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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: GLP guideline study

Data source

Referenceopen allclose all

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

Materials and methods

Objective of study:
toxicokinetics
Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Qualifier:
according to guideline
Guideline:
other: FDA Guideline for Metabolism Studies (1986)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Triclosan
EC Number:
222-182-2
EC Name:
Triclosan
Cas Number:
3380-34-5
Molecular formula:
C12H7Cl3O2
IUPAC Name:
5-chloro-2-(2,4-dichlorophenoxy)phenol
Details on test material:
- Name of test material (as cited in study report): Triclosan
- Physical state: white powder
- Analytical purity: 99.9%
- Lot/batch No.: EN 275927.26 (FAT 80'023/R)
- Expiration date of the lot/batch: December 1999
- Stability under test conditions: storage stability is at least 2 years; stability in solvents assured for 48 h
- Storage condition of test material: room temperature

- Name of radiolabelled test material (as cited in study report): 14C-Triclosan
- Radiochemical test material lot/batch No.: 0542
- Radiochemical purity (if radiolabelling): 98.5 ± 1.0%
- Specific activity (if radiolabelling): 154.05 µCi/mg (5.70 MBq/mg)
- Locations of the label (if radiolabelling): 14C
- Storage condition of the radiolabelled test material: at -20 °C, in the dark
- Stability: the stability of the test article was determined by its radiochemical purity using an aliquot of the formulated test article before and after treatment. The radiochemical purity before and after administration amounted on average to 97.6 ± 0.8 % and 98.6 ± 1.1 %, respectively, indicating that the test material was stable in the formulation during administration.
Radiolabelling:
yes
Remarks:
14C-triclosan

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL Biological Research Laboratories Ltd., Fuellinsdorf/Switzerland
- Age at study initiation: Males: 4-6 weeks, Females: 5-7 weeks
- Weight at study initiation: 21 - 41 g
- Fasting period before study: yes, overnight prior to dosing with 14C-triclosan, except for the repeated (13x) food admixture studies
- Housing: groups of 2 - 5 mice/cage in Makrolon cages (types 2 and 3) with standard soft wood bedding during acclimation.
- Metabolism cages used: yes
- Diet (e.g. ad libitum): pelleted 343-Kliba mice maintenance diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 5 days, including 1-3 days to metabolism cages or to cages equipped with a stainless steel grill.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°C
- Humidity (%): 40 - 70%
- Air changes (per hr): 10-15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hrs/12hrs

Administration / exposure

Route of administration:
other: gavage or intravenous
Vehicle:
other: a mixture of 10% ethanol, 20% cremophor in 70% aqueous CMC (1%) (v/v) for gavage, and physiological saline for iv injection.
Details on exposure:
PREPARATION OF FORMULATIONS (gavage)
Appropriate aliquots of the respective stock solutions containing equivalent amounts of 30 mg of either 0.3 mg 14C-triclosan dissolved in ethanol diluted up to 100 µL or 30 mg 14C-triclosan in acetone evaporated to dryness and re-dissolved in 100 µL ethanol, were formulated with equivalent amounts of 200 µL Cremophor and 700 µL of 1% CMC in bidistilled water to a clear homogenous solution. Consequently, based on dose levels of 200 and 2 mg/kg bw, the volume administered amounted to about 0.7 mL per 100 g of mouse body weight.
In order to exclude variability in the amount administered, radioactivity in the final formulation was always determined by LSC (dpm/mL) immediately before the first administration. All actual amounts administered were determined by weighing of the syringe before and after administration and were correlated to dpm/mL via the specific weight of the application solution.

PREPARATION OF FORMULATIONS (for single iv injection):
For the intravenous low dose level groups (0.2 mg/0.4 mL/100 g mice), 2.5 mg of test material were dissolved in equimolar amounts of NaOH (with 50 % reserve), partially neutralized with HCl to pH 9 and made up to 5.0 mL with physiological saline.
In order to exclude variability in the amount administered, radioactivity in the final formulation was always determined by LSC (dpm/mL) immediately before the first administration. All actual amounts administered were determined by weighing of the syringe before and afteradministration and were correlated to dpm/mL via the specific weight of the application solution.

PREPARATION OF FEED CONTAINING TRICLOSAN:
An amount of 15 kg food was mixed with 1 liter acetone containing 151 mg triclosan (unlabelled) for low dose, or 10 kg food was mixed with 1 liter acetone containing 9.99 g of the test material for high dose. Before pressing, this mixture was humidified with 1100 mL water. Food pellets were stored at 25-30 °C until use.
After appropriate HPLC-analyses, the concentration of non-labelled test material in food proved to be 7.64 mg/kg food (low dose) and 753 mg/kg food (high dose). Based on an assumed food consumption of 25 g food/100 g mouse/day, the mice received ca. 1.9 mg/kg bw/day (low dose) and ca. 188 mg/kg bw/day (high dose).
Duration and frequency of treatment / exposure:
Single oral administration by gavage
Single iv injection
13 times repeated oral administration in feed for the repeated dosage experiment
Doses / concentrations
Remarks:
Doses / Concentrations:
2 mg/kg bw (low dose)
200 mg/kg bw (high dose)
No. of animals per sex per dose / concentration:
Five to 15 animals/sex/group, depending on the scheduled endpoint (balance, kinetics, metabolism).
Control animals:
no
Details on study design:
To evaluate the bioavailability of triclosan, the objectives of the present study were to follow the absorption, distribution, metabolism and elimination of this substance in mice. For this purpose, 14C-labelled triclosan was administered to mice in various separate experiments:
- Balance studies after single oral administration at the low dose level (2 mg/kg bw) and the high dose level (200 mg/kg bw) in both sexes (the highest dose level to male mice was already performed in a previous RCC project 342000).
- Balance studies after repeated (13x) food supply of non-labelled test article followed by single oral administration at both dose levels in both sexes.
- Balance studies after single intravenous administration at the low dose level in both sexes.
- Balance studies after repeated (13x) food supply of non-labelled test article followed by single intravenous administration at the low dose level in both sexes.
- Blood/plasma level studies after single oral administration at two dose levels in both sexes (blood/plasma level studies in males were already performed in RCC project 342000).
- Plasma metabolism studies in males at both dose levels after single and repeated oral administration.
The levels of radioactivity appearing in the urine, feces, bile, blood/plasma and organs/tissues were determined. Furthermore, radioactivity appearing in various fractions (urine, feces, plasma, liver and kidney) was characterized by appropriate methods.
Details on dosing and sampling:
BALANCE STUDIES
Balance studies In both sexes after single oral administration of 14C-triclosan at, on average, 2.1 mg/kg bw and 229 mg/kg bw were
performed. After 14C-triclosan administration, urine and feces were sampled during 96 hours and total radioactivity determined. At sacrifice (96 hours) radioactivity levels in plasma, bile and organs/tissues were determined.
Balance studies in both sexes after repeated (13x) food supply and oral administration of 14C-triclosan at, on average, 2.1 mg/kg bw and 204 mg/kg bw were performed. After 14C-triclosan administration, urine and feces were sampled during 96 hours and total radioactivity determined. At sacrifice (96 hours) radioactivity levels in plasma, bile and organs/tissues were determined.
Balance studies in both sexes at the low dose level after single intravenous administration of 14C-triclosan at, on average, 2.2 mg/kg bw and after repeated (13x) food supply and intravenous administration of 14C-triclosan at, on average, 2.0 mg/kg bw were performed.
After 14C-triclosan administration, urine and feces were sampled during 96 hours and total radioactivity determined. At sacrifice (96 hours) radioactivity levels in plasma, bile and organs/tissues were determined.

TISSUES DISTRIBUTION
At sacrifice (96 hours) organs/tissues were taken from all balance groups and all radioactivity levels expressed as pg parent equivalents per gram organ/tissue or plasma.

BLOOD/PLASMA LEVELS AND KINETICS
Blood/plasma kinetics in both sexes at both dose levels after single oral administration of 14C-triclosan at, on average, 2.2 mg/kg bw and 202 mg/kg bw were performed. After 14C-triclosan administration total radioactivity levels were measured at 12 time intervals from 0.5 - 96 hours after administration. Total radioactivity levels in blood and plasma were expressed in pg parent equivalents per g blood/plasma.

BIORETENTION IN ORGANS/TISSUES AND PLASMA
Bioretention studies in male mice after single oral administration of 14C-triclosan without and with repeated (13x) food supply at, on average, 2.1 mg/kg bw and 201 mg/kg bw, respectively, were performed. At four selected time intervals (Cmax, 1/2Cmax, 1/4Cmax and 1/8Cmax) after 14C-triclosan administration, total radioactivity levels were determined in blood, plasma, liver and kidney.

METABOLISM
Urine pools of all balance groups were partitioned and the organic and aqueous phases were analysed separately.
Feces of the balance groups were extracted, partitioned, and the organic phases were analysed.
Plasma pools at four time intervals (Cmax - 1/8Cmax) from the bioretention groups were analysed after protein precipitation.
Liver and kidney pools from the bioretention groups were similarly extracted, and partitioned.
After appropriate analyses (TLC, HPLC, HCI-hydrolysis, enzymatic treatments) metabolite pattems in urine (U), feces (F), plasma (P), liver (L) and kidney (K) were elucidated. Isolated conjugates in major radioactive zones from organic and aqueous phases of selected urine pools were characterized by HCl-hydrolysis and glucuronidase and sulfatase treatments. The occurrence of conjugates from parent and non-parent metabolites were demonstrated in urine, plasma, liver and kidney by HCI-hydrolysis of organic, aqueous and total extracts from these organs and fluids.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The Tmax values of single and repeated dosing studies were 4-32 hours for the doses used in this study (2, 200 mg/kg bw).
The half-life for free and conjugated triclosan species ranged from 1 to 13 hours.
In plasma, the AUC values at the low dose were 166.1 mg/Lohr (M) and 119.3 mg/Lohr (F), whereas at the high dose, the AUC values were 4505 mg/Lohr (M) and 6322 mg/Lohr (F).
In male mice, the Cmax values were 19.48 and 212.8 µg/g in the low and high dose groups, respectively, whereas for female mice, the Cmax values were 8.79 and 267.2 µg/g, respectively.
Details on distribution in tissues:
SINGLE GAVAGE AND REPEATED (13x) FOOD SUPPLY FOLLOWED BY SINGLE GAVAGE
At the low dose level at 96 hours radioactivity levels were very low. Highest radioactivity levels were found in the excretory organs liver and kidney followed by plasma, bile and intestinal tract. All radioactivity levels are expressed as pg parent equivalents per g, i.e. pg peq/g.
In both sexes, the radioactivity levels in liver and kidney amounted to 0.010 - 0.021 pg peq/g after single and repeated low dose. Plasma values in females were similar after single as well as repeated low dose (0.014 - 0.020 pg peq/g). In males about 2-3 fold lower plasma values were found (0.007 - 0.008 pg peq/g). However, in the corresponding groups 13 and 15 at 96 hours plasma values in females and males were 0.007 pg peq/g and 0.020 pg peq/g. Therefore, these differences were not considered to be relevant. In males, radioactivity levels in remaining organs/tissues were very low i.e. at or below 0.011 pg peq/g. In females, except for bile (0.005 - 0.030 pg peq/g) and intestinal tract (0.018 pg peq/g) values in remaining organs/tissues were very low, i.e. at or below 0.012 pg peq/g.
At the high dose level after 96 hours highest radioactivity levels were found in liver, bile and intestinal tract followed by the plasma and kidney. The radioactivity level in liver, bile and intestinal tract ranged from 1.598 - 2.632 pg peq/g for males after single and repeated high dose administration. Radioactivity levels in plasma and kidney were 2-3 fold lower and ranged from 0.666 -1.115 pg peq/g. In females values in liver, bile, intestinal tract ranged from 1.220 - 1.569 pg peq/g and in plasma as well as kidney somewhat lower values were found (0.871 - 1,263 pg peq/g). Except for fat (1.113 pg peq/g, males, repeated high dose) and carcass (2.482 pg peq/g, males, repeated high dose), in both sexes radioactivity levels in remaining organs/tissues were at or below 0.8 pg peq/g. At the high dose level (single as well as repeated), radioactivity levels in liver were about 2 times higher (males) or similar (females) than the levels in plasma. Taking into account that kidney levels were similar to plasma levels, the results indicate that the liver is likely to be a specific target organ for triclosan in the male mouse. In males radioactivity levels in organs/tissues at about 100-125 fold higher dose levels were between 60-150 times greater than dose obtained with the low dose groups. In females the radioactivity found in the organs/tissues was between 50-90 times greater in the high dose groups than in the low dose groups. Taking into account the persistently higher bile levels as compared to plasma and kidney at the high dose level after single as well as repeated oral administration in males, the results indicate efficient elimination of TRICLOSAN and metabolites from liver via the bile.

SINGLE IV INJECTION AND REPEATED (13x) FOOD SUPPLY FOLLOWED BY SINGLE IV INJECTION
At 96 hours after intravenous administration without and with repeated food supply, all radioactivity levels were very low. Highest radioactivity levels were always found in liver, lung and spleen and 2-15 times lower radioactivity levels were found in plasma and kidney. In males without and with repeated food supply, the radioactivity levels in plasma and kidney were similar (0.007 - 0.014 pg peq/g). The values in liver and spleen were higher (0.039 - 0.052 pg peq/g). The highest value was found in lung after single administration (0.166 pg peq/g) which was reduced about 2-3 fold (0.064 pg peq/g) after repeated administration. In females, similar plasma and kidney values were found (0.015 - 0.021 pg peq/g). Again higher values were found in liver and spleen (0.035 - 0.063 pg peq/g) and the highest value in lungs after single administration (0.182 pg peq/g) which was reduced about 3-fold after repeated
administration (0.065 pg peq/g).
In both sexes, radioactivity levels in remaining organs/tissues were below 0.025 pg peq/g. When compared to the corresponding oral groups plasma levels and most organs/tissues showed similar radioactivity levels after oral and intravenous administration. Only the organs with the highest blood supply (liver, lung and spleen) showed higher levels (generally about 3-15 times) than after oral administration.
These results indicate similar elimination after intravenous administration and oral administration (single and repeated).
Details on excretion:
SINGLE GAVAGE
After single oral administration of 14C-triclosan at low dose (2.1 mg/kg bw) no significant differences in elimination were found between both sexes. Radioactivity eliminated via the urine amounted to 18.9 ± 4.7 % in males and 17.2 ± 8.1 % in females. Respective amounts eliminated via the feces were 75.4 ± 4.0 % and 77.5 ± 6.9 %. Taking into account the cage wash, elimination was virtually complete after 96 hours, being 96.4 ± 2.7 % for males and 97.6 ± 4.2 % for females. At sacrifice low and negligible amounts of radioactivity were found in plasma, residual carcass, organs/tissues as well as intestinal tract (<0.05 - 0.1 %). Total recoveries amounted to 96.6 ± 2.8 % for males and 97.9 ± 4.1 % for females.
After single oral administration of 14C-triclosan at high dose (206 - 251 mg/kg bw) higher amounts of radioactivity were excreted In the urine of the males (29.5 ± 5.5 %) versus that found in the urine of the females (12.3 ± 5.8 %). Accordingly, the amounts eliminated via the feces were 65.6 ± 6.0 % and 78.4 ± 7.2 % for males and females, respectively. Taking into account the cage wash, elimination was virtually complete after 96 hours, being 99.9 ± 4.0 % for males and 93.2 ± 2.0 % for females. At sacrifice low and negligible amounts of radioactivity were found in plasma, residual carcass, organs/tissues as well as intestinal tract (<0.05 - 0.2 %). Total recoveries amounted to 100.1 ± 3.9 % for males and 93.5 ± 2.0 % for females.
In both sexes at the low dose level and in the females at the high dose level comparable amounts were eliminated in urine (12.3 -18.9 %) and feces (75.4 - 78.4 %). Only in males at the high dose level 29.5 % and 65.6 % were eliminated in urine and feces, respectively.

REPEATED (13x) FOOD SUPPLY FOLLOWED BY SINGLE GAVAGE
After repeated (13x) food supply followed by single oral administration of 14C-triclosan at low dose (2.1 mg/kg bw) no significant differences In elimination were found between both sexes. Radioactivity eliminated via the urine amounted to 24.8 ± 5.3 % in males and 17.2 ± 5.0 % in females. Respective amounts eliminated via the feces were 67.1 ± 5.8% and 76.2 ± 5.6 % . Taking into account the cage wash, elimination was virtually complete after 96 hours, being 94.8 ± 4.4 % for males and 96.7 ± 3.5 % for females. At sacrifice low and negligible amounts of radioactivity were found in plasma, residual carcass, organs/tissues as well as intestinal tract (<0.05 - 0.3 %). Total recoveries amounted to 95.2 ± 4.3 % for males and 97.1 ± 3.6 % for females.
After repeated (13x) food supply followed by single oral administration of 14C-triclosan at high dose (204 mg/kg bw) no significant differences in elimination were found between both sexes. Radioactivity eliminated via the urine amounted to 38.9 ± 6.8 % in males and 35.3 ± 8.4 % in females. Respective amounts eliminated via the feces were 50.1 ± 6.9 % and 53.2 ± 9.2 %. Taking into account the cage wash, elimination was virtually complete after 96 hours, being 91.7 ± 1.6 % for males and 92.1 ± 2.1 % for females. At sacrifice low and negligible amounts of radioactivity were found in plasma, residual carcass, organs/tissues as well as intestinal tract (<0.05 -1.4 %). Total recoveries amounted to 93.4 ± 1.9 % for males and 92.4 ± 2.1 % for females. As compared to the low dose level groups after repeated administration in both sexes at the high dose level higher amounts were eliminated in urine (35.3 - 38.9 % against 17.2 - 24.8 %). After 96 hours elimination was virtually complete in both sexes at both dose levels amounting to 91.7-96.7%.

SINGLE IV APPLICATION
After single iv injection of 14C-triclosan at low dose (2.2 mg/kg bw) no significant
differences were found between both sexes. Radioactivity eliminated via the urine amounted to 11.8 ± 1.5 % in males and 10.7 ± 5.2 % in females. Respective amounts eliminated via the feces were 63.9 ± 3.3 % and 89.3 ± 8.9 %. Taking into account the cage wash, elimination was virtually complete after 96 hours, being 77.0 ± 2.7 % for males and 102.7 ± 4.6 % for females. At sacrifice low and negligible amounts of radioactivity were found in plasma, residual carcass, organs/tissues as well as intestinal tract (<0.05 - 0.2 %). Total recoveries amounted to 77.4 ± 2.9 % for males and 103.3 ± 4.6 % for females. As compared to the corresponding groups after single oral administration after normalization no significant differences were found in balance and elimination patterns between single oral and single iv administration at the low dose in both sexes, indicating that absorption was virtually complete after oral administration.

REPEATED (13x) FOOD SUPPLY FOLLOWED BY SINGLE IV INJECTION
After repeated (13x) food supply, followed by single iv administration of 14C-triclosan at low dose (1.9 - 2 mg/kg bw) no significant differences were found between both sexes. Radioactivity eliminated via the urine amounted to 20.2 ± 3.7 % in males and 11.4 ± 4.1 % in females. Respective amounts eliminated via the feces were 69.0 ± 3.4 % and 83.9 ± 7.6 %. Taking into account the cage wash, elimination was largely complete after 96 hours, being 91.4 ± 2.2 % for males and 100.3 ± 4.7 % for females (Table 4). At sacrifice low and negligible amounts of radioactivity were found in plasma, residual carcass, organs/tissues as well as intestinal tract (<0.05 - 0.2 %). Total recoveries amounted to 91.8 ± 2.3 % for males and 100.9 ± 4.8 % for females.
Again, as already found after single administration after normalization no significant differences were found in balance and elimination pattems between oral and intravenous administration at the low dose level after repeated (13x) food supply in both sexes.
Toxicokinetic parameters
Toxicokinetic parameters:
other: see freetext below.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The metabolism of triclosan involves 2 primary parent conjugated metabolites (glucuronide and sulfate), as well as four non-parent conjugates. In the plasma of male and female mice administered single or repeated oral and i.v. doses of triclosan (at both doses), the sulfate species was mainly observed (73-90%), with the glucuronide conjugate detected at levels ranging from 5-21% and the free species detected only at the single low dose (64%). In the kidney primarily the parent (44-67%) and sulfate conjugate (24-51%) were identified, with no glucuronide conjugate observed. The free parent species (24-65%) and sulfate conjugate (34-61%) were the predominant forms observed in the liver, with no glucuronide conjugate detected. In male and female hamsters administered single or repeated oral or i.v. doses, the predominant species in the urine for the single dose was the glucuronide conjugate (23-70%, single low dose male no detectable glucuronide conjugate) and for repeated doses was the free species (18-38%, low dose) and glucuronide conjugate (63-75%, high dose), with negligible levels of the sulfate conjugate detected (0.9-4%). In feces, the parent species was found predominantly (66-96%), with levels of the glucuronide detected (3-10%). No sulfate conjugate was detected in the feces. Given that the sulfate conjugate was found in the liver, kidney, and plasma, the glucuronide conjugate was absent from the liver and kidney, yet found in the plasma and urine, these data suggest that the glucuronide conjugate is rapidly removed from the kidney and liver. The sulfate conjugate in the plasma could readily be transferred to a glucuronide conjugate in the kidney and eliminated in the urine. The high levels of the free species may be due in part to the conjugating ability of microflora enzymes or enterohepatic circulation. Repeated administration of high doses was associated with altered (i.e., longer) half-lives for triclosan and the sulfate conjugates in the kidney and enlarged liver of the male mice. At 1/8 Cmax, the parent levels in liver were similar following single administration at both dose levels or up to 2-fold greater following repeated administration at both dose levels. Overall, based on the plasma levels and balance studies, the liver in the mouse appears to be a specific target organ for the high dose of triclosan. Metabolites: Parent (M1): Parent glucur. (M7), Parent sulfate (M4) and Non-parent; Non-parent: M2 and M3 and conjugates (M5, M6, M8, M9). Excretion: For oral and i.v. administration, excretion was predominantly via the faeces for single and repeated dosing in both sexes (50-89%). The results suggest that triclosan is highly absorbed following oral administration, given that there were no significant differences in the balance and elimination patterns between the oral and i.v. studies.

Any other information on results incl. tables

BLOOD/PLASMA LEVELS AND KINETICS

PLASMA, SINGLE GAVAGE 

in males after single oral administration the Cmax values were reached after 4 hours and increased about 11 times from 19.48 ± 5.26 pg peq/g to 212.8 ± 12.0 pg peq/g at the low and at the high dose levels, respectively.At similar half-lives (9-12 hours) AUC-levels increased about 27 times from 166 to 4505 pg peq/g x hour for the low (2.4 mg/kg) and the high dose (200 mg/kg) groups, respectively.

In females Cmax values were reached at 2-4 hours after administration and increased about 34 fold from 7.67 pg peq/g to 263.3 pg peq/g at the low and at the high dose levels, respectively. At similar half-lives of 9-10 hours, corresponding AUC-levels increased about 53 times from 119 to 6322 pg peq/g x hour for the low (2.0 mg/kg) and the high dose (204 mg/kg) groups, respectively. At the last sampling interval of 96 hours, plasma levels in the females were about 2-3 times lower than the corresponding values in the males.

 

BLOOD, SINGLE GAVAGE (females)

Similar to plasma, in females the Cmax values were reached after 1 and 4 hours and increased about 27 times from 5.49 pg peq/g to 141.7 - 148.2 pg peq/g at the high dose level. The corresponding AUC-levels increased 49 times from 70 to 3409 pg peq/g x hour for the female groups. Analogously to plasma at about 100 fold higher dose levels, AUC values increased only about 50 times. Blood levels were always significantly lower at each sequential sampling interval indicating that protein binding of either triclosan or its metabolites were minimal.

BIORETENTION IN ORGANS/TISSUES AND PLASMA

Bioretention studies on plasma, liver and kidney were performed at both dose levels after single and repeated oral administration to male mice. For the low dose level after repeated (13x) food supply, the Cmax value in plasma was 3-fold lower than after single low dose administration. In liver and kidney these values were similar. At ¼ and 1/8 Cmax, values in plasma, liver and kidney were 3-6 times lower after repeated (13x) food supply against single oral administration. These results suggest already some saturation in plasma after repeated administration at the low dose level.

For the corresponding high dose level groups at Cmax and ½ Cmax, the values in plasma, liver and kidney were approximately 50 % less in the group receiving the repeated (13x) food supply than in the single dose group. At ¼ and 1/8 Cmax, the values in plasma (1.6 times) and in liver as well as kidney (1.1 -1.2 times) were less pronouncely reduced. The results suggest partial saturation in absorption after repeated administration at the high dose level.

As compared to plasma, kidney concentrations from Cmax to 1/8 Cmax were about 2 times lower throughout all groups. These results indicate efficient elimination of triclosan and/or metabolites from the kidney at both dose levels (single and repeated). As compared to plasma, liver concentrations from Cmax to1/8 Cmax were similar or lower after single oral administration at both dose levels. In contrast, after repeated administration at both dose levels, values from Cmax to 1/8 Cmax in liver were always higher than in the plasma (about 1.1 - 1.5 times) indicating that the liver in the mouse is a specific target organ after repeated administration of triclosan.

PLASMA TOXICOKINETICS OF14C-TRICLOSAN AFTER SINGLE ORAL ADMINISTRATION AT TWO DOSE LEVELS TO MALE AND FEMALE MICE

Kinetic Parameter*

Actual Dose Level [mg/kg bw]

2.41 (single)

200 (single)

2.0 (single)

204 (single)

Group

(males)

(males)

(females)

 (females)

1. Cmax[µg/g]

19.48

212.8

8.79

267.2

2. Cmax[µg/g]

-

-

7.67

263.3

1. Tmax[h]

4

4

1

2

2. Tmax[h]

-

-

4

4

T1/2[h]

9.1

11.8

8.9

9.9

AUC [(mg/L)×h]

166.1

4505

119.3

6322

AUChigh dose/ AUClow dose

1

27

1

53

Time interval after regression [h]

4-96

4-96

4-96

4-96

Regression coefficient R

0.945

0.971

0.990

0.986

k1[h]

-0.076

-0.059

-0.078

-0.070

C0[mg/L]

10.03

234.9

7.74

380.7

C168** [mg/L]

0.02

1.716

0.007

0.742

* Based on lnCt=lnC0- k1× t (first order elimination kinetics)
** Sacrifice time

Applicant's summary and conclusion