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Administrative data

Description of key information

Key acute oral (OECD 423) and dermal (OECD 402) studies were identified.
- The oral LD50 was > 2000 mg/kg bw in male rats
- The dermal LD50 was > 2000 mg/kg bw in male and female rabbits

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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.
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
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.
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
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.
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).

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).

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The quality of database was judged as good because the tests were performed in accordance with validated guidelines

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Sep - Nov 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study.
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST SYSTEM
Age when treated: Males: 8 weeks; Females: 11 weeks
ldentification: by unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
Randomization: selected by hand at lime of delivery. No computer generated randomization program.
Acclimatization: under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

HUSBANDRY
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70% (values above 70% during cleaning process possible), automatically controlled, light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Accommodation: during acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. lndividually in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz) during treatment and observation.
Diet: pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 36106 (Provimi Kliba AG, CH-4303 Kaiseraugstl Switzerland) ad libitum. Results of analyses for contaminants are archived at the test facility.
Water: community tap water ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at the test facility.
Type of coverage:
semiocclusive
Vehicle:
polyethylene glycol
Remarks:
Colorless viscous liquid, stable under storage conditions.
Details on dermal exposure:
FEXO-07 was applied undiluted as delivered from the sponsor.
Duration of exposure:
The application period was 24 hours.
Doses:
2000 mg/kg body weight
The test item was diluted in vehicle (PEG 300) at a concentration of 0.33 g/ml and administered at a volume dosage of 6 ml/kg.
No. of animals per sex per dose:
Number of animals per group: 5 males and 5 females.
Total number of animals: 5 males and 5 females.
Control animals:
not specified
Details on study design:
The purpose of this study was to assess the acute dermal toxicity of Fexo-07 when administered to rats by a single semi-occlusive dermal application, followed by an observation period of 14 days.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of Fexo-07 after single dermal administration to rats of both sexes, observed over a period of 14 days is:
LD50 (rat): > 2000 mg/kg body weight.
Executive summary:

Five male and five female HanRcc:WIST (SPF) rats were treated with Fexo-07 at 2000 mg/kg by dermal application. The test item was diluted in vehicle (PEG 300) at a concentration of 0.33 g/mL and administered at a volume dosage of 6 mL/kg.

The application period was 24 hours.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2 -15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during 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. No deaths occurred during the study. No clinical signs of toxicity or local dermal findings were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The quality of database is judged as good because the tests were performed in accordance with validated guidelines

Additional information

Acute oral toxicity

One key study (Klimisch score=1) was identified, in which FEXO-07 were tested for acute oral toxicity in rats using a method according to OECD 423. The material was dispersed in corn oil and administered by gavage (10 mL/kg) to 6 male rats (3 animals per step (6 animals in total for the stepwise procedure) at a single dose of 2000 mg/kg bw (a limit test at a dose of 2000 mg/kg was performed). All animals were monitored daily far 14 days after administration of the test substance.

Clinical examinations were performed: (i) general clinical examination (once a day), (ii) full clinical examination (once a week at least) including functional and neurobehavioural tests. A necropsy was performed to all animals surviving to the end of the 14 day monitoring period. All animals were subjected to gross necropsy and their organs were examined macroscopically.

No mortalities were observed during the study and the LD50 for oral exposure was reported as higher than 2000 mg/kg.

The results of this study indicate that FEXO-07 is not acutely toxic by the oral exposure route and, since the available data does not meet the EU criteria for classification and labelling.

For this end-point a DNEL is not required.

Acute Dermal Toxicity

One key study (Klimisch score=1) was identified, in which FEXO-07 were tested for acute dermal toxicity in rats using a method according to OECD 402 and Directive 92/69/EEC, 8.3. "Acute Toxicity-Dermal". The test item was diluted in vehicle (PEG 300) at a concentration of 0.33 g/ml and administered at a volume dosage of 6 ml/kg; the substance was tested on five male and five female rats. The application period was 24 hours with a semiocclusive coverage followed by an observation period of 14 days.

Clinical examinations were performed: (i) mortality, (ii) body weight and clinical signs.

The LD50 for dermal exposure was reported as higher than 2000 mg/kg.

The result of this study indicates that FEXO-07 is not acutely toxic by the dermal exposure route and, since the available data does not meet the EU criteria for classification and labelling; for this end-poin a DNEL is not required.


Justification for selection of acute toxicity – oral endpoint
Only one end-point was available for the selection. However, it was judged as reliable because the test was performed in accordance with validated guidelines.

Justification for selection of acute toxicity – dermal endpoint
Only one endpoint is available for the selection. However, it is judged as reliable because the test was performed in accordance with validated guidelines.

Justification for classification or non-classification

Based on evaluation of the acute toxicity data discussed above, FEXO-07 does not meet the criteria for classification as oral and dermal acute toxicity under the CLP Regulation (Regulation (EC) n. 1272/2008) and the Directive 67/548/EEC because the LD50 values are greater than the limits for classification defined in the criteria.