Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007/01/10 - 2007/07/18
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
Report date:
2007

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
Article name: KFAP
Chemical name: Potassium tris(pentafluoroethyl)trifluorophosphate
CAS No.: 123215-04-3
Indication: Ionic Liquids
Batch No.: S4693525
Purity (NMR): > 98.0 % (w/w)
Appearance: off white, crystalline powder with a gray tinge
Supplier: Merck KGaA, Darmstadt
Analytical Report: Merck KGaA, Darmstadt, ZD-AIZFA9, Dr. N. Fichtner
Released until: November 30, 2007

Vehicle:
Designation: Methocel K4M Premium solution
Batch: ZDP 02/07, 04/07, 05/07 and 08/07
Released until: March 09, 2007

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Test system
Species: Rat, Wistar HsdCpb: WU, males (m) and females (f)
Breeder: F. Winkelmann, 33178 Borchen
Age: approx. 6 to 8 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, 300, 2000 mg/kg bw
No. of animals per sex per dose:
50 mg/kg: 3 (m) / 3 (f)
300 mg/kg: 0 (m) / 3 (f)
2000 mg/kg: 0 (m) / 3 (f)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
The behavior and general condition of all rats were monitored for at least 6 hours after administration and then checked daily.

- Frequency of observations and weighing:
All animals were weighed before treatment and on days 2, 4, 6, 8, 11, 13, and 15 of the experimental part.

- Necropsy of survivors performed: yes/no
All the rats, which were died or sacrificed at the end of the experimental part by C02-asphyxia, were subjected to gross pathological
examination.

- Other examinations performed:
clinical signs, body weight,organ weights, histopathology
Statistics:
The statistical evaluations of the body weight were carried out with the PC-program "TOX 511A", developed by the Institute of Toxicology of Merck KGaA, Darmstadt. The body weight development of each rat and group was determined. The group mean value was calculated for each measurement and printed out on spread sheets.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 50 - < 200 mg/kg bw
Mortality:
The rats treated with 50 mg/kg survived the observation period.
All rats treated with 300 and 2000 mg/kg died 1 hour up to 2 days after dosing.
Two rats treated with 300 mg/kg died 23 hours after treatment and one rat were killed in a moribund
status 2 days after dosing. One rat treated with 2000 mg/kg was found dead 1 hour after treatment and 2 rats of this group died after 3 hours.
Clinical signs:
No signs of toxicity were seen in the rats treated with 50 mg/kg.
Signs of toxicity were seen in the rats treated with 300 mg/kg 15 minutes after oral administration up to day 2. They consisted of locomotor disturbance, dyspnea, lateral position, incomplete eyelid closure and piloerection.
In rats treated with 2000 mg/kg signs of toxicity were seen immediately after oral administration up to 3 hours. They consisted of salivation, abdominal and lateral position, locomotor disturbance, and dyspnea and cyanosis.
Body weight:
The body weight development of the rats was inconspicuous.
Gross pathology:
All female rats, treated with 300 mg/kg died after 23 hours or were killed in a moribund body condition after 2 days (No. 28).
At necropsy red discoloration of the gastric fundus mucosa was seen in two animals (Nos. 26, 28).
Animal No. 28 showed a mild dilatation of the intestine with gaseous bubbles in the intestinal content.
No gross pathological findings were detected in animal No. 27. At histology mild mixed submucosal infiltrates with mild
focal submucosal edema of the pars glandularis were detected in animal No. 26.
The stomach animal No. 28 showed a focal mild submucosal edema and no abnormalities were detected in the intestine.
The three female rats treated with 2000 mg/kg died after 1 hour (No. 16) or 3 hours (Nos. 17, 18).
Gross pathology revealed fluid-mutinous contents in the stomach and intestine with dark red discoloration of the
glandular stomach in all these rats. Histology of the stomach mucosa revealed acute necrosis with thrombosis and
fibrin exudation. The duodenum showed acute necrosis of villi.
All findings are related to the local irritating properties of the test item at mid and high concentrations.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category III
Remarks:
Migrated information according to OECD 423
Conclusions:
According to the results of this study the LD50 value is expected to be between 50 - 300 mg/kg.
Executive summary:

The test material was tested for acute toxicity in rats after single oral administration of 50, 300 and 2000 mg/kg body weight.

The test was started with 2000 mg/kg. The test material was prepared directly before administration with aqueous Methocel®

K4M Premium solution as the vehicle.

This study was performed according to the "Acute toxic class method" (ATC) as described in the OECD Guideline 423.

No signs of toxicity were seen in the rats treated with 50 mg/kg and all rats survived the observation period.

All rats treated with 300 and 2000 mg/kg died 1 hour up to day 2 after dosing.

Signs of toxicity were seen in the rats treated with 300 mg/kg 15 minutes up to 2 days after oral administration.

They consisted of locomotor disturbance, dyspnea, lateral position, incomplete eyelid closure and piloerection.

In rats treated with 2000 mg/kg signs of toxicity were seen immediately up to 3 hours after oral administration.

They consisted of salivation, abdominal and lateral position, locomotor disturbance, and dyspnea and cyanosis.

Gross pathology revealed no abnormalities in rats treated with 50 mg/kg.

At 300 mg/kg red discoloration of the gastric fundus mucosa was seen in two animals.

One animal showed a mild intestinal dilatation with gaseous bubbles.

Histology revealed mild mixed submucosal infiltrates with a mild focal submucosal edema of the pars glandularis

in one animal and a focal mild submucosal edema in the stomach of the other animal. No abnormalities were detected

in the intestine.

Rats treated with 2000 mg/kg revealed fluid-mucinous contents in the stomach and intestine with dark red discoloration

of the glandular stomach. Histology of the stomach mucosa revealed acute necrosis with thrombosis and fibrin exudation.

The duodenum showed acute necrosis of villi.

All findings found at 300 and 2000 mg/kg are considered to be related to local irritating properties of the test

item at mid and high concentrations.