Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2 Mar 1992 to 30 May 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Materials and methods

Objective of study:

absorption

excretion

metabolism

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Deviations:

yes

Remarks:

The cage wipes of the control group were not analysed. Storage material of the test substance was at approximately -20°C. Some of the male rats were 27 days upon arrival. These deviations would not be expected to have an effect on the study

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

EC Number:

276-696-7

EC Name:

Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Cas Number:

72490-01-8

Molecular formula:

C17 H19 N O4

IUPAC Name:

ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 27 to 63 days old
- Weight at study initiation: 150 g to 174 g for males and 175 g and 199 g for females (arrival Feb 24, 1992) and 75 to 99 g and 150 to 174 g for the males and 125 to 149 g and 175 to 199 g for the females (arrival March 16, 1992)
- Housing: Individual metabolism cages for separation and collection of urine, faeces and expired volatile compounds. Individual, suspended, stainless steel wire-mesh cages in the acclimatisation period
- Diet: Rodent diet ad libitum
- Water: Ad libitum
- Acclimation period: At least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 50 ±20
- Photoperiod (hrs dark / hrs light): 12/12
- Fasting period : Overnight and through 4 hours post dose (oral groups)

IN-LIFE DATES: 2 Mar 1992 to 30 May 1992

Administration / exposure

Route of administration:

other: Oral gavage and IV

Vehicle:

other: PEG 200

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The radiolabelled dosing solutions were prepared by transferring the radiolabelled test substance from its ampule to a serum vial. The ampule was rinsed with acetone and then with acetonitrile. Each rinse was transferred to the vial and solvent evaporated with nitrogen. The test substance was then diluted with a measured amount of polyethylene glycol 200 (PEG 200). The mixture was stirred for a minimum of 20 to 30 minutes, and aliquots were taken to determine the homogeneity and concentration. The nonradio labelled dosing solution was prepared by mixing known amounts of the test substance and PEG 200. The radiolabelled and non-labelled dosing solutions were prepared for 48 hours before the day of dosing and stored at or below 8 °C.

Duration and frequency of treatment / exposure:

Once

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Remarks:

Group D- P- H, oral gavage

Doses / concentrations 2

Dose / conc.:

1 mg/kg bw/day (actual dose received)

Remarks:

Group A, IV dose; Group B, Oral gavage; Group C, Oral gavage, 14 day preconditioned non-radiolabelled dose, followed by a single radiolabelled dose

No. of animals per sex per dose / concentration:

Low dose: 30
High dose: 10

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: The rat is frequently used in metabolism studies as a representative rodent species

Details on dosing and sampling:

See ''Any other information on materials and methods incl. tables''.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After single dose absorption was 66.7-77.0% (females-males), but after repeated dosing 97.7% respectively 98.6% (females and males)

Details on distribution in tissues:

Very low amounts of radioactivity were found in tissues (individual tissues < 1% AR). Relatively high amounts were reported in fat (average: 1618-1795 ng eq./g), liver (average: 683-1140 ng eq./g) and kidneys (average: 282-335 ng eq./g) after a single dose at 300 mg/kg bw.

Details on excretion:

A single or repeated dose of 1.0 mg/kg bw 14C-test substance is excreted mainly via faeces (average per group 69%-82%). After 300 mg/kg bw the amount of radioactivity recovered from faeces is slightly lower (averages over males and females 56-60% AR), while urinary excretion is higher than in the low dose groups (average over males and females both 36% AR).

Any other information on results incl. tables

Table 1. Excretion and retention of radioactivity (% AR) in rats after single and repeated exposure to 14C-test substance

sample	P-H Single oral 300 mg/kgbw		A Single iv 1.0 mg/kg bw		B Single oral 1.0 mg/kg bw		C Repeated oral 1.0 mg/kgbw		D Single oral 300 mg/kg bw
	M	F	M	F	M	F	M	F	M	F
faeces 0-6 h 6-12 h	6.7	0.6	0.01 1.1	0.3 1.6	NA 9.3	<0.01 22	NA 14	<0.01 23	NA 3.7	0.01 5.0
12-24 h	21	25	39	30	41	38	47	38	13	10
24-48 h	26	27	26	29	20	15	17	16	33	27
48-72 h	2.8	3.8	3.7	6.5	2.9	2.5	2.7	2.4	8.8	12
72-96 h	0.3	0.7	0.7	1.5	0.4	0.4	0.3	0.4	0.8	1.5
96-120 h	0.09	0.08	0.2	0.3	0.1	0.1	0.1	0.09	0.1	0.3
120-144 h	0.05	0.04	0.05	0.07	0.03	0.0 2	0.02	0.05	0.05	0.09
144-168 h	0.05	0.03	<0.01	0.05	ND	<0.01	ND	<0.01	0.02	0.05
0-168 h	55.8	57.9	70.0	68.6	73.4	77.7	80.9	80.4	59.6	56.4
urine 0-6 h 6-12 h	11	15	5.2 4.2	6.5 5.0	4.1 3.3	5.5 3.4	5.4 5.6	8.2 5.2	2.3 3.7	4.1 3.5
12-24 h	19	15	6.6	6.4	5.3	3.8	6.3	5.0	7.7	4.8
24-48 h	7.6	8.0	3.6	4.3	2.8	2.8	2.9	3.0	20	20
48-72 h	0.4	0.8	1.1	1.5	0.5	0.6	0.6	0.7	1.5	2.3
72-96 h	0.2	0.2	0.2	0.6	0.1	0.2	0.2	0.3	0.5	0.5
96-120 h	0.2	0.09	0.1	0.2	0.08	0.1	0.07	0.2	0.2	0.3
120-144 h	0.08	0.04	0.06	0.1	0.06	0.07	0.06	0.09	0.1	0.1
144-168 h	0.06	0.03	0.04	0.07	0.03	0.05	0.04	0.07	0.1	0.1
0-168 h	37.8	38.7	21.0	24.7	16.3	16.5	21.0	22.7	36.0	35.2
expired air (CO2 0-168h and volatiles	ND	ND	-	-	-	-	-	-	-	-
carcass 168 h	0.2	0.3	0.3	0.7	0.02	0.2	ND	0.2	0.2	0.3
cage wash/wipe 168 h	0.8	0.5	0.3	0.5	0.3	0.5	0.3	2.3	0.6	0.9
Recovery 168 h	94.6	97.4	91.6	94.5	90.0	94.9	102.2	105.6	96.4	92.8

ND not detectable NA not applicable

Table 2. Distribution of radioactivity in tissues and organs [ng test substance equivalents/g and % AR at 168 post dose 14C-test substance

sample

A Single iv 1.0 mg/kg bw

C Single oral 1.0 mg/kg bw

C Repeated oral 1.0 mg/kg bw

D-P-H Single oral 300 mg/kg bw

M

F

M

F

M

F

M

F

ng

%AR

ng

%AR

ng

%AR

ng

%AR

ng

%AR

ng

%AR

ng

%AR

ng

%AR

Bone

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

103

<0.01

205

<0.01

Brain

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Carcass

3

0.33

7

0.67

<1

0.02

2

0.15

ND

ND

1

0.17

430

0.17

839

0.29

Fat

3

<0.01

2

<0.01

2

<0.01

2

<0.01

1

<0.01

2

<0.01

1618

<0.01

1795

<0.01

Heart

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

11

<0.01

15

<0.01

Kidneys

<1

<0.01

ND

ND

<1

<0.01

ND

ND

1

<0.01

ND

ND

335

<0.01

282

<0.01

Liver

3

0.02

5

0.02

4

0.03

6

0.03

4

0.03

6

0.03

683

0.01

1140

0.02

Lungs

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

83

<0.01

121

<0.01

Muscle

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

68

<0.01

66

<0.01

Ovaries

NA

NA

ND

ND

NA

NA

ND

ND

NA

NA

ND

ND

NA

NA

675

<0.01

Plasma

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

79

NA

66

NA

Red blood cells

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

23

NA

93

NA

Spleen

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

23

<0.01

31

<0.01

Testes

ND

ND

NA

NA

ND

ND

NA

NA

ND

ND

NA

NA

ND

ND

NA

NA

Uterus

NA

NA

ND

ND

ND

ND

ND

ND

NA

NA

ND

ND

NA

NA

102

<0.01

Table 3. Absorption values

Percentage of dose
Group	Sex	Dose mg/kg	Urine (0-168 h) b	Tissue residues b	Carcass residues b	Total c	Absorption %
A (IV)	M	0.93	21.3	0.02	0.33	21.7	100
	F	0.94	25.1	0.02	0.67	25.8	100
B (oral)	M	1.00	16.6	0.03	16.7		77.0
	F	1.00	17.0	0.03	0.15	17.2	66.7
C (oral)	M	0.90	21.4	0.03	ND	21.4	98.6
	F	0.92	25.0	0.03	0.17	25.2	97.7

Applicant's summary and conclusion

Conclusions:

After oral administration of 14C-test substance to male and female rats at the low dose level of approximately of 1.0 mg/kg, 66.7% to 98.6% of the radioactivity was absorbed from the intestinal tract into the general circulation. Negligible amounts of radioactivity were recovered in the expired air (CO2 traps and volatiles), for the preliminary group; therefore, the volatile organic compounds and expired carbon dioxide were not collected for the definitive phase groups. Total recoveries of radioactivity ranged from 90.0% to 105.5% of the total radioactivity administered for the IV and oral dose groups with 56.4% to 80.9% recovered in faeces, 16.6% to 36.8% in urine, not detected to 1.2% in carcass, and small amounts (less than 0.03%) in all other tissues combined. The majority of the radioactivity was eliminated in the urine and faeces within 48 hours after dosing. No apparent sex- related difference was noted for the absorption, elimination, and distribution of radioactivity for all dosing groups. The animals that received the multiple oral low dose show a higher percentage of absorption from the intestinal tract (71.9% for the single dose and 98.2% for the multiple dose). Animals that received a single oral high dose excreted higher amounts of radioactivity in urine (36.6%) compared to the amounts excreted from the single (16.8%) and multiple (23.2%) low dose group. Biliary excretion appeared to be an important elimination route for animals that received the IV dose. For the low-dose groups, at 7 days after dose administration, the mean concentration of radioactivity in the red blood cells and plasma were not detectable. The highest 14C- residue concentrations were detected in liver (0.003 to 0.006 ppm 14C-test substance equivalents), kidney (non-detectable to 0.001 ppm), and fat (0.001 to 0.003 pm), and lower residue concentrations were detected in all other tissues (not detectable to less than 0.001 ppm). At the high dose level, the residues were correspondingly higher.

Executive summary:

The absorption, distribution and elimination of radioactivity were studies in male and female Sprague Dawley rats dosed with 14C-test substance according to EPA 85-1 and GLP principles. The 44 treated animals were divided into a preliminary group of 4 animals (2/sex/group) and 4 definitive groups of 10 animals (5/sex/group), which were dosed orally (gavage) or intravenously (IV) with 14C-test substance as follows: Group P-H (orally), at 300 mg/kg, Group A (IV) and B (orally) at 1.0 mg/kg, Group C received 14 consecutive daily oral doses of nonradio labelled test substance followed by a single radiolabelled oral dose at 1.0 mg/kg, Group D (orally), at 300 mg/kg. Organic volatiles and expired carbon dioxide were collected from the preliminary group (P-H). Based on the results of the preliminary group, organic volatiles and expired carbon dioxide were not collected from the definitive phase groups. Urine and faeces were collected from all treated and control animals at specified time intervals. Treated animals were sacrificed 7 days after administration of the radiolabelled dose. Selected tissue samples and the residual carcasses were collected for radio analysis.

Results showed, for oral dosed animals, faecal excretion was the primary elimination route. Total mean amounts of 75.5% (Group B), 80.6% (Group C), and 57.9% (Group D) were eliminated in faeces with the average majority (46.2% to 77.6%) excreted within 48 hours post dose. The total mean amounts excreted in urine were 16.8% (Group B), 23.2% (Group C), and 36.6% (Group D). A higher amount of radioactivity was excreted in urine from the high dose group than from the low dose group. For the IV dosed animals, 69.3% of the radioactivity was excreted in faeces, indicating biliary excretion was also an important elimination route. The test substance was well absorbed from the tract by rats dosed orally. No significant sex related differences were observed in the absorption, elimination, and/or distribution of radioactivity for any of the treated groups. Seven days after single oral administration at the low dose level, tissue residue levels were less than or equal to 0.006 ppm in all tissues with the exception of the liver (0.003 to 0.007 ppm). At the high dose level the resides were correspondingly higher (ranging from 0.683 to 1.14 ppm in liver). Total mean radioactive recoveries for groups A, B, C and F were 93%, 92.4%, 103.9% and 94.4%, respectively. Total mean radioactive recoveries for groups A, B, C and D were 93.0%, 82%, 103.9% and 94.9%, respectively.

In conclusion, after oral administration of 14C-test substance to male and female rats at the low dose level of approximately of 1.0 mg/kg, 66.7% to 98.6% of the radioactivity was absorbed from the intestinal tract into the general circulation. Negligible amounts of radioactivity were recovered in the expired air (CO2 traps and volatiles), for the preliminary group; therefore, the volatile organic compounds and expired carbon dioxide were not collected for the definitive phase groups. Total recoveries of radioactivity ranged from 90.0% to 105.5% of the total radioactivity administered for the IV and oral dose groups with 56.4% to 80.9% recovered in faeces, 16.6% to 36.8% in urine, not detected to 1.2% in carcass, and small amounts (less than 0.03%) in all other tissues combined. The majority of the radioactivity was eliminated in the urine and faeces within 48 hours after dosing. No apparent sex- related difference was noted for the absorption, elimination, and distribution of radioactivity for all dosing groups. The animals that received the multiple oral low dose show a higher percentage of absorption from the intestinal tract (71.9% for the single dose and 98.2% for the multiple dose). Animals that received a single oral high dose excreted higher amounts of radioactivity in urine (36.6%) compared to the amounts excreted from the single (16.8%) and multiple (23.2%) low dose group. Biliary excretion appeared to be an important elimination route for animals that received the IV dose. For the low-dose groups, at 7 days after dose administration, the mean concentration of radioactivity in the red blood cells and plasma were not detectable. The highest 14C- residue concentrations were detected in liver (0.003 to 0.006 ppm 14C-test substance equivalents), kidney (non-detectable to 0.001 ppm), and fat (0.001 to 0.003 pm), and lower residue concentrations were detected in all other tissues (not detectable to less than 0.001 ppm). At the high dose level, the residues were correspondingly higher.