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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
1996
Deviations:
yes
Principles of method if other than guideline:
Deviations: The liver weights of male no. 15 (recovery group 1) and female no. 100 were not determined and a few tissues were not available for histopathology. Sufficient data was available for evaluation.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,3,3,4,4-pentafluoro-2,5-bis(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-5-methoxyoxolane
EC Number:
812-244-2
Cas Number:
957209-18-6
Molecular formula:
C11H3F19O2
IUPAC Name:
2,3,3,4,4-pentafluoro-2,5-bis(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-5-methoxyoxolane
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Batch: L-21343
- Expiration date of the lot/batch: 27 August, 2014
- Purity test date: 27 August, 2012

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature in the dark.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test article was dosed undiluted.

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Wistar Han sources from Charles River Deutschland, Sulzfeld, Germany.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 11 weeks
- Weight at study initiation: Male mean: 323.5 g, Female mean: 208.5 g
- Fasting period before study: not specified.
- Housing: Pre-mating: animals were housed in groups of 5/sex/cage in Macrolon plastic cages (MIV type, heigh 18 cm). This was also applicable for Recovery animals throughout the complete study eriod. Mating: Main females were caged together with Main males on a one-to-one basis in Macrolon plastic cages (MIII type, height 18 cm). Post-mating: Main males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 animals per cage. Main females were individually housed in Macrolon plastic cages (MIII ype, height 18 cm). Lactation: Pups were kept with the dam until termination in Macrolon plastic cages (MIII type, height 18 cm). During locomotor activity monitoring of the dams, the pups were kept warm in their home cage using bottles filled with warm water.
- Diet (e.g. ad libitum): Pelleted rodent diet (SM R/M-Z from SSNIFF), ad libitum.
- Water (e.g. ad libitum): Tap water, ad libitum.
- Acclimation period: At least 5 days prior to the start of treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):18-24
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 October, 2012 To: 28 December, 2012

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was dosed unchanged.
Analytical verification of doses or concentrations:
no
Remarks:
Test article was dosed unchanged so the initial purity verification was sufficient.
Duration of treatment / exposure:
All rats were exposed once daily for 7 days per week; all males were exposed for a total of 29 days, including 2 weeks of exposure prior to mating and during mating for rats in the 4 main groups, and all females were exposed for a total of 41-47 days prior to mating, during mating, during post mating, and lactation periods. Males in the recovery groups were allowed to recover for 14 days following the last exposure.
Frequency of treatment:
All rats were exposed once daily for 7 days per week; all males were exposed for a total of 29 days, including 2 weeks of exposure prior to mating and during mating for rats in the 4 main groups, and all females were exposed for a total of 41-47 days prior to mating, during mating, during post mating, and lactation periods. Males in the recovery groups were allowed to recover for 14 days following the last exposure.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw (total dose)
Remarks:
Control animals were dosed with water.
Dose / conc.:
100 mg/kg bw (total dose)
Dose / conc.:
300 mg/kg bw (total dose)
Dose / conc.:
1 000 mg/kg bw (total dose)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on a range-finding study.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: Random
- Post-exposure recovery period in satellite groups: 14 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: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: First day of exposure and weekly thereafter.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes, weekly.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Week 4
- Dose groups that were examined: 5 Main animals/sex/group and all Recovery animals.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On the day of necropsy
- Anaesthetic used for blood collection: Yes (isofluorane)
- Animals fasted: Yes
- How many animals: 5 Main animals/sex/group and all Recovery animals.
- Parameters checked: white blood cell count, differential leucocyte count, red blood cell count, red blood cell distribution width, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, platelets, prothrombin time, activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: On the day of necropsy
- Anaesthetic used for blood collection: Yes (isofluorane)
- Animals fasted: Yes
- How many animals: 5 Main animals/sex/group and all Recovery animals.
- Parameters checked: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, albumin, total bilirubin, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, inorganic phosphate, bile acids

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Week 4
- Dose groups that were examined: The selected Main males and all Recovery males were tested during Week 4 of treatment and the selected Main females were tested towards the end of the scheduled lactation period (all before blood sampling) (from lactation Day 4 onwards) and all Recovery females were tesed on the first day a Main female was tested. Since no treatment-related findings were noted in any of the above tests, these tests were not conducted for Recovery animals at the end of the recovery phase.
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Histopathology included adrenal glands, brain, colon, duodenum, eyes, female mammary gland area, femur including joint, heart, ileum, jejunum, kidneys, liver, lung, lymph nodes, peyer's patches, pituitary gland, rectum, sciatic nerve, skeletal muscle, spinal cord, spleen, sternum with bone marrow, stomach, thymus, thyroid, trachea, urinary bladder, cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate gland, seminal vesicles, testes, uterus, and vagina.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity related to the test article were noted in any animal.
Mortality:
no mortality observed
Description (incidence):
No treatment related mortality occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes in body weight and body weight gain were noted.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
no effects observed
Description (incidence and severity):
Food consumption before or after allowance for body weight was similar between treated and control animals.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Pupillary reflex was normal in all selected animals tested in the FOB.
Haematological findings:
no effects observed
Description (incidence and severity):
Hematological parameters of treated rats were considered not to have been affected by treatment.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Clinical biochemistry parameters of treated rats were considered not to have been affected by treatment.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all selected animals.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes were noted in organ weights and organ to body weight ratios.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.
Neuropathological findings:
no effects observed
Description (incidence and severity):
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all selected animals.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment-related microscopic findings.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment-related microscopic findings.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
food efficiency
gross pathology
haematology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
ophthalmological examination
organ weights and organ / body weight ratios

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the test article has a No Observed Adverse Effect Level of 1000 mg/kg/day.
Executive summary:

The repeated dose oral toxicity potential and the reproductive / developmental toxicity potential of the test article was evaluated in male and female Wistar Han rats via daily oral gavage for 28 days. The study was performed in compliance with OECD GLP (1997). The study design was based on OECD 422 (1996) and US EPA OPPTS 870.3650 (2000), and essentially conforms to OECD 421 (1995), US EPA OPPTS 870.3550 (2000), EC 440/2008 Part B B7. L142 (2008), OECD 407 (2008), and US EPA OPPTS 870.3050 (2000). The test article was dosed undiluted and given at a dose volume of 0.055-0.553 mL/kg to four groups of rats by oral gavage. Rats (10/sex/group) were dosed with 0, 100, 300, and 1000 mg/kg-body weight test article per day. Additional rats (5 males/group) were exposed at 0 mg/kg-day or 1000 mg/kg-day for a recovery study. All rats were dosed once daily for 7 days per week; all males were exposed for a total of 29 days, including 2 weeks of exposure prior to mating and during mating for rats in the 4 main groups, and all females were exposed for a total of 41-47 days prior to mating, during mating, during post mating, and lactation periods. Males in the recovery groups were allowed to recover for 14 days following the last dose. Observational parameters evaluated in all main and recovery groups rats included; mortality (twice daily), clinical signs (daily), body weights (first day of exposure and weekly thereafter), food consumption (weekly), and general reproduction data (during mating and post-mating). Pups born to mating mothers were evaluated for mortality (daily), clinical signs (at least once daily), body weights (Days 1 and 4 of lactation), and sex determination (Days 1 and 4 of lactation). Hematology, clinical biochemistry, necropsy, and histopathology and organ weight collection were performed on selected tissues of rats in the main exposure groups (5/sex/group). Histopathology included adrenal glands, brain, colon, duodenum, eyes, female mammary gland area, femur including joint, heart, ileum, jejunum, kidneys, liver, lung, lymph nodes, peyer's patches, pituitary gland, rectum, sciatic nerve, skeletal muscle, spinal cord, spleen, sternum with bone marrow, stomach, thymus, thyroid, trachea, urinary bladder, cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate gland, seminal vesicles, testes, uterus, and vagina. No treatment related mortality occurred during the study period. No clinical signs of toxicity related to the test article were noted in any animal. Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all selected animals tested in a functional observational battery. No toxicologically relevant changes in body weight and body weight gain were noted. Food consumption before or after allowance for body weight was similar between treated and control animals. Hematological and clinical biochemistry parameters of treated rats were considered not to have been affected by treatment. Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment. No toxicologically relevant changes were noted in organ weights and organ to body weight ratios. There were no treatment-related microscopic findings. No toxicologically relevant effects on reproductive parameters were noted. No toxicologically relevant effects on gestation index and duration, parturition, maternal care and postnatal pup development were observed. Based on the results of the study, the test article has a No Observed Adverse Effect Level of 1000 mg/kg/day.