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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
Study period:
04 October to 15 November 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study undertaken at a GLP accredited laboratory, to internationally accepted guidelines

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

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

Test material

Constituent 1
Reference substance name:
Luminova
IUPAC Name:
Luminova
Details on test material:
- Name of test material (as cited in study report): LumiNova
- Substance type: Luminous
- Physical state: Powder
- Analytical purity: 100% w/w
- Lot/batch No.: NR-003-1
- Expiration date of the lot/batch: May 1996
- Stability under test conditions:
- Storage condition of test material: In the dark at room temperature in dry conditions.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Laboratory animal supplier
- Age at study initiation: 5 weeks
- Weight at study initiation: males, 127.1 to 146.9 g and females, 113.0 to 129.5 g
- Fasting period before study: no data
- Housing: Individually in staniless stell cages with wire mesh floor.
- Diet: MF pelleted diet ad libitum
- Water: ad libitum
- Acclimation period: yes, no data.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10 - 15
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food: no data

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 2.0, 0.4 and 0.1% w/v
- Amount of vehicle (if gavage): 10% w/v
- Lot/batch no. (if required): 147RTT, Fujisawa-astra
- Purity:
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10 mg / kg / day
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
40 mg / kg / day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
200 mg / kg / day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg / kg / day
Basis:
actual ingested
No. of animals per sex per dose:
Male: 6 animals at 0 mg/kg bw/day
Male: 6 animals at 10 mg/kg bw/day
Male: 6 animals at 40 mg/kg bw/day
Male: 6 animals at 200 mg/kg bw/day
Male: 6 animals at 1000 mg/kg bw/day
Female: 6 animals at 0 mg/kg bw/day
Female: 6 animals at 10 mg/kg bw/day
Female: 6 animals at 40 mg/kg bw/day
Female: 6 animals at 200 mg/kg bw/day
Female: 6 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Decided from initial 14-day preliminary study.
- Rationale for animal assignment (if not random):
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random):
Positive control:
None

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: Day 1, 2, 3, 5, 8, 10, 12, 14 and 15.

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

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood: At the end of the dosing and recovery period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: no data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the dosing and recovery period
- Animals fasted: No data
- How many animals:No data

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine: At the end of the dosing and recovery period
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see attachment)
HISTOPATHOLOGY: Yes (see attachment)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There was death in one male but this was considered to be an administration error. Salivation was not considered toxicologically significant since this occurred sporadically just after administration.
Mortality:
mortality observed, treatment-related
Description (incidence):
There was death in one male but this was considered to be an administration error. Salivation was not considered toxicologically significant since this occurred sporadically just after administration.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreased food consumption was noted in males of 200 mg / kg group at Day 4 during the administration period, however, this change was not considered related to the treatment since there was no decrease in the 1000 mg / kg group.
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):
At the end of the recovery period there were significant differences in 1000 mg / kg group; however, these were considered to be accidental changes since these differences were not noted at the end of the administration period.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
significant increase in male adrenal and female spleen weights at 1000 mg / kg.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical observations: A single male animal died on day 13 of the study in the 200 mg/kg group. This death was not, however, considered to be treatment-related. No other signs of toxicity were observed.
Laboratory findings: No treatment-related changes were observed.
Effects in organs: Increases in absolute (but not relative) adrenal gland weight were noted in males from the 1000 mg/kg group at the end of the treatment period. There were, however, no abnormal histopathological findings associated with the weight increase.
No other treatment-related gross or microscopic findings were observed.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: organ weights
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: organ weights

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study the results indicate that LumiNova should not be classified.