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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 19, 2001 till September 4, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD guideline 423 (Acute Oral Toxicity - Acute Toxic Class Method) under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Physical state: solid
Batch number: NW-01-028
Purity: >99%
Stable under storage conditions, i.e. in original container at room temperature (17-23°C), not in direct sunlight.
Expiry date: 30 Dec 2001

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on animals: Rat, HanBrl: WIST (SPF)
Source of rats: RCC Ltd (füllingsdorf, Switzerland)
Sex: both
Age: 8-10 weeks
Acclimatization: Under laboratory conditions after health examination. Only healthy animals (judged by visual signs) were used.
Conditions: Standard Laboratory Conditions
- Air-conditioned with 10-15 air changes per hour
- continously monitored environment with target ranges for temperature 22 +/- 3°C and for relative humidity between 30-70%
- 12 hours flurescent light/12 hours dark (light period 6:00 and 18:00h)
- music during light period
Accommodation: In groups of three per sex in Makrolon type-4 cages with wire mesh tops and standardised siftwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland)
Diet: Pelleted standard Provimi Kliba 3433 rat maintenance diet ad libitum (batch no. 72/01 and no. 73/01).
Water: Community tap water from Itingen, Switzerland, ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
The rats received a single oral dose of the test substance by gavage at 2000mg/kg or 200mg/kg after being fastened for 16-20 hours (access to water was permitted). Food was provided again approx. 3 hours after dosing. The application volume was 10ml/kg body weight.
Doses:
2000mg/kg and 200mg/kg
The preparations were made shortly before dosing.
The test substance was weighted into a tared glass beaker on a suitable precision balance and the vehicle (PEG 300, Fluka Chemie AG (Buchs, Switzerland), batch no. 412565/1 50501 (at 2000mg/kg) and 412565/1 51301 (at 200mg/kg)) added (weight:volume) and warmed up to approx. 50°C for approx. 2 minutes. The mixtures were prepared using a magnetic stirrer. Homogeneitty of the test substance in the vehicle was maintained during administration using a magnetic stirrer.
No. of animals per sex per dose:
2000 mg/kg: 3 male and 3 female
200 mg/kg: 3 male
Control animals:
no
Details on study design:
Study duration: 14 days
Frequency of observations and weighing:
- Body weight: on test days 1 (pre admin.), 8 and 15
- Clinical signs: daily during acclimatisation, four times on test day 1 (after admin.), once daily during day 2-15
- Mortality / Viability: Daily during acclimatization, twice daily during days 1-15
Necropsy of survivors performed: yes
Other examinations performed: All animal were discarded after necropsy and macroscopic examination. No organs or tissues were retained
Statistics:
No statistical analysis was used.

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Sex:
male
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Mortality:
2000 mg/kg: All three males, i.e. 100%, were found dead on test day 2 or 3. All females survived until the end of the observation period.
200 mg/kg: All three males survived until the end of the observation period.
Clinical signs:
Fluffled fur, lateral recumbency, sedation and dyspnea were noted in all males at 2000 mg/kg before they were found dead. Ruffled fur was noted in the females at 2000mg/kg on test day 1 and from test day 6 to 14. Hunched posture and slight or moderate emaciation was evident in two females at 2000mg/kg from test day 6 until test day 12. The males at 200mg/kg were without clinical signs.
Body weight:
Females at 2000mg/kg lost weight from the first test day until test day 8. Afterwards, they gained weight. The body weight of the males at 200mg/kg was within the range commonly recorded for this strain and age.
Gross pathology:
In all males at 2000mg/kg, which were found dead, dark red discoloration of the lungs was noted. No macroscopic findings were observed in all survving animals at necrospy.

Any other information on results incl. tables

Body weights

dose (mg/kg) animal ident. sex Day 1 (treatment) Day 8 Day 15
2000 1 f 173.3 152.8 196.7
2000 2 f 172.0 154.0 187.7
2000 3 f 173.0 170.5 204.9
2000 4 m 199.3 - -
2000 5 m 198.7 - -
2000 6 m 196.7 - -
200 7 m 199.7 239.5 251.9
200 8 m 200.9 243.5 265.3
200 9 m 202.2 249.5 278.1

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of ZP-TIX 1014 after single oral administration to rats of both sexes (acc. to OECD guideline 423), observed over a period of 14 days was:
LD50 (female rat): > 2000mg/kg body weight
LD50 (male rat): > 200mg/kg body weight, but < 2000mg/kg body weight
Executive summary:

One group of three male or three female HanBrl: WIST (SPF) rats was treated by oral gavage with ZP-TIX 1014 at 2000 mg/kg body weight. The test item was suspended in vehicle (PEG 300) at a concentration of 0.2 g/mL and administered at a volume of 10 mL/kg.

 

One group of three male HanBrl: WIST (SPF) rats were treated by oral gavage with ZP-TIX 1014 at 200 mg/kg body weight. The test item was suspended in vehicle (PEG 300) at a concentration of 0.02 g/ml and administered at a volume of 10 mL/kg.

 

The animals were examined for clinical signs daily during the acclimatization period, four times during test day 1 and once daily during test days 2-15. Mortality/viability was recorded daily during the acclimatization period and together with clinical signs at the same time intervals on test day 1 and twice daily on test days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15.All animals were necropsied and examined macroscopically.

 

The following animals were treated and percentage of mortality was observed:

 

                                  males                         females

2000 mg/kg bw          100%                         0%

 

200 mg/kg bw            0%

 

The males at 2000 mg/kg were found dead on test days 2 or 3. All other animals survived until the end of the observation period.

Ruffled fur, lateral recumbency, sedation and dyspnea were noted in all males at 2000 mg/kg before they were found dead. Ruffled fur was noted in the females at 2000 mg/kg on test day one and from test day 6 until 14. Hunched posture and slight or moderate emaciation was evident in two females at 2000 mg/kg from test day 6 until test day 12. The males at 200 mg/kg were without clinical signs.

Females at 2000 mg/kg lost weight from the first test day until test day 8, after this period they gained weight. The body weight of the males at 200 mg/kg was within the range commonly recorded for this strain and age.

In all males at 2000 mg/kg wh ich were found dead, dark red discoloration of the lungs was noted. No macroscopic findings were observed in all surviving animals at necropsy.