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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: granules
Details on test material:
- Name of test material (as cited in study report): Preventol CI 7-100

- Physical state: solid
- Analytical purity: 99.2 %
- Composition of test material, percentage of components: 40 % 4- Methylbenzotriazole, 60 % 5- Methylbenzotriazole
- Lot/batch No.: 868
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Versuchstierzucht Winkelmann, Borchen
- Age at study initiation: 5 - 6 weeks
- Weight at study initiation: mean: 89 g (male) 86 g (female)
- Fasting period before study: no
- Housing: standard Makrolon-cages type II
- Diet: Altromin 1324 Pellets, ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2 °C
- Humidity (%): 50 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: the test item was gounded and solved in the vehicle

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): the test item is soluble and stable in the vehicle which is commonly used
- Concentration in vehicle: 10 to 90 mg / ml
- Amount of vehicle (if gavage): 5 ml / kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test item in the vehicle was determined and no significant changes of the composition was observed after 48 hours.
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
50 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
150 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
450 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the doses were selected based on a range finding study
Positive control:
No

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

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: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: only at end of study
- Animals fasted: Yes
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: only at end of study
- Animals fasted: Yes
- How many animals: all

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
arithmetic means and standard deviation
for organ weights the confidence levels 95 and 99 %
Comparision of test and control group results are done with test of significance (U-test) with a= 5 % and a = 1%

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):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
in 450 mg/kg bw groups
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: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
one animal (450 mg/kg bw, female) died during the study
after the daily application, all animals in the dose group of 450 mg/kg bw showed apathy

BODY WEIGHT AND WEIGHT GAIN
no findings

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
no findings

HAEMATOLOGY
no findings in the dose groups 50 and 150 mg/kg bw
reduced levels of eryhtocytes, hematocrit and hemoglobine in the male dose group 450 mg/kg bw

CLINICAL CHEMISTRY
Raised activity of alanin-aminotransferase in male/female dose group 450 mg/kg bw
Reduced concentration of the plasma protein concentration in male/female dose group 450 mg/kg bw

ORGAN WEIGHTS
no findings

GROSS PATHOLOGY
two male and one female animal had pale kidneys

HISTOPATHOLOGY: NON-NEOPLASTIC
no findings


OTHER FINDINGS

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
clinical biochemistry

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In doses up to 150 mg/kg bw / day, no adverse effects were observed.
A dose of 450 mg/ kg bw/day lead to apathy after gavage, to a changed blood count and raised plasma activity of transaminases GOT and GPT