[No public or meaningful name is available]

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2009

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test article (DONOL) was prepared in propylene glycol. The test article was administered to 3 rats at a target dose of 72.6 umol/kg body weight (26.5 mg/kg). A control group received water by oral gavage. After dosing, animals were placed in metabolism cages and urine was collected at specified intervals for 96 hours. Animals were observed daily for clinical signs of toxicity. Body weights were measured prior to dosing and approximately daily thereafter. On Day 4, necropsies were performed and liver weights were recorded for all animals. Blood specimens were collected at necropsy, processed to serum, and frozen for possible future analysis. Urine samples were analyzed for the test articles and for evidence of metabolites by 19F-NMR spectroscopy. Several urine samples were also analyzed by LC/MS-MS to assist in identifying metabolites.

GLP compliance:

no

Remarks:

This was a screening study not intended to be conducted via GLP.

Test material

Test material information

Constituent 1

Reference substance name:

1,1,3-trihydro-4,8-dioxaperfluorononanol

Cas Number:

958445-53-9

Molecular formula:

C7H4F12O3

IUPAC Name:

1,1,3-trihydro-4,8-dioxaperfluorononanol

Test material form:

liquid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: 3M Company, no lot reported
- Purity, including information on contaminants, isomers, etc.:


STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Tightly sealed in original container at room temperature.
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: No data
- Solubility and stability of the test material in the solvent/vehicle and the exposure medium: No data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing (e.g. warming, grinding): Prepared in propylene glycol

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Commonly used test system for toxicological studies.

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Labs
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 232-244 grams
- Housing: All animals were acclimated under study conditions for a minimum of 3 days prior to the initiation of treatment. During acclimation and when not in metabolism cages, the rats were group housed in solid-bottomed polycarbonate cages. Immediately after dosing, the rats were placed in commercially available polycarbonate metabolism cages for urine collection
- Diet (e.g. ad libitum): Harlan Teklad Rat/Mouse 2018 Diet (Harlan Teklad, Madison, WI) was freely available to the animals throughout the study
- Water (e.g. ad libitum): Tap water (St. Paul, MN municipal water supply) was freely available to the animals throughout the study
- Acclimation period: 3 days
- Health status: Only healthy animals were utilized.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 69-75
- Humidity (%): 30-70
- Air changes (per hr): at least 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12
- Fasting period : None

IN-LIFE DATES: From: 28 August, 2006 To: 01 September, 2006

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test article was prepared in propylene glycol (DONOL). The test article was administered to 3 rats at a target dose of 72.6 umol/kg body weight (26.5 mg/kg).

Duration and frequency of treatment / exposure:

A single oral dose was administered via gavage

Doses / concentrations

Dose / conc.:

26.5 mg/kg bw/day (nominal)

Remarks:

Dose volume was 5 mL/kg body weight.

No. of animals per sex per dose / concentration:

3 males were utilized

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

None

Details on study design:

The test article (DONOL) was prepared in propylene glycol. The test article was administered to 3 rats at a target dose of 72.6 umol/kg body weight (26.5 mg/kg). A control group received water by oral gavage. After dosing, animals were placed in metabolism cages and urine was collected at specified intervals for 96 hours. Animals were observed daily for clinical signs of toxicity. Body weights were measured prior to dosing and approximately daily thereafter. On Day 4, necropsies were performed and liver weights were recorded for all animals. Blood specimens were collected at necropsy, processed to serum, and frozen for possible future analysis. Urine samples were analyzed for the test articles and for evidence of metabolites by 19F-NMR spectroscopy. Several urine samples were also analyzed by LC/MS-MS to assist in identifying metabolites.

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, serum (at necropsy)
- Time and frequency of sampling: Immediately after dosing, all test article-treated rats were placed in individual metabolism cages and urine was collected over the following intervals: 0-6 hours, 6-24 hours, 24-48 hours, and 72-96 hours postdose. Animals were removed from the metabolism cages after the 24-48 hour collection and group housed in solid-bottomed polycarbonate cages until the beginning of the 72-96 hour collection. Urine specimens were transferred into labeled polypropylene tubes and the approximate total urine volumes were recorded. Serum was collected on Day 4 at necropsy.
- Other:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): Urine and serum were evaluated for metabolites via 19F-NMR spectroscopy and LCMS.
- Time and frequency of sampling: See above section.
- From how many animals: 3 animals, not pooled
- Method type(s) for identification: 19F-NMR spectroscopy and LCMS

Results and discussion

Main ADME results

Type:

excretion

Results:

Based on the metabolites, calculated urinary recovery for DONOL from 0 to 96 hours post dose was 52.2% of the administered dose

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption was observed as metabolites of DONOL were identified in the urine.

Details on distribution in tissues:

Not examined

Details on excretion:

Based on the metabolites, calculated urinary recovery for DONOL from 0 to 96 hours post dose was 52.2% of the administered dose

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

A carboxylate metabolite was identified.

Applicant's summary and conclusion

Conclusions:

DONOL is expected to have low bioaccumulation potential as the urinary half-life was < 4 days.

Executive summary:

This study assessed the urinary elimination and potential toxicity of DONOL (liquid, purity 98.4%) in male Sprague Dawley rats after a single oral dose. This study was based on a custom protocol and was not intended to comply with GLP guidelines. The test article (DONOL) was prepared in propylene glycol. The test article was administered to 3 rats at a target dose of 72.6 umol/kg body weight (26.5 mg/kg). A control group received water by oral gavage. After dosing, animals were placed in metabolism cages and urine was collected at specified intervals for 96 hours. Animals were observed daily for clinical signs of toxicity. Body weights were measured prior to dosing and approximately daily thereafter. On Day 4, necropsies were performed and liver weights were recorded for all animals. Blood specimens were collected at necropsy, processed to serum, and frozen for possible future analysis. Urine samples were analyzed for the test articles and for evidence of metabolites by 19F-NMR spectroscopy. Several urine samples were also analyzed by LC/MS-MS to assist in identifying metabolites. No mortality or abnormal clinical signs occurred during the study. Transient significantly decreased mean body weight gains occurred from Day 0 – 1 for the DONOL-treated groups relative to the control group. Over the entire study (Days 0 - 4), mean body weight gains for the test article-treated group was similar to the control group mean. There were no gross abnormalities observed during the necropsy. Mean liver-to-body weight ratios were increased for the DONOL-treated groups relative to the control group. DONOL was recovered in the urine as a carboxylate metabolite. The parent compound (DONOL) was not detected in urine samples. Based on the metabolites, calculated urinary recovery for DONOL from 0 to 96 hours post dose was 52.2% of the administered dose. DONOL was excreted as metabolites. A significant increase in liver-to-body weight ratio was observed in the test article-treated group. DONOL is expected to have low bioaccumulation potential as the urinary half-life was < 4 days.