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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD Guideline 417. Only minor restrictions: e.g. no details about fasting prior to gavage or body weight at initiation

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Phenol
EC Number:
203-632-7
EC Name:
Phenol
Cas Number:
108-95-2
Molecular formula:
C6H6O
IUPAC Name:
phenol
Details on test material:
Two lots of uniformly ring-labelled 14C-phenol (Lot Nos. UB4767 and BE9049) from Amersham Corporation, Arlington Heights, IL.
Lot No. UB4767: specific activities of 20mCi/mmol, radiochemical purities > 99%, used for the oral bolus dose and drinking water studies.
Lot No. BE9049: specific activities of 18.3 mCi/mmol, reported radiochemical purities > 99%, used for the inhalation studies.
Radiochemical purity of each lot was redetermined: 100% with a detection limit of 0.2% by high performance liquid chromatography.

Radiolabeled phenol was diluted with unlabeled phenol as necessary to obtain a suitable specific activity for the conduct of each study. Unlabeled phenol (Lot No. 00225EW; Aldrich Chemical Co., Irrc., Milwaukee, WI.), chemical purity >99%; chemical purity was redetermined prior to starting the study: 100% by gas chromatography and infrared spectroscopy. Stability in aqueous solutions: at least 28 days.
No further details.
Radiolabelling:
yes
Remarks:
(uniformly ring-labelled 14C-phenol)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation: 7-9 weeks of age at the time of treatment
- Weight at study initiation: no data
- Fasting period before study: no data (presumably no fasting)
- Individual metabolism cages: yes
- Diet and tap water ad libitum except during the inhalation exposures; no contaminations (analysed)
- Acclimation period: at least one week, then randomization; acclimatization to metabolism cages for 2 days

Rats used for phenol blood concentration time-course anaesthetized and indwelling jugular vein cannula implanted; cannulated rats allowed to recover overnight prior to phenol treatment. Rats used for inhalation studies acclimated to the nose-only inhalation chamber on at least three days prior to phenol exposure (acclimation time increased on each day of acclimation up to five hours).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): adequate environmental conditions (no further details)
- Humidity (%): adequate environmental conditions (no further details)
- Air changes (per hr): adequate environmental conditions (no further details)
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: oral gavage, oral drinking water, vapour inhalation
Vehicle:
other: water in oral studies and water/air in inhalation studies
Details on exposure:
Repeated dose experiment: 7 daily doses of unlabelled phenol followed by a dose of 14C-phenol
a) Gavage studies
14C-labelled and unlabelled phenol dissolved in purified and deionized water; target dose levels of 1.5, 15, and 150 mg/kg bw; administration of 5 ml/kg bw (concentration: 0.3, 3.0, and 30 mg/g dose solution, respectively. These doses are related to data on acute oral toxicity and an acute neurological toxicity range-finding study. Targeted radioactivity: 200 µCi/kg bw. Concentrations determined by HPLC; radioactivity in solutions determined by liquid scintillation counting.
Rats weighed on the day of dosing (days 1, 4 and 8 for rats given repeated 1.5 mg/kg bw) and corresponding volume of solution administered by gavage; for radioactive doses, the quantity of dose solution administered was determined by weighing the syringe before and after dosing.
The actual doses ranged from 99% to 121% of target calculated from individual doses.

b) Drinking water study
Phenol in the same vehicle than in a); concentration 5000 ppm (5 g/l; this concentration was selected to match the high-dose concentration in the chronic rat bioassay, see Section 7.7) and targeted radioactivity concentrations of 2.26 and 2.58 µCi/g solution for the 1-day and 8-day treatment groups, respectively; concentration analysed by HPLC and radioactivity by liquid scintillation counting (actual concentrations of phenol and radioactivity in the drinking water ranged from 97% to 100% and 96% to 97% of target, respectively). Rats weighed before being given 14C-phenol (in the 8-day treatment group rats weighed on days 1, 4, 5, 6, 7 and 8). Doses determined by monitoring water consumption and drinking water dripping from the water bottles.

c) Inhalation exposure
Nose-only inhalation chamber, dynamic flow-through conditions, simultaneous vapour exposure of up to 8 rats possible; target exposure concentration was 25 ppm phenol (dose related to results in Deichmann et al., 1944; well tolerated in rats). Concentrated phenol vapour generated by pumping air through the U-tube (containing aqueous phenol solution) with gentle heating; phenol/water vapour trapped in a 100 liter teflon bag; concentrated vapour pumped from the bag with an FMI pump and diluted with air in a J-tube packed with glass beads to obtain a total flow through the chamber of approximately 2.0 l/min. Targeted radioactivity vapour was approximately 0.4 µCi/liter; sampling ports positioned in the animals' breathing zones to repeatedly sample the chamber atmosphere (analyzed for phenol concentration by gas chromatography with flame ionization detection). Flow rates of air and/or concentrated phenol vapour adjusted to 25 ppm target. Leakage of radioactivity prevented.
Details on dosing: single or repeated inhalation exposure to 25 ppm (96 mg/m³) corresponding to an average of 11.5 and 17.8 mg/kg bw estimated for single exposure in males and females, respectively; in males exposed to 25 ppm phenol 6 hours/day for 8 days, the estimated phenol dose from the last radioactive exposure was 21.4 mg/kg bw.
Duration and frequency of treatment / exposure:
a) single and repeated (once daily for 8 days) doses of 14C-phenol by gavage (1.5, 15, 150 mg/kg bw); repeated dose experiment: 7 daily oral doses of unlabeled phenol followed by an oral dose of 14C-phenol

b) 5000 ppm via drinking water for 1 day (24 h) or 8 days (continuously); rats in the 8 day treatment group were exposed to unlabeled phenol in the drinking water for 7 days followed by treatment with I4C-phenol in the drinking water on day 8 (24 h).

c) single 6 h exposure to 25 ppm or 6 h per day for 8 days to 25 ppm; 5 male rats was exposed to 25 ppm unlabeled phenol 6 h/day for 7 d followed by a 6 h exposure to 25 ppm I4C-phenol on day 8.
Doses / concentrations
Remarks:
Doses / Concentrations:
a) 1.5, 15, 150 mg/kg bw via gavage
b) 5000 ppm via drinking water; in the 24 h-exposure study the measured/calculated dose level was 291 mg/kg bw and at the final day of the multiple-day phenol drinking water study was 405 mg/kg bw/day.
c) single or repeated inhalation exposure to 25 ppm (96 mg/m³).
No. of animals per sex per dose / concentration:
5 rats per sex per dose
Control animals:
no
Positive control reference chemical:
no
Details on study design:
a) Gavage studies
After application rats were housed in glass Roth-type metabolism cages for the separation and collection of urine, feces, expired 14C-organics, and 14C02. Cage air flow was maintained at 500 mI/minute. All urine voided during the 24 hour interval after oral dosing was collected in dry-ice chilled containers; following collection of urine specimen, the cage was rinsed with water to ensure complete collection of urinary 14C. Expired air (14C-organics and 14C02) was collected for 24 hours following 150 mg/kg bw bolus dose. Since less than 0.2% of the applied radioactivity was collected in exhaled air during the 0-12 hour post-dose sampling period, no further collections or analyses of expired air were conducted.
Blood samples were collected from cannulated rats as follows: single 1.5 mg/kg bw bolus - I, 3, 5, 10, 15, 30, 45 and 60 minutes after dosing; single 150 mg/kg bw bolus -1, 3, 5 , 10, 15, 30, 60 and 90 minutes after dosing. Blood analyzed for total radioactivity and free phenol.

b) Drinking water studies
During and after drinking water exposure rats housed in metabolism cages for separation and collection of urine and feces. All urine voided was collected in dry-ice chilled containers; following collection of urine specimen, the cage was rinsed with water to ensure complete collection of urinary 14C.

c) Inhalation exposure
Urine and feces were collected from all treatment groups during the 6 h exposure to radiolabeled phenol. After exposure to 14C-phenol, the rats were individually housed in plastic metabolism cages. Urine and feces were collected for an additional 24 hours. All urine voided during the 24 hour interval after inhalation exposure was collected in dry-ice chilled containers; cage washings as above.
Blood samples were collected from cannulated rats as follows: single 6 hour inhalation exposure - 2, 4 and 6 hours during exposure and 5, 10, 15, 30 and 60 minutes after exposure. Blood analyzed for total radioactivity and free phenol.

Uniform methods concerning all three exposure routes
Urine samples stored frozen at -8O°C until further analysis; samples analyzed by HPLC to determine qualitative and quantitative 14C metabolite profiles; pooled high-dose male urines were also analyzed by mass spectrometry (MS) for identification of major metabolites; samples also analysed for radioactivity.
Faeces collected at 24 hour intervals in dry-ice chilled containers and stored at -80°C; aqueous homogenate (25-33%, w/w) prepared and analyzed for radioactivity.
All animals sacrificed (exsanguinated via cardiac puncture) 24 hours post-dosing or post-exposure and following tissues collected and stored frozen at -20°C until analyzed for radioactivity: blood, bone (femur), brain, fat (perirenal sample), gonads, heart, kidneys, liver, lung, skeletal musc1e (hindlimb sample), spleen, skin (dorsal sample), and remaining carcass. All samples prepared for radioactivity analysis via liquid scintillation counter (Beckman LS 3801; corrected for
background and quench).
Details on dosing and sampling:
see study design
Dosing solution concentrations were quantitated.
Statistics:
No data; mean and standard deviation calculated (see Tables below)

Results and discussion

Preliminary studies:
Clinical signs in main studies a-c
At 150 mg/kg bw oral bolus dose males and females clinical signs of toxicity characterized by tremors, sudden jerks, hyperreactivity to stimulae, and excessive eye closure and blinking. The onset of these clinical signs developed immediately after dosing and disappeared 37 min after dosing. Clinical signs were not observed in any rats exposed to phenol at <=15 mg/kg bw (including repeated-dose groups), in the drinking water, or by inhalation.
Clinical signs are correlated directly with the peak blood phenol, and abated rapidly with the clearance of phenol from blood (see details below). Clinical signs were not observed in high dose rats by 45 minutes after dosing, at which time phenol blood concentrations were approximately 3 µg/g blood; a threshold concentration can be estimated: 5 -17 µg/g blood.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Regardless of route of administration phenol is rapidly absorbed since excretion of radioactivity via urine was greater than 90% of applied radioactivity within 24 h after termination of exposure.
Details on distribution in tissues:
Only small amount of radioactivity (<1%) remained in tissues and carcass of males and females following any mode of 14C-phenol dosing; repeated exposure (oral or inhalation) did not result in accumulation of radioactivity.
Single gavage of 1.5 mg/kg bw resulted in an average peak of free phenol of approximately 0.02 µg/g blood within 1-3 minutes after dosing which was rapidly cleared (t1/2 of 8 minutes); after 150 mg/kg bw the average peak blood free phenol concentration of 46.4 µg/g blood 1 minute after dosing; the estimated half-life was 12 minutes.
Free phenol was not detected in the blood of males exposed to 25 ppm by inhalation; the blood concentrations of radioactivity (metabolites) peaked during (after 2 h) and following inhalation exposure (10 min after exposure) and rapidly cleared from blood.
Details on excretion:
Independent on the route of exposure most of radioactivity (>90% of applied dose) is excreted via urine and only 1-3% via faeces, less than 1% of applied radioactivity was found in tissues and carcass; phenol or metabolites (including CO2) were not exhaled.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The urinary metabolite profile, predominantly conjugates of phenol, was dose dependent. The ratio of glucuronide/sulfate conjugates of phenol was 0.61 after 1.5 or 15 mg/kg bw and rose to 1.16 after 150 mg/kg bw. Thus, the saturation of sulfate conjugation results in predominance of the glucuronide conjugate. Metabolic profiles obtained after drinking water were equivalent to the high dose gavage profile, while profiles after inhalation resembled the low dose gavage profile. Male and female rats were equivalent in all studies. These studies support the conclusion that free phenol in blood and associated clinical toxicology are seen only at doses that saturate the conjugation pathways.

Any other information on results incl. tables

Absorption:

Regardless of route of administration, excretion of radioactivity via urine was greater than 90% of recovered radioactivity. Urinary excretion was rapid and was essentially complete by 24 h after termination of 14C exposure (see Tables below).

Distribution

The small amount of radioactivity remaining in tissues and carcass (generally less than 1% of recovered radioactivity) was consistent with the rapid and extensive urinary clearance of radioactivity. The clearance of radioactivity was similar in male and female rats (14C-phenol by oral bolus or inhalation treatment). Liver and kidney generally contained the highest (only 0.01% of recovered radioactivity) concentrations. There was no evidence of tissue-selective retention of radioactivity in any tissue following any mode of 14C-phenol dosing. Compared to the single-exposure, repeated exposure (oral gavage, drinking water, or inhalation) did not result in accumulation and/or retention of radioactivity in any tissues.

Concentration in blood after single gavage (see also Table below)

The concentrations of free phenol (vs. metabolite) in blood of male rats receiving a single oral dose of either 1.5 or 150 mg/kg bw 14C-phenol via gavage have shown that the low dose resulted in an average peak of free phenol of approximately 0.02 µg/g blood within 1-3 minutes after dosing. These low concentrations of free phenol in blood were rapidly cleared; a terminal half-life (t1/2) of 8 minutes was calculated. In rats receiving a single oral dose 150 mg/kg bw an average peak blood free phenol concentration of 46.4 µg/g blood was attained by 1 minute after dosing. This peak phenol blood concentration represented a 2320-fold increase in peak blood concentration relative to the low oral dose. Since the low and high oral phenol doses were separated only by a factor of 100, a profound nonlinear relationship was established between phenol dose and peak phenol blood concentrations. Despite the relatively high peak phenol blood concentrations after 150 mg/kg 14C-phenol, phenol was cleared rapidly from blood with an estimated half-life of 12 minutes.

Blood concentration after single inhalation exposure for 6 h (see also Table below)

Free phenol was not detected in the blood of males exposed to 25 ppm by inhalation (exception: 2 of the 5 exposed rats had small amounts of free phenol in blood [0.2 and 0.25 µg/g blood] 2 hour after start of exposure). The peak blood concentrations of total radioactivity (representing phenol metabolites) during (max. 3 µg eq/g blood at 2 h) and following inhalation exposure (max. 3 µg eq/g blood 10 min after exposure) was slightly less than the peak blood concentrations after the 1.5 mg/kg bw oral bolus phenol. After termination of exposure, radioactivity was rapidly cleared from blood. Greater than 70% of the total recovered urinary radioactivity was excreted during exposure period; the remainder of the recovered urinary radioactivity was excreted in the 24 hour period after termination.

Excretion

Independent on the route of exposure most of radioactivity (>90% of applied dose) is excreted via urine and only 1-3% via faeces (see Table below). Less than 1% of applied radioactivity was found in tissues and carcass (1.2 [m] and 1.7% [f] after single 6h-exposure). Exhaled radioactivity was less than 0.1% of total recovered radioactivity after 150 mg/kg bw, indicating that phenol or metabolites (including CO2) were not exhaled.

Details on metabolites

Similar distribution of urinary metabolites between males and females in all treatment groups (the impact of dose and route was examined by combination of male and female data). Main metabolites found in urine regardless of dose or route of administration(see Table below): predominately sulfate and glucuronide conjugates of phenol itself. However, the ratio of glucuronide to sulfate conjugates was not constant with increasing oral doses: in the low bolus dose group (1.5 mg/kg bw) the sulfate conjugate of phenol represented 59% of the total recovered urinary radioactivity, while the glucuronide conjugate accounted for 36% of total urinary radioactivity. The ratio of glucuronide to sulfate conjugate of phenol increased at 150 mg/kg bw, the glucuronide conjugate became the major metabolite. The glucuronide to sulfate conjugate ratios of phenol were 0.61 for both the low (1.5 mg/kg bw) and mid-dose (15 mg/kg bw) bolus dose, but increased to 1.16 at 150 mg/kg bw. Repeated low-dose oral treatment had no effect on the ratio (identical to that seen after a single dose; 0.60 vs. 0.61).

In rats administered phenol in drinking water the glucuronide to sulfate ratio was similar to that of the high dose gavage group, reflected by glucuronide to sulfate ratios of 1.43 and 1.87 for single or repeated day exposures, respectively. The glucuronide to sulfate ratios following inhalation exposure(s) to 25 ppm ranged from 0.24 to 0.39, and were less than the ratios seen in rats receiving low or mid-dose oral bolus phenol treatment. The percentage of urinary metabolites recovered as the glucuronide conjugate of hydroquinone increased with increasing oral bolus doses (approximately 17% of recovered radioactivity at 150 mg/kg bw). Similar amounts were found at 8 days of phenol drinking water administration. Hydroquinone glucuronide conjugate was recovered in similar percentages to that seen after a single high oral bolus dose.

Recovery of hydroquinone conjugates after inhalation exposure was similar to that seen in rats given a single mid-level oral bolus phenol dose. A small amount of the urinary radioactivity was recovered as an unidentified metabolite (unaffected by either dose or route of administration). Identification of this metabolite was not attempted (only 2-4% of total recovered urinary radioactivity). Small amounts of unconjugated phenol were recovered only in urines of high oral bolus dose females (1.3% of recovered radioactivity) and in urine collected from male rats during inhalation exposure (2.7%).

Distribution of radioactivity recovered 24 h after gavage of 1.5, 15 or 150 mg 14C-Phenol/kg Body Weight

Parameter

Percent of applied dose

Single dose

Multiple dose

Single dose

Single dose

1.5 mg/kg bw

1.5 mg/kg bw

15 mg/kg bw

150 mg/kg bw

Males

Urine

94.47 ±4.15

93.24 ± 2.67

91.99 ±5.0

96.55 ±2.33

Faeces

1.85 ± 1.87

2.15 ±2.07

2.42 ± 2.47

0.85 ± 0.45

Tissues & carcass

0.56 ± 0.17

0.75 ± 0.11

0.63 ± 0.25

0.41 ± 0.09

Volatile organics & 14CO2

NC

NC

NC

0.04 ± 0.01

Cage wash

1.60 ± 1.78

1.11 ± 0.43

2.17 ± 1.62

1.49 ± 0.97

Total

98.47 ± 1.17

97.25 ± 0.46

97.21 ± 1.16

99.34 ± 1.38

Females

Urine

93.06 ± 2.37

92.03 ± 3.19

93.83 ± 3.68

91.21 ± 1.60

Faeces

0.92 ± 0.57

0.89 ± 0.46

1.80 ± 2.00

1.15 ± 0.71

Tissues & carcass

0.41 ± 0.12

0.56 ± 0.21

0.47 ± 0.15

0.69 ± 0.16

Volatile organics & CO2

NC

NC

NC

0.08 ± 0.02

Cage wash

1.93 ±1.98

0.84 ± 0.49

1.85 ± 1.31

2.23 ±1.81

Total

96.32 ±1.00

94.32 ± 3.72

97.94 ±1.07

95.37 ± 0.67

Values represent mean ± SD for 5 rats. NC = Not Collected. 14C volatile organic and 14C02 traps for the 0-12 hr interval contained less than 0.1% of

the 14C dose, therefore, subsequent samples were not analyzed and traps were not used for the 1.5 and 15 mg/kg oral bolus dose studies.

Distribution of radioactivity recovered 48 h after initiation of oral exposure (duration 24 h) to 5000 ppm 14C-phenol via the drinking water# or 30 h after initiation of exposure (duration 6 h) to 14C-phenol via inhalation$

Parameter

Percent of administered dose

Drinking water 5000 ppm

Inhalation - 6 h/d - 25 ppm

Males 1 day

Males 8 days

Females 1 day

Males 1 day

Males 8 days

Urine

95.11 ± 1.47

93.53 ± 0.64

90.92 ± 5.45

94.48 ± 2.43

97.40 ± 0.51

Faeces

1.18 ±0.67

0.81 ± 0.47

2.02 ± 1.12

3.33 ± 2.71

0.81 ± 0.51

Tissues & carcass

0.47 ± 0.11

0.29 ± 0.04

1.66 ± 1.00

1.22 ± 0.52

0.85 ±0.15

Cage wash

1.44 ± 0.63

1.50 ± 0.09

5.41 ± 4.39

0.99 ± 0.43

0.94 ±0.29

Total

98.20 ± 0.91

96.13 ± 1.24

100.00 ± 0.01

100.01 ± 0.01

100.00 ± 0.01

#: Percents of ingested radioactivity recovered during the 24 hr exposure and during the 24 hr post-exposure. $: Percents of recovered radioactivity during the 6 hr exposure and during the 24 hr post-exposure. Values represent mean+-SD for 5 rats.

Concentrations of radioactivity and free phenol in the blood of male rats after oral or inhalation exposure

Dosing

Sampling time

14C-phenol in µg eq/g blood

Free phenol in µg/g blood

Gavage, 1 x 1.5 mg/kg bw

1 min after exposure

2.20

0.0192

3 min

4.87

0.0190

5 min

3.15

0.0158

10 min

4.19

NQ

15 min

2.40

NQ

30 min

1.33

NQ

45 min

0.87

NQ

60 min

0.48

NQ

Gavage, 1 x 150 mg/kg bw

1 min after exposure

59.05

46.40

3 min

60.17

39.81

5 min

61.78

34.99

10 min

61.91

25.61

15 min

63.93

18.24

30 min

54.85

7.77

60 min

33.38

1.16

90 min

17.86

NQ

Inhalation 1 x 6 h, 25 ppm

120 min after start of exposure

3.021

NQ

240 min

1.799

NQ

360 min

1.838

NQ

5 min after termination of exposure

2.034 .

NQ

10 min

3.065

NQ

15 min

1.491

NQ

30 min

0.975

NQ

60 min

0.517

NQ

NQ: not quantifiable, dpm value less than or equal to 2 times average background; mean of 5 rats

Identification of metabolites in rats after oral and inhalation exposure

Dose (sex)

% of recovered radioctivity

Ratio of phenyl glucuronide / phenyl sulphate

Hydroquinone glucuronide

Unidentified metabolite

Phenyl glucuronide

Phenyl sulfate

Gavage 1 x 1.5 mg/kg bw (m)

2.4(0.4)

1.7(0.5)

37.4(1.6)

58.5(1.8)

0.64

Gavage 1 x 1.5 mg/kg bw (f)

3.5(0.9)

3.2(0.3)

34.4(1.3)

58.9(1.3)

0.58

Gavage 1 x 1.5 mg/kg bw (m&f)

3.0(0.9)

2.4(0.9)

35.9(2.1)

58.7 (1.5)

0.61

Gavage 1 x 15 mg/kg bw (m)

6.1(1.5)

2.7(0.4)

34.3(2.1)

56.9(3.4)

0.60

Gavage 1 x 15 mg/kg bw (f)

9.6(1.4)

3.3(0.8)

32 8(1.7)

53.4(2.0)

0.61

Gavage 1 x 15 mg/kg bw (m&f)

7.8(2.3)

3.0(0.7)

33.6(2.0)

55.2(3.2)

0.61

Gavage 1 x 150 mg/kg bw (m)

15.2(1.2)

4.2(0.6)

42.9(1.8)

37.6(1.7)

1.14

Gavage 1 x 150 mg/kg bw (f)

18.9(1.2)

4.0(0.7)

40,7(1,7)

34.8(2.2)

1.17

Gavage 1 x 150 mg/kg bw (m&f)

17.0(2.3)

4.1(0.7)

41.8(2.0)

36.2(2.4)

1.16

Gavage 8 x 1.5 mg/kg bw (m)

2.7(0.7)

2.6(0.6)

36.1(4.4)

58.7(4.7)

0.61

Gavage 8 x 1.5 mg/kg bw (f)

1.5(0.4)

1.6(0.4)

35.3(2.8)

59.6(1.8)

0.59

Gavage 8 x 1.5 mg/kg bw (m&f)

2.1(0.8)

2.1(0.7)

35.7(3.5)

59.2(3.4)

0.60

Drinking water, 24 h 5000 ppm (m)

17.0(1.6)

4.0(0.4)

46.3(1.2)

32.4(1.5)

1.43

Drinking water, 8 d 5000 ppm (m)

15.0(0.4)

2.0(0.2)

54.0(2.9)

28.8(2.5)

1.87

Inhalation, during 1 x 6 h, 25 ppm (m)

7.4(1.6)

2.0(0.3)

22.2(0.7)

65.7(1.0)

0.34

Inhalation, during 1 x 6 h, 25 ppm (f)

9.0(1.2)

3.7(0.4)

26.7(0.8)

59.3(1.5)

0.45

Inhalation, during 1 x 6 h, 25 ppm (m&f)

8.2(1.6)

2.8(0.9)

24.4(2.5)

62.5(3.6)

0.39

Inhalation, after 1 x 6 h, 25 ppm (m)

6.9(1.6)

3.3(1.4)

16.2(3.2)

73.5(3.3)

0.22

Inhalation, after 1 x 6 h, 25 ppm (f)

8.3(0.61

4.1(0.6)

18.4(3.5)

69.1 (3.5)

0.27

Inhalation, after 1 x 6 h, 25 ppm (m&f)

7.6(1.3)

3.7(1.1)

17.3(3.4)

71.3(3.9)

0.24

Inhalation, 8 x 6 h, 25 ppm, during 8th exposure (m)

8.8(1.1)

2.9(0.3)

24.8(3.5)

63.2(3.9)

0.39

Inhalation, 8 x 6 h, 25 ppm, after 8th exposure (m)

8.1(0.7)

2.4(0.9)

24.7(2.9)

64.8(3.8)

0.38

Mean (SD); n= 5 males (m) or 5 females (f)

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: rapid absorption, metabolism and excretion after oral or inhalation exposure
In oral and inhalation studies phenol is rapidly absorbed and metabolised mainly to sulfate and glucuronide conjugates of phenol. More than 90% of the applied radioactivity is excreted via urine within 24 h after exposure, minor amounts were excreted via faeces or were found in tissues and carcass at termination.
Executive summary:

This study is comparable to OECD Guideline 417.

In this study toxicokinetic parameters as well as metabolism was investigated after oral and inhalation exposure. Male and female F344 rats were exposed to single and repeated (8 days) doses of 14C-phenol by gavage: 1.5, 15, 150 mg/kg; drinking water: 5000 ppm, and inhalation 25 ppm, 6 hours. For all exposure routes radioactivity was rapidly eliminated in urine (>90% in 24 hours), only 1 -3% via faeces and traces via expiration; less than 1% remained in tissues and carcass. After gavage of jugular vein cannulated animals with 150 mg/kg bw, peak concentrations of 46 µg free phenol/g blood were observed within 1 min, declining to 1 µg/g blood by 60 min (half-life =12 min). Muscle twitching also developed rapidly in these animals and disappeared by 45 minutes as blood levels of phenol declined. The threshold concentration for systemic clinical effects is considered to be 5 -17 µg/g blood. Gavage with 1.5 mg/kg did not result in the appearance of significant amounts of phenol in blood (peak < 0.1 µg phenol/g blood; no muscle twitching). Free phenol was not detected in blood during inhalation exposures and muscle twitching was absent. The urinary metabolite profile (predominantly conjugates of phenol) was dose dependent. The ratio of glucuronide/sulfate conjugates of phenol was 0.61 after 1.5 or 15 mg/kg bw and rose to 1.16 after 150 mg/kg. Thus, the saturation of sulfate conjugation results in predominance of the glucuronide conjugate. Metabolic profiles obtained after drinking water were equivalent to the high dose gavage profile, while profiles after inhalation resembled the low dose gavage profile. Male and female rats were equivalent in all studies. These studies support the conclusion that phenol in blood and associated clinical toxicology are seen only at doses that saturate the conjugation pathways.

Conclusion: In oral and inhalation studies phenol is rapidly absorbed and metabolised mainly to sulfate and glucuronide conjugates of phenol. More than 90% of the applied radioactivity is excreted via urine within 24 h after exposure, minor amounts were excreted via faeces or were found in tissues and carcass at termination.