Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April - July 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to
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:
Appearance: off-white to white crystals.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Identification: Animals were identified individually by marking the tail with a felt tip marker.
Age: 8-12 weeks at the time of administration.
Number: 3 animals per step.
Weight: within ± 20% of the mean weight of any previously dosed animals.
Acclimatisation: Seven days before treatment in the laboratory animal house where the experiment tookplace.
Housing: Daily observations were performed at the time of delivery of the animals and during the period of acclimatisation ( except on D5 of the second step ). Animals were housed in cages of standard dimensions with sawdust bedding (or equivalent). Cages were cleaned at least once per week.
The animals were placed in an air-conditioned (19-23 o C) animai house kept at relative humidity between 45% and 65% in which non-recycled filtered air was changed approximate1y 10 times per hour. The artificial day/night cycle involved 12 hours light and 12 hours darkness with light on at 7.30
a.m.
Feeding: RMl(E)-SQC SDS/DIETEX feed (quality controlled/radiation sterilised) was availab1e ad libitum except during the fasting experimental period. The criteria for acceptable levels of contaminants in the feed supply was within the limits of the ana1ytical specifications established by the diet
manufacturer. A certificate of analysis concerning this feed product was included in the report of the study.
Drinking water: Potable water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple. A specimen of water is obtained every 6 months and sent to the Laboratoire Départemental d' Analyse du Cher- 216, Rue Louis Mallet- 18014 Bourges Cedex, France, for analysis.
The criteria for acceptable levels of contaminants in the water supply was within the limits of the analytical specifications. Certificates of analysis were included in the report of the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
It was chosen on the basis of the physical - che mical characteristics of FEXO - 07: test substance was administered as a whitish opaque homogeneous suspension in corn oil.
Details on oral exposure:
The test was based on a stepwise procedure with the use of a minimum number of animals per step.
The substance is administered orally to a group of experimental animals at one of the defined doses. The substance is tested using a stepwise procedure, each step using three animals of a single sex.
Doses:
A limit test at a dose of 2000 mg/kg was performed.
FEXO-07 was administered orally to animals, deprived of food since the previous day, in a volume of 10 mL/kg as a homogeneous suspension in corn oil
No. of animals per sex per dose:
3 animals per step (6 animals in total for the two steps performed).
Control animals:
not specified
Details on study design:
The aim of this study was to assess the toxicity of the FEXO - 07 after single dose administration by the oral (gavage) route in the rat. The acute toxic class method was a stepwise procedure with the use of 3 animals of a single sex per step.
Statistics:
All data were recorded as and when obtained using forms identified by the study number.
Data were presented tabulated by dose level and time, nature, severity and durati an of effects. Results of the weight was given as means ± SEM (Standard Errar of the Mean). If the number of animals was not sufficient (< 3) the SEM was not calculated.
sufficient ( < 3), the SEM was not calculated

Results and discussion

Preliminary study:
The limit test is primarily used in situations where the experimenter has information indicating that the test substance is likely to be nontoxic, i. e., having toxicity only above regulatory limit doses.
Information about the toxicity of the test substance can be gained from knowledge about similar tested compounds or similar tested mixtures or products.
Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No clinical signs were observed during the course of the first step of the study (D7).
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality was observed.
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No organ or tissue gross findings were seen at necropsy.
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: On D1, slight decrease of Iocomotor activity or bent back were observed in animals of the second step of the study
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: On D2 and/or D3, piloerection was noted in two animals of tbe second step of the study.
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: From D3 or D4 to D 14, no other clinical signs were observed.
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Mean weight gain in treated animals but it was considered as normal when compared with strain data.
Mortality:
No mortality occured during the study.

Mortality was recorded twice a day, i. e. in the morning and at the end of the working day. Throughout the study animals found in a moribund condition and animals showing severe pain or enduring signs of severe distress was humanely euthanised.
Clinical signs:
Slight decrease of locomotor activity or bent back were observed in animals of the second step.
On D2 and/or D3, piloerection was noted in two animals of the second step of the study.
From D3 or D4 to D 14, no other clinical signs were observed.

Generai clinical examination (once a day)
Animals were examined clinically twice on the day of treatment (between 30 and 90 minutes after administration and then again between 3 and 4 hours post-dose). Thereafter they were examined clinically at least once a day for 14 days.
Body weight:
Mean weight gain in treated animals was normal when compared with strain data.
Gross pathology:
No organ or tissue gross findings were seen at necropsy.
Other findings:
Full clinical examination (once a week at least)
On D1 between 30 and 90 minutes after administration and on D7 the animals were submitted to a full clinical exarnination outside the housing cage, including functional and neurobehavioural tests. If clinical changes were recorded on D7, the full clinical examination will be repeated at the termination of the study (D14).
As no clinical changes w ere recorded on D7, the full clinical examination was not repeated at the termination of the study (D14).

Any other information on results incl. tables

All animals surviving to the end of the 14-day monitoring period were euthanised on Dl5 by subtotal exsanguination, after sodium pentobarbital anaesthesia by the intraperitoneal route. All animals were subjectcd to gross necropsy and their organs (liver, spleen, kidneys, stomach, intestines, gonads/reproductive tract, lungs and heart) were examined macroscopically. All organs showing macroscopic signs of pathology were fixed in an appropriate fixative for possible histopathological examination (not included in cost estimate).

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the experimental conditions adopted, oral administration of the test substance FEXO - 07 (batch 1/03) at a dose of 2000 mg/kg caused no
mortality and did not require euthanasia during 14-day periods, in the male Sprague-Dawley Rat.
Under the experimental conditions adopted, the LD50 is higher than 2000 mglkg body weight.
Executive summary:

At the request of the sponsor of the study, the toxicity of the test substance FEXO - 07 (batch 1/03) was evaluated after a single dose administration by the oral (gavage) route in the Rat in compliance with generai requirements of OECD Guideline No. 423 (December 17, 2001) and Globally Harmonised Classification System (GHS).

A limit test at the starting dose of 2000 mg/kg body weight was carried out with three males. At the first step, a group of three males was treated with the starting dose, followed by an additional group of three animals of the same sex at the same dose level of 2000 mg/kg to confìrm the results obtained during the first step of the study. The test substance FEXO - 07 was administered orally to animals, deprived of food since the previous day, in a volume of 10 mL/kg as a homogeneous suspension in corn oil. All animals were monitored daily far 14 days after administration of the test substance. All animals were weighed on days DI, 07, Dl4 and 015.

Under the experimental conditions adopted, results obtained were as follows: No mortality occurred during the study. No clinical signs were observed during the course of the first step of the study. On D1, slight decrease of locomotor activity or bent back were observed in animals of the second step of the study. On D2 and/or D3, piloerection was noted in two animals of tbe second step of the study. From D3 or D4 to D14, no other clinical signs were observed. Mean weight gain in treated animals was normal when compared with strain data. No organ or tissue gross fìndings were seen at necropsy. Under the experimental conditions adopted, oral administration of the test substance FEXO - 07 (batch 1/03) at a dose of 2000 mg/kg cansed no mortality and did not require enthanasia during 14-day periods, in the male Sprague-Dawley Rat.

According to the Globally Harmonised Classificatiou System (GHS), FEXO - 07 (batch 1103) is in category 5. Under the experimental conditions adopted, the LD50 is higher than 2000 mg/kg body weight.