Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted in compliance with GLP regulations with the exception of a final report being written.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2004

Materials and methods

Principles of method if other than guideline:
3 female rats per group were dosed daily for 5 days with 150, 450, or 1000 mg/kg test article. Clinical signs (daily), body weights (Day 1 and 5) and food consumption (over Days 1-5) were noted for all animals. Gross necropsy was performed on Day 5.
GLP compliance:
yes
Remarks:
With the exception of a final report being written.
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report): T-7867
- Substance type: mono-constituent
- Physical state: Liquid
- Analytical purity: 98.5%
- Lot/batch No.: Lot 4 with spikes
- Expiration date of the lot/batch: 30 December 2005
- Storage condition of test material: Refridgerated
- Other:

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: Not reported
- Fasting period before study: No data
- Housing: Group housed by sex in Marcrolon plastic cages (type IV, height 18 cm).
- Diet (e.g. ad libitum): Altromin (code VRF 1) pelleted lab diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: At least 5 days before the start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 C
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: No data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Perfluorohexane: PF-5060 (FC-72)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The test article was dosed at 150, 450, and 1000 mg/kg/day.
- Amount of vehicle (if gavage): Dose volumes were 0.09375, 0.28125, and 0.6250 mL/kg/day, respectively.
- Justification for choice of vehicle: Solubility and to reduce volatility.
- Lot/batch no. (if required): 040183

MAXIMUM DOSE VOLUME APPLIED: 0.6250 mL/kg/day

DOSAGE PREPARATION (if unusual):

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: This was a range-finding study for a future repeat-dose study.
Doses:
150, 450, and 1000 mg/kg/day.
No. of animals per sex per dose:
3 females per dose.
Control animals:
no
Details on study design:
- Duration of observation period following administration: None, necropsy was conducted on Day 5.
- Frequency of observations and weighing: Observations were made at least once daily and body weights were recorded on Days 1 and 5.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, food consumption.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 450 - < 1 000 mg/kg bw
Based on:
test mat.
Mortality:
1000 mg/kg-day: All rats were euthanized between days 2 and 4 due to moribund condition. 450 mg/kg-day: All animals survived. 150 mg/kg-day: All animals survived.
Clinical signs:
1000 mg/kg-day: The following clinical observations were noted in all rats: lethargy, flat/hunched posture, abnormal gait, labored respiration, piloerection, diarrhea, brown staining of genital region, pale, hypothermia, and/or abdominal swelling. 450 mg/kg-day: The following clinical observations were noted in all rats: lethargy, hunched posture, piloerection, diarrhea, brown staining of genital region, lean appearance, and abdominal swelling (1 animal). 150 mg/kg-day: The following clinical observations were noted in all rats: hunched posture, piloerection, and diarrhea.
Body weight:
1000 mg/kg-day: Weight changes were not recorded as all animals were euthanized prior to beigh weighed on Day 5. 450 mg/kg-day: All animals lost up to 21% of their body weights. 150 mg/kg-day: All animals lost up to 20% of their body weights.
Gross pathology:
1000 mg/kg-day: Macroscopic examination revealed: gastrointestinal tract distended with gas (all animals), reduced size of the spleen and thymus (2 animals), thickened and pale discolored liver with accentuated lobular pattern (1 animal), and enlarged adrenal glands (1 animal). 450 mg/kg-day: Macroscopic examination revealed: gastrointestinal tract distended with gas (all animals) and reduced size of the spleen and/or thymus (2 animals). One animal had a slightly lower liver weight. Other liver and kidney weights were normal. 150 mg/kg-day: Macroscopic examination revealed: gastrointestinal tract distended with gas (all animals), red discoloration of mesenteric lymph nodes (1 animal), and reduced size of the spleen (1 animal). Liver and kidney weights were normal.
Other findings:
Food consumption: 450 mg/kg-day: Reduced food consumption was observed in all animals. 150 mg/kg-day: Reduced food consumption was observed in all animals.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The 5-day oral LD50 of MTDID 948 is greater than 450 mg/kg-day but less than 1000 mg/kg-day.
Executive summary:

The oral toxicity of the test article was (clear, colorless liquid; CASRN 84650-68-0, purity 98.5%; Lot 4, with spikes) was evaluated in Wistar rats in order to determine appropriate doses for a 28-day subacute study. This study was performed under OECD GLP (1997) conditions. Female rats (3/group) received 150, 450, or 1000 mg/kg-day of the test article by oral gavage for 5 days. After the last dose, all surviving animals were euthanized, and macroscopic examinations were performed. Body weights and clinical observations were recorded. Kidney and liver weights were recorded. 1000 mg/kg-day: All rats were euthanized between days 2 and 4 due to moribund condition. The following clinical observations were noted in all rats: lethargy, flat/hunched posture, abnormal gait, labored respiration, piloerection, diarrhea, brown staining of genital region, pale, hypothermia, and/or abdominal swelling. Macroscopic examination revealed: gastrointestinal tract distended with gas (all animals), reduced size of the spleen and thymus (2 animals), thickened and pale discolored liver with accentuated lobular pattern (1 animal), and enlarged adrenal glands (1 animal). 450 mg/kg-day: All animals survived. Reduced food consumption was observed, and all animals lost up to 21% of their body weights. The following clinical observations were noted in all rats: lethargy, hunched posture, piloerection, diarrhea, brown staining of genital region, lean appearance, and abdominal swelling (1 animal). Macroscopic examination revealed: gastrointestinal tract distended with gas (all animals) and reduced size of the spleen and/or thymus (2 animals). One animal had a slightly lower liver weight. Other liver and kidney weights were normal. 150 mg/kg-day: All animals survived. Reduced food consumption was observed, and all animals lost up to 20% of their body weights. The following clinical observations were noted in all rats: hunched posture, piloerection, and diarrhea. Macroscopic examination revealed: gastrointestinal tract distended with gas (all animals), red discoloration of mesenteric lymph nodes (1 animal), and reduced size of the spleen (1 animal). Liver and kidney weights were normal. The 5-day oral LD50 of the test article is greater than 450 mg/kg-day but less than 1000 mg/kg-day.