Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
07.02-17.05.2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was performed in compliance with the Good Laboratory Practice (GLP) regulations (revised in 1997, ENV/MC/CHEM(98)17). The method followed that described in the OECD Guidelines for Testing of Chemicals (Adopted: 4 April 1984) No 423 "Acute Oral Toxicity – Acute Toxic Class Method".

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
- Test system
Species: Rat, Crl:WI (Han), males (m) and females (f)
Breeder: Charles River Wiga, Kißlegg
Age: approx. 7 (males) and 9 (females) weeks

I- dentification and adaptation
Healthy young animals were allocated to the study group at least 7 days before dosing to allow for acclimatization.
The rats were identified by an ear tattoo.

- Housing and diet
The rats were housed in an air-conditioned room of about 25 m^2 in the Institute of Toxicology. Lighting was controlled by a timer to provide a 12 hour light - 12 hour dark regime.

The rats were kept separately in type III Makrolon cages with a shelter, placed on mobile racks. Conventional softwood granulate was used
as the bedding. One day before treatment, and up to 24 hours after dosing, metal grids were placed above the softwood granulate.
The cages and the metal grids had been machine-cleaned before the start of the experimental part. The bedding was changed two times per
week.

Temperature and humidity were measured using a thermohygrograph. The room temperature during the experimental period was 20 to 22 °C
and the relative atmospheric humidity 51 to 80 %.

Diet was withheld from 17 hours before until up to 4 hours after treatment. At all other times food and tap water from Makrolon drinking
bottles were available to the rats ad libitum.

According to the specifications given by the manufacturer, the diet, Provimi Kliba 3433.0, had been checked by independent laboratories.
Analysis included qualitative and quantitative evaluation for heavy metals, aflatoxins, pesticides, and antibiotics.
The drinking water was periodically analyzed according to the German regulations for human drinking water.

The softwood granulate was analytically checked by independent laboratories.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: see section Details on Test Materials
Doses:
50 mg/kg bw
300 mg/kg bw
No. of animals per sex per dose:
50 mg/kg bw: 3 (m) / 3 (f)
300 mg/kg bw: 3 (f)
Control animals:
no
Details on study design:
A dose of 300 mg/kg bw test material was administered orally (gavage) to 3 female rats. Due to mortality at the dose of 50 mg/kg, 6 further rats (3 male, 3 females) were subsequently dosed with 50 mg/kg bw test material.
Statistics:
none

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000
Mortality:
No mortality occured at a dose of 300 mg/kg. One female rat died on day 2 of the study, the two remaing rats were killed in a moribund state on day. At a dose of 50 mg/kg all rats (3 f, 3 m) survived the observation period.
Clinical signs:
Signs of toxicity observed the after treatment with the test material consisted of salivation (all rats). In two rats dosed with 300 mg/kg locomotor disturbances, dyspnea and piloerrection were seen on day 4.
Body weight:
At a dose of 300 mg/kg the body weight decreased until day 4 of the study. At 50 mg/kg the body weight development of the treated male rats was inconspicuous, the body weight of the female rat increased during the course of the study, but the increase was not constant.
Gross pathology:
300 mg/kg: at necropsy the following organ alterations were seen: enlargement of the lungs combined with foamy contents in the trachea and alveolar edema. In one female that died on day 2, congestion of the liver was reported
50 mg/kg: no organ alterations were observed
Other findings:
None

Any other information on results incl. tables

3 female rats did not tolerate the treatment with 300 mg/kg bw. At necropsy, enlargement of the lungs combined with foamy contents in the trachea and alveolar edema were observed.

At a dose of 50 mg/kg, all rats (3 males and 3 females) all rats survived the observation period. At necropsy, no organ alterations were seen.

Applicant's summary and conclusion

Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the result of this study, it is concluded, that the test item is acutely toxic after oral uptake and that the LD50 value is in the range of 50 to 300 mg/kg bw following oral treatment in rats.
Executive summary:

Purpose

The purpose of this assay was to provide information on possible health hazards for the test material and serve as a rational basis for risk assessment to the potential of acute oral toxicity of the test item in man.

Study design

The test material was tested for acute toxicity in rats after oral administration of 50 and 300 mg/kg body weight. Directly before the administration the test material was prepared with aqueous Methocel K4M Premium solution as vehicle.

This study was performed according to the ,,Acute toxic class method" (ATC).

Results

No signs of toxicity were detected in the 3 male and 3 female rats after treatment with 50 mg/kg and no rat died.

The gross pathological examination revealed no organ alterations.

Treatment with 300 mg/kg bw was not tolerated by 3 female rats. One rat died spontaneously on day 2, the two remaing rats were killed in moribund state on day 4. Gross pathological effects observed were enlargement of lungs combined with foamy contents in the trachea and alveolar oedema.

Conclusions

According to the results of this study the LD50 value is expected to be in the range of 50 to 300 mg/kg bw.