1-phenoxypropan-2-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study methodology followed was equivalent or similar to OECD TG 417 and EPA OPPTS 870.7485 and was conducted in accordance with the Principles of GLP

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Reference 2

Reference Type:

publication

Title:

Oral absorption, metabolism, elimination of 1-phenoxy-2-propanol in rats

Author:

Saghir SA, Brzak KA and Bartels MJ

Year:

2003

Bibliographic source:

Manuscript submitted for publication

Materials and methods

Objective of study:

other: This study was conducted to determine the absorption, elimination and metabolism of 1-phenoxy-2- propanol (DOWANOL PPh) in Fischer 344 rats following oral administration.

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1-phenoxypropan-2-ol

EC Number:

212-222-7

EC Name:

1-phenoxypropan-2-ol

Cas Number:

770-35-4

Molecular formula:

C9H12O2

IUPAC Name:

1-phenoxypropan-2-ol

Constituent 2

Reference substance name:

1-phenylpropan-2-ol

EC Number:

211-821-0

EC Name:

1-phenylpropan-2-ol

Cas Number:

698-87-3

IUPAC Name:

1-phenylpropan-2-ol

Details on test material:

- Name of test material (as cited in study report): Dowanol PPh
- Physical state: clear colorless liquid
- Analytical purity: 93%
- Impurities (identity and concentrations): not specified
- Composition of test material, percentage of components: not specified
- Isomers composition: not specified
- Purity test date: not specified
- Lot/batch No.: Lot # 04114EU (non-radiolabeled) and Lot # 090H9215 (radiolabeled)
- Expiration date of the lot/batch: not specified
- Radiochemical purity (if radiolabelling): 95.7%
- Specific activity (if radiolabelling): 6.8 mCi/mmol
- Locations of the label (if radiolabelling): 14C-phenyl ring
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions: stable
- Storage condition of test material: not specified

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 11 weeks
- Weight at study initiation: 200-208 grams
- Fasting period before study: 16 hours prior to administration of Dowanol PPh
- Housing: individually housed
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 40-70 %
- Air changes (per hr): 12-15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: methyl cellulose ether

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The oral doses were prepared as aqueous suspensions in 0.5% METHOCEL, cellulose ether. Appropriate amounts of 14C-labeled and non-radiolabeled DOWANOL PPh were mixed to obtain the target concentration of 2 and 20 mg/g METHOCEL. Dose suspensions were achieved by mixing DOWANOL PPh and METHOCEL with a magnetic stirrer for 24 hr at 4 oC. The targeted radioactivity in the dose solutions was 50 mCi/g METHOCEL. The dose solutions were continuously mixed for homogeneity with a magnetic stirrer until dosed.

VEHICLE
- Justification for use and choice of vehicle (if other than water): recommended by various regulatory agencies
- Concentration in vehicle: 2 and 20 mg/g METHOCEL
- Amount of vehicle (if gavage): The dose suspensions were administered at a target volume of 5 g/kg body weight.
- Lot/batch no. (if required): not specified
- Purity: not specified

HOMOGENEITY AND STABILITY OF TEST MATERIAL: The concentration of DOWANOL PPh and radioactivity in each of the dose solutions is
shown in Table 1. The target concentrations of DOWANOL PPh in METHOCEL dose solutions were 2 and 20 mg/g, however the actual concentrations of the dosing solutions were 1.99 and 18.7 mg/g, 93.5-99.5% of the target concentrations. Similarly, the target radioactivity in dose solutions was 100 mCi/g and the actual radioactivity in dose solutions was 96.2 and 102.2 mCi/g for the low and high doses, respectively (Table 1).
Table 2 shows the amount of DOWANOL PPh administered to individual animal in each dose group. The low dose was administered with an average of 9.83 ± 0.19 mg/kg DOWANOL PPh (98% of the targeted dose), with each animal receiving an average of 97 ± 1 mCi of radioactivity. The high dose animals received an average of 93.2 ± 3.4 mg/kg DOWANOL PPh (93% of the target amount). The average radioactivity administered to animals in the high dose group was 104 ± 2 mCi (104% of the target amount)

Duration and frequency of treatment / exposure:

48 hour(s)

Doses / concentrations

Remarks:

Doses / Concentrations:
Males: 10 or 100 mg/kg

No. of animals per sex per dose / concentration:

Males: 6

Control animals:

no

Positive control reference chemical:

not applicable

Details on study design:

- Dose selection rationale: based on acute studies
- Rationale for animal assignment: random

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, cage washes
- Time and frequency of sampling: Urine - All urine voided by individual animals at 0-12 hr, 12-24 hr, and 24-48 hr post dosing were collected in dry-ice cooled traps. Cages were rinsed with water at the time the traps were changed and the rinse collected. Urine specimens and cage rinses were weighed, and weighed aliquots of each sample were analyzed for radioactivity by LSC, as described below. Urine samples of each dose and time were pooled using equal volume aliquots and stored at –80oC until analyses were performed. Feces - Feces were collected in dry ice, chilled containers for 24-hr intervals. An aqueous homogenate (~25% w/w) was prepared and weighed aliquots of these homogenates were placed in scintillation vials, solubilized, and quantitated for radioactivity by LSC. In addition, equal volume aliquots of fecal homogenates from each animal were taken from the 0–24-hr collection interval, pooled and stored at –80oC until analysis. Cage wash - Following the terminal sacrifice of the animals, a final cage wash was performed. The final cage wash and contents were collected, and the weight of the sample was determined. A weighed aliquot of the final cage wash was analyzed for radioactivity for mass-balance.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: As most of the administered DOWANOL PPh was eliminated in urine within the first 24 hr after dosing, only samples collected between 0-12 and 12-24 hr were used for metabolite identification. Urine samples collected between 24-48 hr were not analyzed for metabolite(s). Since <10% of the administered dose was excreted in feces, no chemical analysis was performed on pooled fecal samples.
- From how many animals: Pooled urine samples from 0-12 and 12-24 hr time points of the 10 and 100 mg/kg doses were centrifuged to remove solid particles and analyzed by HPLC with 14C-detection to obtain radiochemical profiles of urinary activity. There was no loss of radioactivity during
centrifugation
- Method type(s) for identification: HPLC separations with electrospray ionization (ESI) and detection by mass spectrometry (MS). Pooled urine samples from the 0-12 hr time point, from 100 mg/kg dosed animals, were analyzed by two different mass spectrometers using HPLC/ESI/MS and HPLC/ESI/MS/MS for identification of urinary metabolites.
- Limits of detection and quantification: as shown in Appendix 1

Statistics:

Descriptive statistics were used (i.e., mean ± standard deviation). All calculations in the database were conducted using MicrosoftÒ ExcelÒ, spreadsheets and databases in full precision mode (15 digits of accuracy).

Results and discussion

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The administered doses were absorbed relatively rapidly from the GI tract, with 81-90% of the dose absorbed and excreted in urine within 12 hr after the administration of both of the doses

Details on distribution in tissues:

not applicable

Details on excretion:

Almost all the administered dose was eliminated in urine within 48 hr, accounting for 88 ± 12% of the low and 96 ± 3% of the high dose. Fecal elimination accounted for less than 10% of the administered dose (5.5 - 8.1%), with the exception of one rat (01B1556) in the low dose group in which the fecal elimination was 20% of the dose and this high fecal elimination was probably due to contamination of fecal droppings with urine. Rats were able to eliminate virtually all the administered dose within 48 hr. Mean recovery of the administered dose was 103 ± 1% for the low dose group and 103 ± 3% for the high dose group. As greater than 95% of the administered dose was eliminated from the body within 48 hr, no analysis of radioactivity in carcasses and skin was performed.
Most of the dose, 83- 91%, was eliminated in the urine within the first 12 hours. Within the second 12 hours, additional urinary excretion was 3.3-6.8% of the original dose; within the last 24-hour period, an incremental 1.0 to 2.7% was excreted in the urine. A total of 93 ± 5% of the low dose (10 mg/kg) was excreted in the urine within the entire 48 hours collection period and 96 ± 3% of the high dose (100 mg/kg) was excreted in urine within this timeframe. Over the 48-hour collection period, fecal excretion accounted for 7.1 ± 1.3% (low dose) and 5.6 ± 0.13% (high dose) of the administered dose. Urinary and fecal excretion together accounted for virtual total elimination of the administered dose within 48 hours

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolite profiles of urinary C14-activity were qualitatively and, to some extent, quantitatively similar between dose levels. The following urinary metabolites were tentatively identified within Liquid Chromatography (LC) peaks using HPLC/ESI/MS and HPLC/ESI/MS/MS techniques:

LC Peak A (<1%) - Glucuronide conjugate of hydroquinone
LC Peak B (1-2%) - Not identified
LC Peak C (1.3-3.8%) - Not identified
LC Peak D (<1%) - Not identified
LC Peak E/F (60-63%) - Sulfate and glutathione conjugates of phenol; Sulfate and glucuronide conjugates of PPh, sulfate conjugates of ring-hydroxylated PPh and
1-phenoxy-2-propanone
LC Peak G (<1%) - Not identified
LC Peak H (1-2%) - Not identified
LC Peak I (4-5%) - Glucuronide conjugate of PPh
LC Peak J (<1%) - Not identified
LC Peak K (8-9%) - Glucuronide conjugate of PPh
LC Peak L (9- 10%) - Sulfate conjugate of PPh

Based on comparisons of chromatographic retention times with authentic materials, acid hydrolysis of urine yielded free phenol (61%), hydroquinone (1.5%), and parent PPh (13%).

Any other information on results incl. tables

Because the radiolabel was on the phenol moiety of PPh, it was not possible to follow the disposition of propylene glycol after cleavage from phenol. Other studies have shown that  propylene glycol is consumed in intermediary metabolism and/or exhaled as  propylene glycol or CO2.  Some metabolites found in the urine from this  study reflect those found when free phenol is administered to rats (i.e.,  sulfate and glucuronide conjugates of phenol, glucuronide conjugate of  hydroquinone).  The administered high dose in this study, 100 mg/kg, is  approximately 1/3 to 1/5 the oral LD50 in rats published in Patty's  Toxicology; 340 to 530 mg/kg (5th Ed., Vol 4, pp. 386).  Frank symptoms  of neurotoxicity (e.g., tremors, convulsions) have been reported in rats  receiving a single phenol dose of 224 mg/kg (ibid).  The rat oral LD50 of  PPh is <2,000 mg/kg (1 death in 10 - highest dose tested).  The much  higher LD50 of PPh compared to phenol without similar symptoms would  suggest that the production of phenol from O-dealkylation of PPh does not  occur at a rate or to an extent to cause similar acute toxicity.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In male rats, PPh is rapidly absorbed, distributed, and quickly metabolized and eliminated. Virtually all the administered dose is eliminated within 48 hours in the urine and feces. The three major routes of metabolism are 1) cleavage of PPh by O-dealkylation, yielding propylene glycol and phenol, followed by excretion of phenol as a sulfate, or glutathione conjugate in the urine; 2) direct sulfate or glucuronide conjugation of parent PPh and excretion into the urine; and 3) ring hydroxylation of parent PPh or its oxidized propanone metabolite, followed by sulfate conjugation and excretion into the urine. Minor urinary metabolites included the glucuronide conjugate of hydroquinone.

PPh is rapidly absorbed, distributed throughout the body, and eliminated, similar to other propylene glycol ethers (PGEs). The major routes of elimination, urine and feces, also are similar to other PGEs. The types of metabolites, parent ether conjugates, hydrolyzed propylene glycol, and hydrolyzed alcohol (phenol) conjugates, also are similar.

Executive summary:

This study was conducted to determine the absorption, elimination and metabolism of 1-phenoxy-2 -propanol (DOWANOL PPh) in Fischer 344 rats following oral administration. Adult, male F344 rats were administered a single oral dose of 10 or 100 mg/kg radiolabeled DOWANOL PPh as a

suspension in 0.5% METHOCEL cellulose ether. Urine was collected at 0 – 12, 12 – 24, and 24 – 48 hr and feces at 0 – 24, and 24 – 48 hr post-dosing in dry ice cooled traps and radioactivity was determined. Urine samples were pooled by time-point and dose level and analyzed for metabolites

using LC/ESI/MS and LC/ESI/MS/MS. Both of the administered doses were rapidly absorbed from the GI tract and excreted. The major route of elimination of DOWANOL PPh was through urine, accounting for 88 ± 12% of the low and 96 ± 3% of the high dose. Most of the urinary excretion of

DOWANOL PPh derived radioactivity occurred within 12 hr after dosing; 81 ± 9% of the low and 90 ± 1% of the high dose. Total fecal elimination remained < 10% during the course of the study. Rats eliminated the entire administered dose within 48 hr after dosing, with total recovery ranging from 100 – 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulfate, glutathione), as well as conjugates of parent compound (glucuronide, sulfate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol detected in non-acid-hydrolyzed urine. In acidhydrolyzed urine, 61% of the dose was identified as phenol and 13% as DOWANOL PPh. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolyzed urine may have come from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates.