very slight or slight hypertrophy of centrilobular hepatocytes ( males only); >- 250 kidney: increased number of hyalin droplets in the proximal tubular cells in males

HISTOPATHOLOGY: NEOPLASTIC (if applicable): at >-250 mg/kg very slight or slight hypertrophy of centrilobular hepatocytes in malesand at 1000 mg/kg kidneys inreased number of hyalin droplets in the proximal tubular cells in males.

HISTORICAL CONTROL DATA (if applicable)

OTHER FINDINGS: animals found dead on D5- dehydration, rectal prolapse blood on the limbs and the muzzle

Effect levels

Dose descriptor:
NOAEL
Effect level:
62.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: increased absolute and/ot relative liver weights (females), very slight or slight hypertrophy of centrilobular hepatocytes ( males only),slightly increased potassium levels (females only), ptylism ( only one female)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

For the reversibility study:

D50: all clinical signes were reversible; no treatment related effects for hematology and for blood chemistry.

necropsy:

macrsopy: no treatement related chnges.

organ weight - increased relative liver wieghts in males and females

microsopy- kidneys hyalin droplets in the proximal tubular cells in males.

Applicant's summary and conclusion

Conclusions:
NOAEL 62.5 mg/kg bw/day(nominal).