Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-compliant study, minor restrictions in design and/or reporting but otherwise adequate for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Two groups of 5 male rats were administered a single oral dose of either radiolabeled (14C) tripropylene glycol or non-radiolabeled monopropylene glycol by gavage in water at target concentrations 40 mg/kg bw and 50 mg/kg bw, respectively. The animals were placed in metabolism cages and excreta were collected for ca. 24 hours post-dosing. After sacrifice 24 hours post-dosing the remaining radioactivity in tissues and the amount of mono-, di- and tripropylene glycol in urine was determined for the first group and urine was analyzed for free and acid-abile conjugates of mono-, di- and tripropylene glycol for both groups.
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test materials (as cited in study report): tripropylene glycol, monopropylene glycol
- Substance type: organic
- Physical state: liquids
- Analytical purity: 99.8% for tripropylene glycol, 99.7% for monopropylene glycol
- Impurities (identity and concentrations): for tripropylene glycol: 0.08% dipropylene glycol, 0.08% unidentified components; 0.06% water. For monopropylene glycol: 0.12% dipropylene glycol, 0.16% water.
- Lot/batch No.: non-radiolabelled tripropylene glycol: TB930101-07-2, radiolabelled tripropylene glycol: 911204; monopropylene glycol: 933385
- Supplier: non-radiolabelled tripropylene glycol: Designed Chemicals TS&D (The Dow Chemical Company, Midland, MI); radiolabeled tripropylene glycol: Wizard Laboratories (Davis, CA); monopropylene glycol: Fisher Scientific.
- Isomers composition (for tripropylene glycol) not determined, but the material currently produced by the Dow Chemical Company is ~70% secondary hydroxyl
- Radiochemical purity (for tripropylene glycol): 84.0± 2.0% tripropylene glycol with a 11.7± 1.7% impurity consisting of the higher molecular weight polymer tetrapropylene glycol. Another 1.7% of the radioactivity eluted at the retention time of dipropylene glycol.
- Specific activity (for tripropylene glycol): 10.50 mCi/mmol
- Locations of the label (for tripropylene glycol): at secondary C atom in α position with respect to either ther function or hydroxide moiety
Radiolabelling:
yes
Remarks:
14-C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation:
- Weight at study initiation: 187-197 g
- Fasting period before study: 17 hours
- Diet (e.g. ad libitum): certified rodent chow #5002 (Purina Mills, Inc.), ad libitum, except withdrawn approx. 17 hours prior to the administration of the test material and returned ca. 4 hours post-dosing.
- Water (e.g. ad libitum): municipal tap water, ad libitum
- Acclimation period: ca. 1 week, plus 2 days in metabolism cages prior to the dosing


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
The rooms were designed to maintain adequate environmental temperature, relative humidity and airflow for the rat.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The oral dose solutions were prepared in distilled water to provide target doses of 40 mg/kg tripropylene glycol and 50 mg/kg monopropylene glycol when administered in an amount of 4 g dose solution/kg bw.
The tripropylene glycol dose solution was prepared by adding appropriate amounts of 14C-tripropylene glycol and non-radiolabeled tripropylene glycol to distilled water to obtain a target dose of 40 mg tripropylene glycol/kg bw. The target radioactivity was ca. 125 μCi per animal. Aliquots of the tripropylene glycol dosing solution were analyzed to determine the amount of radioactivity and actual tripropylene glycol concentration in the dosing solution.
The monopropylene glycol dose solution was prepared by adding appropriate amounts of non-radiolabeled monopropylene glycol to distilled water to obtain a target dose of 50 mg/kg bw. Aliquots of the monopropylene glycol dosing solution were analyzed to determine the actual monopropylene glycol concentration in the dosing solution.


VEHICLE
Water
- Amount of vehicle (if gavage): 4 g dose solution/kg bw (target); 4.5 g dose solution/kw bw (actual for 14C-tripropylene glycol); 4.2 g dose solution/kg bw (actual for monopropylene glycol).
Duration and frequency of treatment / exposure:
Single oral target dose
Doses / concentrations
Remarks:
Doses / Concentrations:
Target:
40 mg/kg bw for 14C-tripropylene glycol (labelled at secondary C atom in α position with respect to ether function or hydroxide moiety)
50 mg/kg bw for non-radiolabelled monopropylene glycol

Actual received:
48.2 mg/kg bw for 14C-tripropylene glycol
59.4 mg/kg bw for monopropylene glycol
No. of animals per sex per dose:
5 males/dose
Control animals:
no
Details on study design:
- Dose selection rationale: a dose of 40 mg tripropylene glycol/kg bw was selected based on recent studies on dipropylene glycol dimethyl ether (DPGDME) where a low dose of 30 mg 14C-DPGDME was administered.
Assuming that one mole of tripropylene glycol could be metabolized to 3 moles of monopropylene glycol, a 50 mg/kg dose of monopropylene glycolwas selected as 3-fold molar dose to tripropylene glycol.
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, liver, kidney, fat, brain, muscle, and remaining carcass.
- Time and frequency of sampling: for approx. 24 hours post-dosing for excreta; at sacrifice 24-hours post-dosing for blood, liver, kidney, fat, brain, muscle, and remaining carcass.
- From how many animals: 5 (samples pooled for urine)
- Method type(s) for identification: liquid scintillation counting (radioactivity determination); GC/NCI/MS (chemical analysis)


Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Following the administration of 48.2 mg 14C-tripropylene glycol/kg bw to male rats, an average of 91.4 ±2.07 % (SD) of the 14C label administered to animals was recovered from excreta, CO2, skin, tissues and carcass when the animals were sacrificed approximately 24 hours post-dosing. This indicates that 14C-tripropylene glycol is rapidly absorbed if administered by oral gavage.
Details on distribution in tissues:
Approximately 10% of the radiolabelled dose was recovered from tissues and carcass. Expressed as percent of administered dose per gram of tissue, the liver and kidney had the greatest amounts of radiolabel per gram of tissue 24 hours after dosing with 14C-tripropylene glycol (0.20 ± 0.02% and 0.09 ± 0.00%, respectively). The remaining carcass had 0.06 ± 0.02% of the administered dose per gram. The 14C concentration in the liver and kidneys, on a per gram of tissue basis, was approximately 6.4-fold and 2.8 fold greater than blood (0.03 ± 0.00%), respectively. Skin, brain, muscle and fat all had less radiolabel per gram of tissue than blood (< 0.03%).
Details on excretion:
The greatest percentage of the administered radiolabeled dose was recovered in the urine (52.3 ± 3.54%), with most of the remaining radioactivity exhaled as 14CO2 (20.7±0.59%). Approximately 5% and 3% of the dose was recovered in the feces and the final cage wash, respectively.
Toxicokinetic parameters
Toxicokinetic parameters:
other: No information

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
tripropylene glycol is extensively metabolized, as only 5.8% of the dose was recovered as unmetabolized parent compound in the urine, while 7.2% was recovered as acid-labile conjugates of tripropylene glycol, 5.1% and 3.3% as free and acid-labile conjugates of dipropylene glycoland 3.3% and 0.6% as free and acid-labile conjugates of monopropylene glycol, respectively. Approximately 5%, 10%, and 3% of the administered dose was found in the feces, tissues, and carcass, respectively. Further metabolism of tripropylene glycol appears to involve entry into intermediary metabolism via monopropylene glycol formation, and monopropylene glycol itself and suggests that some or all of the 14C remaining in the tissues and carcass at 24 hours post-dosing could be metabolically incorporated single 14C carbon atoms. It is noteworthy that a large fraction (21%) of the 14C-tripropylene glycol dose was catabolized all the way to 14-CO2, indicating considerable breakdown of tripropylene glycol. The data indicate tripropylene glycol is readily biotransformed to dipropylene glycol and monopropylene glycol which is then further oxidized to CO2. The isomeric composition was approximately 70% (2,2’) secondary isomer, which is typical of the production method.

Following the administration of the 59.4 mg monopropylene glycol/kg bw to male rats, free monopropylene glycol was detectable in the urine at an amount of 1127 μg monopropylene glycol per rat, corresponding to 10.6% of the dose of monopropylene glycol. After acid hydrolysis, 1197 μg monopropylene glycol per rat was observed, 11.2% of the dose. Following monopropylene glycol administration 69 μg monopropylene glycol were recovered as acid-labile conjugates, or less than 1% of the dose of monopropylene glycol administered.

Any other information on results incl. tables

Excretion Following an oral dose of 48.2 mg tripropylene glycol/kg bw, 5.8% of the dose was recovered unchanged in urine (537.9 μg recovered as tripropylene glycol/9240 μg tripropylene glycol administered). Following acid hydrolysis of the urine, total amounts of 1205, 813.4 and 537.6 μg of tripropylene glycol, dipropylene glycol and monopropylene glycolG, respectively, per rat were observed. Therefore, by difference, 667.1, 323.6 and 170.6 μg of tripropylene glycol, dipropylene glycol and monopropylene glycol were recovered in the acid-labile fractions. The 1205 μ tripropylene glycol is equivalent to 13% of the administered dose (1205 μg recovered as tripropylene glycol/9240 μg tripropylene glycol administered). Of the total amounts of the propylene glycols recovered in the urine, 55%, 43% and 32% were recovered as acid-labile conjugates of tripropylene glycol, dipropylene glycol and monopropylene glycol, respectively. The data of the animals administered monopropylene glycol indicate that approximately 11% of the monopropylene glycol administered was recovered in the urine as free monopropylene glycol with < 1% of the dose recovered as acid-labile conjugates.

Applicant's summary and conclusion