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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 29 1991 to February 12 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: 84/449/EWG, B.1
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Test material form:
liquid
Specific details on test material used for the study:
Not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Cr1:CD (SD) BR rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
Body weight (on receipt): Males: 225-250 g
Females: 200-225 g
Age (on receipt): About 7-9 weeks
Supplier: Charles River Italia S.p.A. Via Indipendenza, 11, 22050 - CALCO (Como),
Shipping slip number: 00621 dated Jan. 21, 1991
Acclimation: at least 5 days before the start of the test. Animals were observed daily to ascertain their fitness for the study.
Housing: 5 animals/sex/cage in air-conditioned rooms.
- Temperature: 22 ° C ± 2
- Relative humidity: 55% ± 10
- Air changes: about 20/hour filtered on HEPA 99.97%.
- Light: 12 hour cycle (7 a.m. - 7 p.m.)
- Cage size: grill cages cm 40.5x38.5x18h with stainless steel feeder. The waste that
dropped through the grill bottom on removable paper 􀇣as periodically disposed of.
Animal identification: By nicks or tipping's of the outer ear. Cage card gave experiment number,
dosage group, sex and date of administration.
Diet: GLP 4RF21 pelleted diet produced by Charles River Italia' s feed licensee Yucedola
Sl., Settimo Yilanese. The declared contents, on the label, on dry m a t t e r basis (moisture 12%), were:
crude protein 13.50%
crude fat 3.00%
crude fiber 6.00%
ash 7.00%
The diet was supplemented by the Producer with vitamins and trace elements. The Producer supplies a certificate of anal:-sis for nutrients and contaminants, the levels of which are within the limits proposed by EPA-TSC-4 (44FR:4053-44093, July 26, 1979). RBM has the animal feed re-analyzed at Least twice a year for bacterial contamination. The diet was available "ad libitum" to the animals.
Water: from the municipal water main system. water is filtered and distributed "act· libitum" to the animals by an automatic valve system.
Periodically drinking water is analyzed for microbiologic count. heavy metals, other contaminants (e.g. solvents, pesticides) and other chemical and physical characteristics. The acceptable limits of quality of the drinking water were those defined in EEC Directive 80/778.

Contaminants that might interfere with the objectives of the study 􀆉ere not expected to be present in diet or drinking water.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
Preparation and administration of test article
Just before the treatment of the animals a weighed amount of test article , was suspended with the suitable volume of 0.5% methylcellulose 400 cps water solution. In order to maintain a good homogeneity the suspension was kept stirred by magnetic
stirring until the end of the treatment.
The suspension was administered at the constant volume of 20 ml/kg. The volumes to be administered were measured with appropriately gauged plastic syringes.
The administration was done by gavage to rats which had been fasted about 16 hours.
Analysis:
Stability - Not requested by the Sponsor
Concentration check - Not requested by the Sponsor
Doses:
Single dose of 5000 mg/Kg body weight.
No. of animals per sex per dose:
5 males + 5 females/group
Control animals:
not specified
Details on study design:
Administration route: oral (by gavage)
Reason for selection of administration route : Possible accidental ingestion by humans.
Administration frequency: Single.
Experimental design: The test article was administered as follows:
Dose: (mg/Kg): 5000
Administration volume (ml/Kg): 20
Treatment date: January 29 1991

Observation period: 14 days after the administration.
Observation of clinical signs and mortality: At 30 minutes, 2, 4 and 6 hours on the first day after administration and then twice a day up to termination of the observation period.

Body weight: Once pre-trial, on days 1, 3, 8 and 14. On day 1 the animals were weighed after a 16 hour fasting period. The volume of administration was based on day 1 body weight. Feed was returned to rats three hours after the test article administration.

Gross pathology: On all the animals that died during the study and all the animals (fasted overnight) killed by excision of the femoral arteries, after i.p. anaesthesia with 5% sodium pentobarbital, at the end of the observation period.

Histology: Portions of abnormal entities found in any of the necropsied animals were collected. The tissue samples were fixed and preserved in 10 % buffered formalin.
Histological examinations were not performed as no macroscopic findings emerged from necropsy.
Statistics:
The LD50 calculations were not possible.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed in animals treated at 5000 mg/Kg.
Clinical signs:
other: Signs of toxicity related to dose levels: Piloerection was observed only two hours after test article administration in two male and three female rats.
Gross pathology:
Effects on organs:
At the gross pathology examination carried out at the end of the observation period no changes were noted in all necropsied animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No signs of toxicity were seen in any animals dosed with 5000 mg/Kg of the test article. Therefore the LD50 of the test article is concluded to be >5000 mg/Kg bw.
Executive summary:

A acute oral toxicity study was carried out in rats treated with test article ANOX – BF,  according to test guideline 84/449/EWG, B.1, in compliance with GLP.

The test article was suspended in 0,5% methylcellulose 400 cps water

Solution and administered to rats at the volume of 20 ml/kg.

All rats were treated after a 16 hrs fasting period. The animals were weighed on days 1, 3, 8 and 14; clinically observed for 14 days following the treatment and killed at the end of the study by excision of the femoral arteries after having been completely anesthetized with an i.p. injection of 5% sodium pentobarbital . A thorough autoptic  examination was performed in animals killed at the end of the observation period .

No animals died during the observation period.

Two male and three female treated rats only showed transient piloerection 2 hours after treatment.

The body weight gain appeared unaffected by treatment .

At the gross pathology examination performed on rats killed at the end of the observation period no changes were noted.

In conclusion ANOX - BF, when administered by oral rout to rat, under' the conditions adopted in this study, did not cause overt signs of toxicity- and showed an LD50 higher than 5000 mg/kg.