Methyl 3-[3-(2H-benzotriazol-2-yl)-4-hydroxy-5-(2-methyl-2-propanyl)phenyl]propanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991-1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD Guideline Study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Remarks:

RCC, Itingen, Switzerland

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

400-820-2

EC Name:

-

Cas Number:

84268-33-7

Molecular formula:

C20 H23 N3 O3

IUPAC Name:

methyl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate

Details on test material:

- Physical state: white solid
- Analytical purity: 99%
- Lot/batch No.: OPZ 288/1 U (unlabeled) and CFQ 6155 (labeled)
- Radiochemical purity (if radiolabelling): 98.3 - 99.0 % on December 17, 1990
- Specific activity (if radiolabelling): 56 µCi/mg (2.07 MBq/mg) or 19.8 mCi/mmol (0.733 GBq/mmol)
- Locations of the label (if radiolabelling): phenolic ring U-C14
- Storage condition of test material: dark, -20°C

Radiolabelling:

yes

Remarks:

14-C

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL Biological Research Laboratories Ltd., Wolferstrasse 4, CH-4414 Fuellinsdorf/Switzerland
- Age at study initiation: Males: 6 weeks / Females: 7-8 weeks
- Weight at study initiation: 145 - 201 g for males and from 150 - 190 g for females
- Fasting period before study: overnight
- Housing: 3/cage
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Five to six days to laboratory environment, including 1-3 days to metabolism cages.

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: acetone, cremophor and 0.9% NaCl

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Based on the high target dose level of 10 mg/kg, a rat body weight of 0.2 kg and a target administration volume of 1 ml/100g rat, an aliquot of 134 µL of the acetonic solution of the test article (corresponding to about 2.0 mg substance) was mixed with 100 mg CREMOPHOR EL (BASF, Ludwigshafen/Germany) and 1765 µL 0.9 % NaCl. The suspension obtained was turbid and not enough homogeneous. Therefore, another aliquot of 134µL of the acetonic solution of the test article was first suspended in about 200 mg CREMOPHOR before being mixed with
1665µL 0.9 % NaCl. A clear and homogeneous suspension was obtained. In conclusion, the high dose level (1 mg test article/100 g rat) was efficiently
formulated in about 67µL acetone, 100 mg CREMOPHOR and 833µL NaCl 0.9 %. Consequently, the low dose level was formulated identically.

Duration and frequency of treatment / exposure:

single treatment

Doses / concentrations

Remarks:

Doses / Concentrations:
1 mg/kg = 56 µCi/mg = 2.07 MBq/mg
10 mg/kg = 20 µCi/mg = 0.74 MBq/mg

No. of animals per sex per dose / concentration:

10

Control animals:

no

Details on study design:

- Dose selection rationale:
- Rationale for animal assignment (if not random):

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, organ/tissues, cage washes
- Time and frequency of sampling: Urine/Feces: It was taken 8, 24, 48, 72, 96, 120, 144 and 168 hours after the administration. Additionally, at
sampling intervals of 8 and 24 hours, metabolism cages were rinsed with a small amount of bidistilled water (about 2 ml) to remove remaining droplets of urine which were added to the initially sampled urine. Final volumes were noted. Feces was collected at room temperature 24, 48, 72, 96, 120, 144 and 168 hours after the administration. Fresh weights were noted.
Blood: After 168 hours, animals were killed by carbon dioxide.
Organs/Tissues and Residual Carcass: The following organs and tissues were taken after 168 hours: Heart, lung, liver, stomach (contents were separately determined), spleen, kidney, muscle, bones (femur), brain, fat, pancreas, intestinal tract (with contents), adrenal glands, gonads (ovary and uterus or testicle and epididymes), thyroid gland, skin (backregion) and residual carcass.
Cage Wash: At the end of the study, the cages were washed with water/acetone (50+50, v/v). The washing solutions were then used for determination of remaining radioactivity.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

low but significant amounts from the gastro-intestinal tract

Main ADME results 2

Type:

distribution

Results:

Negligible amounts (<0.1%) of radioactivity were found in organs/tissues, intestinal tract, blood and residual carcass

Main ADME results 3

Type:

excretion

Results:

Excretion proceeded mainly via the faeces and urine. In both cases > 87% of the dose was excreted within the first 24 hours.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

At the low dose level, In both sexes, very low or negligible (0.1 % - <0.05 %) amounts of radioactivity were found at 168 hours after the administration in organs/tissues, blood, intestinal tract and residual carcass.
At the high dose level, negligible or very low amounts of radioactivity (<0.05 % - 0.1 %) were found in organs/ tissues, blood, intestinal tract and residual carcass.
At 168 hours after low dose level administration for both sexes, very low residual radioactivity levels were found in the excretory organs liver (0.007 - 0.009 µg/g) and kidney (0.006 - 0.007 µg/g). In spleen, residual radioactivity levels (0.005 µg/g) approached the limit of quantitation. In females, residual radioactivity levels in blood, plasma, adrenal glands, brain, intestinal tract with contents and stomach contents (0.003 - 0.007 µg/g) also approached the limit of quantitation. In all other organs/ tissues, intestinal tract with contents (only for males) and residual carcass, residual radioactivity levels were negligible, i.e. at or below the limit of quantitation.
At a ten times higher dose level, residual radioactivity levels at 168 hours in the excretory organs liver (0.058 - 0.074 µg/g), kidney (0.036 - 0.064 µg/g) and intestinal tract with contents (0.014 µg/g - 0.022 µg/g) were about 4-7 times the limit of quantitation. Residual radioactivity levels in blood/plasma, spleen, fat, skin backregion, stomach contents (only females) and residual carcass ranged from 0.009 µg/g (residual carcass; males) to 0.062 µg/g (blood; females) and amounted to 2-4 times the limit of quantitation. In the remaining organs/tissues, radioactivity levels were negligible or below two times the limit of quantitation.

Details on excretion:

At the low dose level, excretion of radioactivity via the urine represented after 168 hours, on average, 4.8 % and 6.1 % of the radioactivity administered
in males and females, respectively. Already 24 hours after the administration, urinary excretion accounted for 4.5 % (males) and 5.8 % (females). Excretion proceeded mainly via the feces and accounted after 168 hours, on average, for 96.8 % (males) and 95.8 % (females) of the radioactivity administered. Already after 24 hours, fecal excretion amounted to 87.8 % and 86.9 % in males and females, respectively (see table 1). Together with the cage wash (0.4 % - 0.5 %), total excreted radioactivity amounted to 102.0 % (males) and 102.4 % (females).
A similar excretion pattern was found at a ten times higher dose level in both sexes. After 168 hours, urinary excretion accounted for 5.1 % and 8.8 % of the radioactivity administered in males and females, respectively. Already after 24 hours, urinary excretion amounted to 4.8 % (males) and 8.6 % (females). After 168 hours, fecal excretion accounted, on average, for 93.1 (males) and 92.3 % (females). Again, the major amount (83.1 % in males and 85.2 % in females) was excreted within the first 24 hours. Together with the cage wash (0.6 % - 0.3 %), total excreted radioactivity amounted to 98.8 % and 101.5 % in males and females, respectively.

Any other information on results incl. tables

Table 1: Elimination after a single dose of 1 or 10 mg/kg bw

Dose level		1 mg/kg bw		10 mg/kg bw
Time after administration		24h	168h	24h	168h
Males (n=5)	Radioactivity in feces [%]	87.8	96.8	83.1	93.1
	Radioactivity in urine [%]	4.5	4.8	4.8	5.1
Females (n=5)	Radioactivity in feces [%]	86.9	95.8	85.2	92.3
	Radioactivity in urine [%]	5.8	6.1	8.6	8.8

Table 2: Amount [mg CG 20-571 per g] of CG 20-571 in rat tissues 168 h after a single dose of 1 or 10 mg/kg bw

Dose		1 mg/kg bw	11 mg/kg bw
Males and females	liver	0.008	0.058 – 0.074
	kidney	0.0065	0.036 – 0.064
	spleen	0.005	0.014 – 0.022
	intestinal tract with contents		0.014 – 0.022
Females only (values for males are lower and therefore not given)	blood plasma adrenal glands brain intestinal tract + contents stomach contents	0.007 0.005 0.005 0.003 0.003 0.003	0.062 0.042 0.017 0.008 0.022 0.018
	spleen	0.005	0.022
	Uterus ovaries	0.002* 0.002*	0.018 0.012*
Males only	Testes epididymes	0.002* 0.003*	0.007* 0.011*

*Mean level at or below the limit of quantitation