Potassium 2-(3-trifluoromethoxy-1,1,2,2,3,3-hexafluoropropoxy)-2,3,3,3-tetrafluoropropionate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted in complaince with OECD GLP (1997) regulations.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

MV31 K-Salz

IUPAC Name:

MV31 K-Salz

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): MV31 K-Salz
- Substance type: Mono-constituent
- Physical state: Solid (grey granules)
- Analytical purity: 88%
- Purity test date: 30 November 2001
- Lot/batch No.: 1268147/1-1268154/1
- Expiration date of the lot/batch: 31 December 2002
- Stability under test conditions: Guranteed for 15 days in deionized water by HPLC analysis
- Storage condition of test material: Darkness at approximately 20 C in a fume hood

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Gartenstrasse 27, D-33178 Borchen
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: Male mean: 128.7 g, Female mean: 126.02 g
- Fasting period before study: None
- Housing: 5 animals per cage, separated by sex in macrolon (type IV) cages on soft wood granulate
- Diet (e.g. ad libitum): Ssniff R/M-H (V 1534), ad libitum except when in diuresis cages
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 C
- Humidity (%): 30-70%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 January 2002 To: 11 March 2002

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test article was dissolved in deionized water for dosing via gavage

VEHICLE
- Concentration in vehicle: 0 (vehicle control), 0.02, 0.06, 0.60, 2.00% (w/v)
- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Animals were dosed via oral gavage once daily

Frequency of treatment:

Animals were dosed for 29 days (28 applications)

Doses / concentrations

Remarks:

Doses / Concentrations:
0 (vehicle control), 0.1, 0.3, 3.0, 10.0 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

10/sex/dose at 0 and 10 mg/kg/day (recovery groups of 5/sex/dose in those groups) and 5/sex/dose at all other doses.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose rationale was based on a preliminary rat 28 day oral toxicity study with dose levels of 5, 20, and 80 mg/kg bw, which resulted in moderate (5 mg/kg bw) to marked (>20 mg/kg bw) multifunctional organic disturbances with emphasis to the liver as the major target organ, and severe general clinical disturbances at 80 mg/kg bw.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: Vehicle control and high dose animals were compared for recovery groups
- Post-exposure recovery period in satellite groups: 28 days

Positive control:

None

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Before the start of the study and twice weekly thereafter

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination (main study and recovery animals)
- Anaesthetic used for blood collection: Yes (Ketamine-Hydrochloride and Xylazine)
- Animals fasted: No
- How many animals: All animals (main study and recovery groups)
- Parameters checked: Erythrocyte counts, Heinz body counts, Hematocrit, Hemoglobin, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Mean corpuscular volume, Reticulocyte counts, Differential leukocyte counts, Leukocyte counts, Coagulation time, Thrombocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination (main study and recovery animals)
- Animals fasted: No
- How many animals: All animals (main study and recovery groups)
- Parameters checked: gamma-Glutamyltranspeptidase, Alanine Aminotransferase, Albumin, Albumin/Globulin ratio, Alkaline Phosphatase, Aspartate Aminotransferase, Bilirubin direct, Bilirubin total, Calcium, Chloride, Cholesterol, Creatinine, Globulin, Glucose, Inorganic Phosphorous, Potassium, Sodium, Total Protein, Triglycerides, Urea, Uric Acid

URINALYSIS: Yes
- Time schedule for collection of urine: Overnight from Day 25 to Day 26
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Food withdrawn during time in metabolism cage
- Parameters checked: Urine appearance, Bilirubin, Blood, Color, Glucose, Ketone bodies, Microscopic examination of sediment, pH, Protein, Urobilinogen

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once before treatment and weekly thereafter
- Dose groups that were examined: All animals
- Battery of functions tested: sensory activity, grip strength, motor activity.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, the following organ weights were recorded: Adrenals, Brain, Epididymides, Heart, Kidneys, Liver, Spleen, Testes, Thymus. The following tissues were grossly examined: Adrenals, Bone marrow, Brain, Epidiymides, Heart, Small intestine, Large intestine, Colon, Kidneys, Liver, Lungs, Lymph nodes, Sciatic never, Ovaries, Prostate, Seminal vesicle, Spinal cord, Spleen, Stomach, Testes, Thymus, Thyroid gland, Trachea, Urinary bladder, Uterus.

HISTOPATHOLOGY: Yes, the following organs and tissues were examined microscopically in the control and high dose animals: Adrenals, Bone marrow, Brain, Epidiymides, Heart, Small intestine, Large intestine, Colon, Kidneys, Liver, Lungs, Lymph nodes, Sciatic never, Ovaries, Prostate, Seminal vesicle, Spinal cord, Spleen, Stomach, Testes, Thymus, Thyroid gland, Trachea, Urinary bladder, Uterus.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY: All animals survived. There were no toxicologically relevant clinical observations during the study.

BODY WEIGHT AND WEIGHT GAIN: Body weight gains were slightly increased in 10 mg/kg/day-treated males, attaining statistical significance on Days 18 and 25.

HAEMATOLOGY: Females treated at 10 mg/kg/day had reduced coagulation time and an increased number of platelets. After the recovery period, the reduced coagulation time was observed in males and females treated at 10 mg/kg/day. Statistically significantly decreased red blood cell counts and hematocrit and hemoglobin values were observed in males and females treated at 3 or 10 mg/kg/day.

CLINICAL CHEMISTRY: Statistically significantly decreased red blood cell counts and hematocrit and hemoglobin values were observed in males and females treated at 3 or 10 mg/kg/day. Statistically significantly increased urea nitrogen levels were observed in males and females treated at 10 mg/kg/day. In addition, statistically significantly increased uric acid levels were observed in 10 mg/kg/day-treated males and in recovery group males. Statistically significant decreases in triglycerides (10 mg/kg/day group only), total protein, and globulin and an increase in liver enzymes activity. Statistically significantly reduced globulin levels were also observed in females treated at 10 mg/kg/day. After the recovery period, slightly increased ALAT (females only), increased A/G ratio (both genders), and decreased triglycerides (males only) were observed.

URINALYSIS: No toxicologically significant changes were observed in the parameters examined in urinalysis.

NEUROBEHAVIOUR: No abnormal findings were observed in the neurobehavior screens.

ORGAN WEIGHTS: Mean liver weights were markedly increased (ca. 90%) and statistically significant in males treated at 3 or 10 mg/kg/day and were moderately increased (ca. 50%) and statistically significant in females treated at 3 or 10 mg/kg/day. Relative liver weights showed a clear dose-response relationship and were statistically significantly increased in all treatment group males and in females treated at 3 or 10 mg/kg/day.

GROSS PATHOLOGY: No gross abnormalities were observed in any animals.

HISTOPATHOLOGY: NON-NEOPLASTIC: Nearly all 10 mg/kg/day-treated males and females and most 3 mg/kg/day-treated males exhibited slight to moderate diffuse hepatocellular hypertrophy. Increased mean liver weights and hepatocellular hypertrophy were still present in both genders after the recovery period. No other histopathological changes were observed any any other organs in any animals.

HISTOPATHOLOGY: NEOPLASTIC: No neoplastic histopathological changes were observed in any animals.

Effect levels

Dose descriptor:

NOAEL

Effect level:

ca. 10 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: There were no toxicologically relevant clinical observations or changes in food consumption. Body weight gains were slightly decreased in 10 mg/kg/day-treated males, attaining statistical significance on Days 18 and 25.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

All animals survived. There were no toxicologically relevant clinical observations or changes in food consumption. Body weight gains were slightly decreased in 10 mg/kg/day-treated males, attaining statistical significance on Days 18 and 25. Increased liver weights were observed in animals treated at 3 mg/kg/day and greater. Nearly all 10 mg/kg/day-treated males and females and most 3 mg/kg/day-treated males exhibited slight to moderate diffuse hepatocellular hypertrophy. Based on the results of the study, the subacute repeat dose No Observed Adverse Effect Level (NOAEL) of the test article is 10 mg/kg/day.

Executive summary:

The subacute oral toxicity of the test article (grey granules, purity approx. 88 Fl.%, CASRN 496805-64-2, Lot no. 1268147/1-1268154/1) was evaluated in Sprague Dawley (SD) rats following 28 consecutive daily doses. This study was performed in compliance with OECD GLP (1999) and the German Chemical Law (2001). The study method was based on OECD 407 (1995), US EPA OPPTS 870.3050 (2000), and Commission Directive 96/54/EC B.7 (1996). The test article was prepared in deionized water (vehicle) prior to dosing. Rats (5/sex/group) received 0 (vehicle), 0.1, 0.3, 3.0, or 10 mg/kg/day of test article via oral gavage at a dose volume of 5 mL/kg for 28 consecutive days. Two additional groups (5/sex/group) were designated as recovery groups and were similarly dosed at 0 or 10 mg/kg/day of test article. All animals, except for recovery group animals, were euthanized following the last dose. The recovery group animals were euthanized 28 days after the last dose. Parameters evaluated: clinical observations (daily), body weights (pre-test, twice weekly, termination), food consumption, functional observation battery (termination), clinical chemistry (termination), hematological examination (termination), urinalysis (termination), gross necropsy (termination), organ weights of select organs (termination), and histopathology of select tissues (termination). All animals survived. There were no toxicologically relevant clinical observations or changes in food consumption. Body weight gains were slightly decreased in 10 mg/kg/day-treated males, attaining statistical significance on Days 18 and 25. Mean liver weights were markedly increased (ca. 90%) and statistically significant in males treated at 3 or 10 mg/kg/day and were moderately increased (ca. 50%) and statistically significant in females treated at 3 or 10 mg/kg/day. Relative liver weights showed a clear dose-response relationship and were statistically significantly increased in all treatment group males and in females treated at 3 or 10 mg/kg/day. Nearly all 10 mg/kg/day-treated males and females and most 3 mg/kg/day-treated males exhibited slight to moderate diffuse hepatocellular hypertrophy. Increased mean liver weights and hepatocellular hypertrophy were still present in both genders after the recovery period. In 3 or 10 mg/kg/day-treated males, there were statistically significant decreases in triglycerides (10 mg/kg/day group only), total protein, and globulin and an increase in liver enzymes activity. Statistically significantly reduced globulin levels were also observed in females treated at 10 mg/kg/day. After the recovery period, slightly increased ALAT (females only), increased A/G ratio (both genders), and decreased triglycerides (males only) were observed. The observed hepatocellular hypertrophy in the 3.0 and 10.0 mg/kg/day exposure groups were considered to be adaptive effects. This determination of adaptive was based on the absence of histopathological evidence of structural degeneration or necrotic changes in the livers or a dose dependent and biologically significant and consistent increase in at least two other liver parameters. Since other liver enzyme levels were not markedly increased and hepatocellular necrosis was absent, the liver findings in all animals were deemed adaptive (US EPA Health Effect Division (HED) Guidance Document #G0201-(2002 and Hall, Toxicologic Pathology 40: 971-993 (2012))). Females treated at 10 mg/kg/day had reduced coagulation time and an increased number of platelets. After the recovery period, the reduced coagulation time was observed in males and females treated at 10 mg/kg/day. Statistically significantly decreased red blood cell counts and hematocrit and hemoglobin values were observed in males and females treated at 3 or 10 mg/kg/day. These findings were still present after the recovery period. No histopathological changes were observed in the spleen. Statistically significantly increased urea nitrogen levels were observed in males and females treated at 10 mg/kg/day. In addition, statistically significantly increased uric acid levels were observed in 10 mg/kg/day-treated males and in recovery group males. No histopathological changes were observed in the kidneys. Based on the results of the study, the subacute repeat dose No Observed Adverse Effect Level (NOAEL) of the test article is 10 mg/kg/day.