N,N,N',N'-tetramethyl-2,2'-oxybis(ethylamine)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was not performed according to any established regulatory guidelines, rather, an internal BRRC protocol. A few minor details were not described in the report, however all major report elements are present, and the study was conducted in accordance to established GLP procedures. Material balance was not established.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

N,N,N',N'-tetramethyl-2,2'-oxybis(ethylamine)

EC Number:

221-220-5

EC Name:

N,N,N',N'-tetramethyl-2,2'-oxybis(ethylamine)

Cas Number:

3033-62-3

Molecular formula:

C8H20N2O

IUPAC Name:

{2-[2-(dimethylamino)ethoxy]ethyl}dimethylamine

Test material form:

liquid

Specific details on test material used for the study:

- Name of test material (as cited in study report): Bis(2-(dimethylamino)-ethyl)ether
- Physical state: liquid
- Analytical purity: 97.5-97.8%
- Specific activity (if radiolabelling): minimum of 5 uCi
- Stability under test conditions: stable
- Storage condition of test material: room temperature - no special requirements

Radiolabelling:

yes

Remarks:

C14

Test animals

Species:

rat

Strain:

other: CDF® Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc. (Indianapolis, IN)
- Age at study initiation: 11 - 12 weeks old
- Weight at study initiation: 0.232 +/- 0.010 kg (males); 0.146 +/- 0.006 kg to 0.169 +/- 0.010 kg (females)
- Fasting period before study: not applicable
- Housing: prior to use in the study, animals were housed in plastic shoe box cages in groups of 3 to 4 rats.
- Individual metabolism cages: yes - animals selected for the material balance study were transferred to individual Roth-type metabolism cages.
- Diet (e.g. ad libitum): Agway Certified Rodent Chow, St. Marys, OH, ad libitum
- Water (e.g. ad libitum): Municipal drinking water (Municipal Authority of Westmoreland County, Greensburg, PA), ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 deg C
- Humidity (%):40-70%
- Air changes (per hr): Air change ca.. every 5 minutes
- Photoperiod (hrs dark / hrs light): 12-hour photoperiod

IN-LIFE DATES: From: 1987-02-04 To: no data

Administration / exposure

Route of administration:

dermal

Vehicle:

water

Details on exposure:

ADMINISTRATION:
- Type of exposure: cutaneous administration (dose solution applied to a 4-6 cm2 area in the interscapular region of the back using a syringe; amount of dose delivered determined by weighing the syringe before and after delivery); application site was occluded to prevent oral ingestion and maximize skin penetration

- Target doses: dose selected was determined from kinetic information obtained via the i.v. route.

Duration and frequency of treatment / exposure:

single dose, 48-hour exposure duration

Doses / concentrations

Remarks:

Doses / Concentrations:
Nominal doses: 200.0 mg/kg nominal dose level for the main and additional percutaneous studies. [Target radioactivity was 10-15 microCuries/0.2 ml of the tracer to a 200 g rat]

Actual doses reported as follows:
- Percutaneous Males: 184.0 mg/kg actual dose level with 73.6 +/- 0.24 uCi/kg radioactive dose level
- Percutaneous Female Group I: 184.0 mg/kg actual dose level with 71.275 +/- 1.59 uCi/kg radioactive dose level
- Percutaneous Female Group II: 200.0 mg/kg actual dose level with 63.275 +/- 0.88 uCi/kg radioactive dose level
- Percutaneous Male Repeat Study: 198.0 mg/kg actual dose level with 169.8 +/- 9.7 uCi/kg radioactive dose level
- Percutaneous Female Repeat Study: 205.2 mg/kg actual dose level with 318.0 +/- 15.7 uCi/kg radioactive dose level

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

-Cutaneous Study Design (Pharmacokinetics and Material Balance in Rats):
This part of the investigation was conducted in separate segments for each sex. Eight rats were implanted with indwelling jugular cannulas and placed individually into Roth-type glass metabolism cages for acclimation prior to dose administration. The animals were lightly clipped in a 4-6 cm2 area in the shoulder region of the back at the dosing site. Animals were allowed between 24 and 36 hours to recover from surgery.

On the first day of the test, four rats that had patent cannulae were selected for treatment and the test substance was administered as previously described. Blood samples were collected at 0 (pre-administration), 0.5, 1, 2, 4, 6, 12, 18, 24, 36 and 48-hr post-dosing. The plasma samples were processed for LSC and analyzed for parent compound. Urine was collected in 12-hr intervals and feces in 24-hr intervals under dry ice freezing conditions and assayed for 14C. Selected urine samples were analyzed by HPLC to assess the amount of unchanged test substance eliminated by this route.

Forty-eight hours after administration of dose, the animals were killed. Skin sections from each animal (dosed site, skin around the periphery of the site, pelt) were removed. Following removal of the pelts, the liver, kidney, bone marrow, brain, fat (perirenal), heart, lung, muscle, spleen and testes/ovaries were isolated from the carcass. The dose site and peripheral skin were weighed and skin segments from two remote areas (ventral surface and sacral regions) were taken in order to examine the possibility of both radial diffusion of the test substance from the dose site and systemic distribution of the test substance to the skin. The skin sections, tissues, organs, carcass, feces, blood, and occlusive were assessed for radioactivity.

Additional studies: Pharmacokinetic experiments, the following modifications were made: blood collection times were 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 30, 36, and 48 hr; urine samples were collected at 6, 12, 24, 36, and 48 hr, feces were collected at 24 and 48 hr; the pelt was not removed before homogenization of the carcass.

The pharmacokinetic description of the fate of 14C-test substance was evaluated using RSTRIP to derive optimum parameter estimates for the plasma data. Mean plasma 14C concentrations (microgram Equiv/g) were used to fit a two compartment open pharmacokinetic model in which elimination and transfer of l4C-test substance between compartments was assumed to be first-order processes. The parameters which were estimated included: the rate constant of absorption, ka; the rate constant of elimination, ke; and the half-lives (t1/2) of absorption and elimination.

Details on dosing and sampling:

Dose volume: Target volume of 1.0 ml/kg, or 0.5 ml/kg (in the additional rat experiments)

Rationale for dose selection: The dose selected for the dermal administration was determined from kinetic information obtained via the intravenous LD50 preliminary study.

DOSING SOLUTION ANALYSIS: Dosing solutions were analyzed for the test substance by capillary GC with a flame ionization detector after dosing.

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum or other tissues, cage washes
- Time and frequency of sampling:
-- Collection of blood: Blood samples (approx. 0.1 ml) were collected via the indwelling jugular cannulae of rats at 0 (pre-administration), 0.5, 1, 2, 4, 6, 9, 12, 18, 24, 36 and 48 hours post-dosing. In the additional rat percutaneous pharmacokinetic experiments, the following modifications were made: blood collection times were 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 30, 36 and 48 hr.
-- Collection of urine and faeces: Urine and feces were collected in 12-hr intervals. In the additional rat percutaneous pharmacokinetic experiments, the following modifications were made: urine samples were collected at 6, 12, 24, 36 and 48 hr, feces were collected at 24 and 48 hr.
-- Collection of expired air: In the additional rat percutaneous pharmacokinetic experiments, the following modifications were made: CO2 trapping
solutions and volatile traps were collected at 24 and 48 hr.
-- Analysis of organs: Following removal of the pelts the liver, kidney, bone marrow, brain, fat (perirenal), heart, lung, muscle, spleen and tested ovaries were isolated from the carcass.

SAMPLE PREPARATION
- Storage procedure: Blood was collected in heparinized capillary tubes. Urine and feces were collected under dry ice conditions and the urine samples were frozen at approximately -80 deg C until the preliminary metabolite analysis was conducted.
- Preparation details:
-- Blood: The blood collected was placed in heparinized capillary tubes and plasma prepared. An aliquot of the plasma was added to 10 ml of Aquasol-2(R) counting scintillant and counted by liquid scintillation spectrometry. Based on radioactivity levels observed, selected samples of the remaining plasma were then analyzed for metabolites and parent chemical.
-- Expired air: Forty-eight hours after administration of dose, the animals were anesthetized with methoxyflurane (rats).
-- Skin: Skin sections from each animal were removed in the following manner. The dosed area of skin, as well as the skin around the periphery of this site, were separated from each animal using blunt dissection techniques. The pelts were removed from the carcass prior to removal of organs. The dose site and peripheral skin were weighed and skin segments from two remote areas (ventral surface and sacral regions) were taken in order to examine the possibility of both radial diffusion of the test substance from the dose site and systemic distribution of test substance to the skin. The skin from both the dose site and directly surrounding it (approximately 1 cm from edge of dose site) were pulverized at liquid nitrogen temperatures in a Spex Freezer Mill and an aliquot from each sample was counted directly in a suspension of 10 ml Aquasol-2QD and 6 ml water. In the additional rat percutaneous pharmacokinetic experiments, the following modifications were made: the pelt was not removed before homogenization of the carcass.

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting. Radioactivity was determined by tissue oxidation of isolated organs, and tissues, aliquots of homogenized carcass and feces (33% w/v in distilled water), and red blood cells from all collection intervals. Radioactivity recovered from the dose site and from the occlusive bandage was also quantified. Tissue oxidation was conducted in a Biological Materials Oxidizer and 14CO2 derived from combustion of these tissues was quantified by liquid scintillation spectrometry.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Percutaneous Route Pharmacokinetics: The absorption rate constant was significantly greater for males than for females. The cutaneous bioavailability of the test substance was calculated to be 78.2% in males and 50.8% in females.

Details on distribution in tissues:

Initial Experiment:
- Small amounts of the dose were recovered in the residual carcass, while 6.4 and 8.0% recoveries were observed in organs selected for analysis in males and females, respectively.

Additional Experiment:
- Approximately 10% was recovered in the residual carcass and the dosed skin/occlusive devices. Minor amounts of the dose were recovered in the tissues collected at necropsy; there was a modest apparent accumulation of radiolabel in several tissues relative to plasma, including lung, kidney and bone marrow.

Details on excretion:

Initial Experiment:
- Percutaneous Route Pharmacokinetics: The major fraction of the excreted dose was found in the urine, accounting for 24% of the dose (approximately 95% of the excreted dose). Approximately 1 to 2% of the dose (ca. 5% of the excreted dose) was recovered in the feces of male and female rats. There was no remarkable tissue specific accumulation in male or female rats. The relatively high recovery of radioactivity from the pelt suggests that the dose solution was not completely contained by the dose occlusion devices.

Additional Experiment:
- Approximately 50% of the dose was recovered in the urine and cage wash in both sexes. Minor amounts of the dose were recovered in the feces, expired CO2 and organic volatiles.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

other: Ka (male) = 0.02621/min / Ka (female) = 0.008504/min

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: half-life of absorption (male) = 26.45 min / half-life of absorption (female) = 81.51 min

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

other: Ke (male) = 0.0003976/min / Ke (female) = 0.000367/min

Toxicokinetic parameters 4

Test no.:

#1

Toxicokinetic parameters:

half-life 2nd: half-life of elimination (male) = 1744 min / half-life of elimination (female) = 1888 min

Toxicokinetic parameters 5

Test no.:

#1

Toxicokinetic parameters:

Cmax: Cmax (male) = 12.86 ug/g / Cmax (female) = 5.511 ug/g

Toxicokinetic parameters 6

Test no.:

#1

Toxicokinetic parameters:

Tmax: tmax (male) = 117.1 min / tmax (female) = 238.9 min

Toxicokinetic parameters 7

Test no.:

#1

Toxicokinetic parameters:

AUC: AUC through 48 hrs (male) = 13866 ug/g*min / AUC through 48 hrs (female) = 8426 ug/g*min

Toxicokinetic parameters 8

Test no.:

#1

Toxicokinetic parameters:

AUC: AUC to infinite time (male) = 19220 ug/g*min / AUC to infinite time (female) = 12484 ug/g*min

Toxicokinetic parameters 9

Test no.:

#2

Toxicokinetic parameters:

other: Ka (male) = 6.393/hr Ka (female) = 4.945/hr

Toxicokinetic parameters 10

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: half-life of absorption (male) = 0.1084 hr / half-life of absorption (female) = 0.1402 hr

Toxicokinetic parameters 11

Test no.:

#2

Toxicokinetic parameters:

other: Kd (male) = 6.225/hr Kd (female) = 4.550/hr

Toxicokinetic parameters 12

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: half-life of distribution (male) = 0.1114 hr / half-life of distribution (female) = 0.1524 hr

Toxicokinetic parameters 13

Test no.:

#2

Toxicokinetic parameters:

other: Ke (male) = 0.0300/hr Ke (female) = 0.0382/hr

Toxicokinetic parameters 14

Test no.:

#2

Toxicokinetic parameters:

half-life 3rd: half-life of elimination (male) = 23.10 hr / half-life of elimination (female) = 18.145 hr

Toxicokinetic parameters 15

Test no.:

#2

Toxicokinetic parameters:

Cmax: Cmax (male) = 86.83 ug/g / Cmax (female) = 175.7 ug/g

Toxicokinetic parameters 16

Test no.:

#2

Toxicokinetic parameters:

Tmax: Tmax (male) = 0.1650 hr / Tmax (female) = 0.2197 hr

Toxicokinetic parameters 17

Test no.:

#2

Toxicokinetic parameters:

AUC: AUC through 48 hrs (male) = 266.1 ug/g*hr / AUC through 48 hrs (female) = 338.4 ug/g*hr

Toxicokinetic parameters 18

Test no.:

#2

Toxicokinetic parameters:

AUC: AUC to infinite time (male) = 338.3 ug/g*hr / AUC to infinite time (female) = 383.6 ug/g*hr

Toxicokinetic parameters 19

Test no.:

#2

Toxicokinetic parameters:

other: Bioavailability (male) = 82.55% / Bioavailability (female) = 93.60%

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Percutaneous Route Pharmacokinetics: While no evidence of metabolism was observed (no metabolites seen in urine), attempts to accurately measure plasma concentrations of the test substance were unsuccessful and large fractions of the dose were not recovered. The time courses of plasma 14C concentrations showed a similar elimination phase in both sexes, but males showed generally higher plasma concentrations.

In the initial HPLC analyses of urine samples, there was no indication of urinary metabolites; however, in the additional rat percutaneous experiments, a second component, possibly a metabolite of the test substance, accounted for a maximum of approximately 10% of the total urinary radioactivity.

Any other information on results incl. tables

Relatively large amounts of the dose were associated with the dosing site and occlusion devices in both males and females. However, large fractions of the dose (51.8% in males and 39.3% in females) could not be accounted for (see Table 1).

Table 1: Disposition of Radioactivity Following Cutaneous Administration of 200 mg/kg to Fischer 344 Rats - Initial Experiment

	% Recovery - Males	% Recovery - Females
A. Tissues & Excreta
Collected Blood	0.034 +/- 0.015	0.025 +/- 0.010
Urine (0 - 24 hr)	12.376 +/- 3.892	12.176 +/- 5.110
Urine (24 - 48 hr)	4.767 +/- 1.711	7.452 +/- 2.169
Cage Wash	6.394 +/- 2.825	4.209 +/- 2.116
Subtotals	23.537 +/- 1.787	23.837 +/- 3.915
Feces (0 - 24 hr)	1.506 +/- 2.407	0.944 +/- 0.968
Feces (24 - 48 hr)	0.246 +/- 0.145	0.062 +/- 0.074
Subtotals	1.752 +/- 2.511	1.006 +/- 0.900
Tissues	6.399 +/- 1.035	8.029 +/- 2.880
Carcass	1.916 +/- 0.188	2.163 +/- 0.327
Section A Totals	33.639 +/- 2.513	35.061 +/- 5.350
B. Occlusion Devices and Skin
Tape, jacket & plastic rinses	11.570 +/- 2.618	20.931 +/- 5.485
Combustion of plastic	0.008 +/- 0.003	0.006 +/- 0.001
Skin rinses	0.392 +/- 0.106	0.192 +/- 0.131
Recovery in skin	2.534 +/- 0.440	4.558 +/- 2.200
Section B Totals	14.504 +/- 2.825	25.688 +/- 7.560
Total % Recovered Dose	48.142 +/- 5.003	60.749 +/- 12.042

- Additional studies: Additional percutaneous pharmacokinetic experiments were conducted in four male and three female (one of the original four animals died during the study of unknown causes). The total recovery of the dose was approximately 75 to 80% (see Table 2), which, while markedly higher than in the initial experiment, is relatively low. The cause of the reduced recoveries is unknown. 

Table 2: Disposition of Radioactivity Following Cutaneous Administration of 200 mg/kg to Fischer 344 Rats - Additional Experiment

	% Recovery - Males	% Recovery - Females
A. Tissues & Excreta
Collected Blood	0.076 +/- 0.045	0.250 +/- 0.294
Urine (0 - 12 hr)	21.464 +/- 4.292	16.021 +/- 5.932
Urine (12 - 24 hr)	12.480 +/- 2.683	8.149 +/- 1.501
Urine (24 - 48 hr)	12.712 +/- 5.585	11.231 +/- 4.478
Cage Wash	5.533 +/- 2.356	11.240 +/- 5.687
Subtotals	52.189 +/- 3.407	46.641 +/- 2.518
Feces (0 - 24 hr)	0.282 +/- 0.131	1.404 +/- 0.529
Feces (24 - 48 hr)	0.224 +/- 0.222	0.529 +/- 0.244
Subtotals	0.506 +/- 0.342	1.933 +/- 0.698
Expired ^14CO2 (0 - 24 hr)	0.368 +/- 0.029	0.244 +/- 0.039
Expired ^14CO2 (24 - 48 hr)	0.177 +/- 0.051	0.092 +/- 0.008
Subtotals	0.545 +/- 0.070	0.336 +/- 0.046
Volatiles (0 - 48 hr)	3.763 +/- 0.125	1.954 +/- 0.370
Tissues	0.907 +/- 0.204	0.882 +/- 0.126
Carcass	11.438 +/- 1.560	10.869 +/- 2.211
Section A Totals	69.424 +/- 2.907	62.866 +/- 0.538
B. Occlusion Devices and Skin
Tape, jacket & plastic rinses	6.846 +/- 1.358	9.396 +/- 0.426
Combustion of plastic	0.003 +/- 0.001	0.006 +/- 0.004
Skin rinses	0.281 +/- 0.106	0.176 +/- 0.065
Recovery in skin	2.881 +/- 0.572	3.127 +/- 0.288
Section B Totals	10.011 +/- 1.825	12.705 +/- 0.153
Total % Recovered Dose	79.435 +/- 2.769	75.571 +/- 0.432

The distribution of 14C to selected tissues (see Table 3) indicated that no remarkable tissue-specific accumulation occurred in male or female rats. The relatively high recovery of radioactivity from the pelt suggests that the dose solution was not completely contained by the dose occlusion devices.

Table 3 Distribution of Radioactivity in Tissues from Fischer 344 Rats Following Cutaneous Exposure - Initial Experiment

	Male		Female
Tissue	% of Dose	µg Equiv /g	% of Dose	µg Equiv /g
Liver	0.307 +/- 0.048	15.388 +/- 1.507	0.388 +/- 0.041	18.917 +/- 1.512
Kidney	0.189 +/- 0.059	46.004 +/- 10.577	0.214 +/- 0.020	47.448 +/- 5.386
Bone Marrow	---^a	61.831 +/- 17.800	---^a	70.755 +/- 15.091
Spleen	0.045 +/- 0.016	17.967 +/- 5.017	0.067 +/- 0.007	26.403 +/- 2.700
Brain	0.040 +/- 0.009	9.667 +/- 1.988	0.040 +/- 0.012	7.236 +/- 2.684
Heart	0.007 +/- 0.001	4.098 +/- 0.654	0.010 +/- 0.003	4.929 +/- 0.891
Lung	0.048 +/- 0.026	19.472 +/- 7.760	0.077 +/- 0.024	21.902 +/- 10.127
Muscle	---^a	4.062 +/- 1.796	---^a	4.324 +/- 0.930
Skin (Pelt)	5.673 +/- 0.997	74.735 +/- 13.191	7.212 +/- 2.850	84.757 +/- 31.756
Fat	---^a	2.180 +/- 2.683	---^a	0.651 +/- 0.756
Ovaries	---	---	0.003 +/- 0.001	9.285 +/- 2.727
Uterus	---	---	0.009 +/- 0.004	8.483 +/- 3.483
Testes	0.084 +/- 0.025	15.036 +/- 3.383	---	---

^a Percent of dose not expressed since tissue was only partially sampled (entire tissue not collectable).

In the Additional Experiment,minor amounts of the dose were recovered in the tissues collected at necropsy (see Table 4). There was a modest apparent accumulation of radiolabel in several tissues relative to plasma, including lung, kidney and bone marrow.

Table 4. Distribution of Radioactivity in Tissues from Fischer 344 Rats Following Cutaneous Exposure - Additional Experiment

Tissue	Male		Female
	% of Dose	µg Equiv /g	% of Dose	µg Equiv /g
Plasma	0.008 +/- 0.002^b	1.549 +/- 0.228	0.006 +/- 0.000^b	1.356 +/- 0.106
Liver	0.438 +/- 0.088	23.899 +/- 2.737	0.397 +/- 0.053	21.194 +/- 1.365
Kidney	0.195 +/- 0.052	51.335 +/- 11.720	0.222 +/- 0.040	52.985 +/- 9.150
Bone Marrow	0.007 +/- 0.001^b	98.051 +/- 14.361	0.009 +/- 0.001^b	91.393 +/- 9.411
Spleen	0.046 +/- 0.013	25.757 +/- 7.149	0.038 +/- 0.025	16.937 +/- 10.609
Brain	0.041 +/- 0.004	10.655 +/- 1.577	0.055 +/- 0.010	10.406 +/- 0.276
Heart	0.011 +/- 0.002	7.056 +/- 1.311	0.025 +/- 0.021	13.234 +/- 11.279
Lung	0.084 +/- 0.037	35.837 +/- 13.805	0.120 +/- 0.030	40.637 +/- 9.065
Muscle	0.005 +/- 0.001^b	6.756 +/- 1.896	0.006 +/- 0.000^b	6.718 +/- 0.891
Fat	0.000 +/- 0.000^b	1.709 +/- 0.488	0.001 +/- 0.000^b	1.472 +/- 0.429
Ovaries	---	---	0.003 +/- 0.000	10.184 +/- 0.611
Uterus	---	---	0.007 +/- 0.002	10.373 +/- 0.621
Testes	0.080 +/- 0.011	14.058 +/- 2.177	---	---

^a Means were computed from groups of four males and three females.

^b Percent of dose expressed for sample assayed but tissue was only partially sampled (entire tissue not collectable).

The time courses of plasma ¹⁴C concentrations following cutaneous exposures in male and female rats show that absorption and distribution of the test substance were very rapid in both sexes. The estimated maximal ¹⁴C plasma concentration was reached within 0.25 hr, while the distribution phase was apparently complete by 2 to 4 hr. Elimination of ¹⁴C was moderately slow in both sexes although it appeared to occur slightly more rapidly in females. The calculated percutaneous bioavailability was greater than 80% in both sexes. 

The major differences in the outcomes of the initial and additional percutaneous rat studies are: 1) a greater fraction of the dose was recovered in the additional studies, with greater recovery in the urine and less in the dose skin/occlusion devices; 2) the absorption half-life and time to Cmax were much shorter in the additonal studies and the half-life of elimination was decreased; 3) the apparent percutaneous bioavailability was higher in the additional studies, particularly in females.

Applicant's summary and conclusion

Conclusions:

Pharmacokinetic profile is consistent with a two-compartment open model in which elimination is primarily by urine excretion of the unchanged test material. Metabolism is not a major feature of Bis(2-(dimethylamino)-ethyl)ether elimination.