Benzenesulfonic acid, mono-C10-13-alkyl derivs., compds. with diethanolamine

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Diethanolamine absorption, metabolism and disposition in rat and mouse following oral, intravenous and dermal administration

Author:

Mathews JM, et al.

Year:

1997

Bibliographic source:

Xenobiotica, 27, 733-746

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The disposition of [14C]diethanolamine (DEA) was determined in rat after oral, i.v. and dermal administration.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-iminodiethanol

EC Number:

203-868-0

EC Name:

2,2'-iminodiethanol

Cas Number:

111-42-2

Molecular formula:

C4H11NO2

IUPAC Name:

2,2'-iminodiethanol

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC, USA)
- Age at study initiation: adult
- Weight at study initiation: 123-206 g
- Housing: individual in glass metabolism chambers permitting separate collection of CO2, urine and faeces
- Individual metabolism cages: yes
- Diet: furnished Purina Rodent C. diet ad libitum
- Water: ad libitum

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

ethanol

Duration of exposure:

Dermal dose formulations contained from 6 to 20 mCi, an appropriate amount of unlabelled DEA and 95% ethanol for a total dose volume of 25 µL per dose. Dermal doses were applied to an area of skin (2 cm²) from which hair had been clipped the previous day. After dosing, a hemispherical dome of wire mesh (histology tissue capsule) was glued over the dose area with cyanoacrylate adhesive to serve a non-occlusive protective appliance.

No. of animals per group:

oral dosing studies: 5 rats
intravenous dosing studies: 5 rats
dermal dosing studies: 5 rats
repeated dose studies: four to five rats (as further indicated)

Control animals:

no

Remarks:

no data

Details on study design:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, adipose, brain, heart, kidney, liver, lung, muscle, skin, spleen,
- Time and frequency of sampling: 48 hours
- Other: The dose site skin was excised and thoroughly rinsed with acetone. The rinsing solutions and gauzes were collected and analyzed. The washed dose site skin was digested in 2N ethanolic sodium hydroxide.


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine

Results and discussion

Absorption in different matrices:

Dermal absorption was poor (3-16 % in 48 h); most of the material remained at the site of application.

Percutaneous absorption

Percutaneous absorption 1

Key result

Time point:

48 h

Dose:

2 mg/kg bw

Parameter:

percentage

Absorption:

3 %

Percutaneous absorption 2

Key result

Time point:

48 h

Dose:

28 mg/kg bw

Parameter:

percentage

Absorption:

16 %

Any other information on results incl. tables

Results summary:

Absorption:

Gastrointestinal absorption of single doses up to at least 200 mg/kg bw was nearly complete (measured 48 hours after exposure).

Dermal absorption was poor(3-16 % in 48 h)and most of the "adsorbed" material remained at the site of application.

Distribution:

Similar patterns of distribution was observed following intravenous, oral or dermal application. The highest concentrations of DEA equivalents were present in liver, kidney, heart, lung, brain and spleen with liver and kidney representing the main target organs.

Metabolism:

Single oral and iv doses of the test compound were excreted predominantly unchanged.

Excretion:

The total percentage of excreted test compound was comparable after oral and intravenous application with 25 -30%. Excretion was mainly urinary within 48 hours (about 20-30%). The test substance demonstrated to exhibit a bioaccumulative potential.

Repeated dose experiments:

The tissue distribution after repeated dosing was similar to the tissue distribution after single application of the test substance.

The test substance accumulated with repeated dosing, reaching a steady state between 4 and 8 weeks. At this time excretion profile of the test substance chanced excreting poorly retained metabolites in significant amounts as well as N-methylDEA and one further mor cationic metabolite.

Tissue half lifes of the test substance after repeated exposure were found at highest in blood with 54 days.

Results details:

Absorption and distribution:

Very similar patterns of tissue distribution and retention of [¹⁴C]-DEA were observed 48 hours after i.v. and oral administration to rats.

The total percentage of the dose present after 48 h in tissues (adipose, blood, brain, heart, kidney, liver, lung, muscle, skin, and spleen) was 54% after i.v. administration and 57% after oral administration.

The highest concentrations of DEA equivalents were found in liver, kidney, heart, lung, brain and spleen whereas the concentration in blood (ca. 260 ng. equiv./g blood) was relatively low. DEA was observed to have a particularly high affinity for liver and kidney as evidenced by tissue/blood ratios of 150-200. Residues in liver and kidney combined accounted for nearly one-third of the administered dose 48 h after administration.

The data further indicate, that gastrointestinal absorption of single was nearly complete up to oral doses of at least 200 mg/kg bw. in each case excretion was primarily in urine and total excretion accounted for only 20-30% of the dose in 48 hours.

Excretion:

The total percentage of the dose recovered in excreta (urine, faeces, carbon dioxide, and volatiles) was 29% after i.v. and 24% after oral administration to rats. The primary route of excretion was the urine.Only 0.2% of an i.v. dose of DEA was excreted as CO₂or other volatile metabolites in 48 h. Excretion was primarily in urine, but 30% of the i.v. or oral doses were excreted in 48 h. Further, HPLC analysis of urine indicated that virtually all the radioactivity in urine was present as the parent compound. Most of the dose remained in the tissues.

Disposition of radioactivity 48 h after administration of [¹⁴C]DEA (7 mg/kg bw)

Tissue	i.v. dose		oral dose
	% dose in total tissue	Tissue/blood ratio	% dose in total tissue	Tissue/blood ratio
adipose	1.05 ± 0.11	4.28 ± 0.43	1.64 ± 0.33	6.70 ± 1.19
blood	0.18 ± 0.00	unity	0.18 ± 0.01	unity
brain	0.30 ± 0.02	9.85 ± 0.17	0.27 ± 0.02	8.80 ± 0.41
heart	0.19 ± 0.01	17.9 ± 0.60	0.19 ± 0.01	17.5 ± 1.00
kidney	3.95 ± 0.53	148 ± 11.0	5.01 ± 1.04	197 ± 12.0
liver	27.1 ± 1.50	166 ± 17.0	27.3 ± 1.20	155 ± 7.00
lung	0.76 ± 0.11	38.7 ± 14.6	0.71 ± 0.02	29.4 ± 5.20
muscle	15.3 ± 1.00	9.10 ± 0.47	16.3 ± 1.19	73.0 ± 0.62
skin	4.54 ± 0.13	7.61 ± 0.19	5.10 ± 0.40	8.59 ± 0.44
spleen	0.31 ± 0.04	36.8 ± 5.60	0.32 ± 0.01	36.5 ± 1.20
total	53.7±1.80		57.1±2.70
urine	28.3 ± 2.50		22.0 ± 1.80
faeces	0.60 ± 0.03		2.4 ± 0.30
CO2	0.2± 0.00		-
volatiles	0.01		-
total	29.1± 2.00		24.4± 1.30

Values are means± SD for three to five rats

Disposition of radioactivity 48 h after dermal application of[¹⁴C]DEA

	Percentage of dose
	2.1 mg/kg (n=5)	7.6 mg/kg (n=5)	27.5 mg/kg (n=4)
Absorbed
Tissues	1.1 ± 0.8	4.3 ± 2.0	7.3 ± 4.1
urine	0.6 ± 0.4	1.7 ± 0.6	4.2 ± 2.9
Faeces	0.03 ± 0.02	0.2 ± 0.1	0.2 ± 0.2
Dose site skin	1.2 ± 0.3	4.3 ± 0.9	4.5 ± 0.9
Total	2.9 ± 1.3*	10.5 ± 2.6	16.2 ± 7.7
unabsorbed	91.4 ± 2.0	82.9 ± 6.5	70.2 ± 8.2
Total recovery	94.3 ± 1.3	92.9 ± 4.2	86.4 ± 2.4
Tissue/blood ratio
Tissues
adipose	1.66 ± 0.73	4.54 ± 0.72	7.22 ± 1.64
brain	2.60 ± 1.11	5.36 ± 1.30	6.12 ± 1.74
heart	6.76 ± 2.42	15.5 ± 2.0	17.8 ± 3.0
kidney	47.3 ± 22.9	123 ± 25	153 ± 26
liver	56.0 ± 24.2	135 ±18	140 ± 25
lung	10.1 ± 3.9	34.2 ± 14.1	44.7 ± 13.9
muscle	2.80 ± 1.27	6.95 ± 1.03	7.29 ± 1.18
skin	2.85 ± 1.38	6.34 ± 1.40	7.70 ± 1.61

*significantly different from the 7.6 and 27.5 mg/kg bw dosing groups

Repeated dose experiments:

At no point of the study period the excretion did keep pace with the rate of administration. Only 40% of the administered dose was excreted during the time period. The tissue distribution after repeated dosing was similar to the tissue distribution after single application of the test substance. Concentration of DEA equivalents in tissues of repeated dose animals were about 3-5 times higher compared to those of single dose animals, but tissue-to-blood ratios were quite similar, indicating a potential for bioaccumulation of the test compound with continued exposure.

After repeated dose exposure for more than 1 week (5 days) examination of residues in tissues indicated that the maximum of tissue equivalents of DEA was reached following 4-8 weeks of administration, since the rats have been found to be near the steady state for bioaccumulation with exception of the blood levels which continued to accumulate DEA.

The liver represented the organ with the highest tissue concentration. The half lives of the test compound after 4 weeks of repeated exposure calculated for the various organs was found to be at highest in blood with 54 days.

Tissue distribution of radioactivity 48 h after the last of five daily oral doses of [¹⁴C]DEA (7 mg/kg/day) to the male F-344 rat (n= 4).

Tissue	eq.DEA per g tissue (in ng)	Tissue/blood ratio	% dose in total tissue
adipose	6150 ± 870	5.81± 0.93	1.24 ± 0.16
blood	1060 ± 10	Unity	0.16 ± 0.01
brain	12400 ± 900	11.7 ± 0.8	0.31 ± 0.02
heart	19100 ± 800	18.0 ± 1.9	0.18 ± 0.01
kidney	197000 ± 35000	188 ± 45	4.56 ± 0.48
liver	146000 ± 21000	188 ± 45	18.2 ± 1.00
lung	37700 ± 7600	35.2 ± 4.6	0.62 ± 0.03
muscle	9030 ± 1210	8.47 ± 0.34	12.4 ± 1.20
skin	8480 ± 580	8.01 ± 0.75	4.18 ± 0.27
spleen	35500 ± 4500	33.8 ± 6.4	0.25 ± 0.02
total			42.1 ± 1.8 0

Values are mean ± SD for four rats

Tissue distribution of radioactivity 72 hours after the final dose administered in repeated oral dosing of [¹⁴C]DEA to male F344

Tissue	eq.DEA per g tissue (in ng)	Tissue/blood ratio	% dose in total tissue
2-week repeated dose
blood	1790 ± 110	unity	0.137 ± 0.010
brain	18300 ± 1400	10.2 ± 0.7	0.191 ± 0.020
liver	205000 ± 16000	114 ± 4	12.3 ± 1.2
spleen	45900 ± 1700	26 ± 1	0.154 ± 0.013
4-week repeated dose
blood	4110 ± 620	unity	0.156 ± 0.020
brain	28100 ± 2400	7.0 ± 1.2	0.131 ± 0.037
liver	295000 ± 14000	73 ± 10	7.9 ± 0.4
spleen	60400 ± 3500	15 ± 2	0.107 ± 0.010
8-week repeated dose
blood	5750 ± 970	unity	0.115 ± 0.021
brain	31200 ± 2800	5.6 ± 1.2	0.080 ± 0.010
liver	294000 ± 22000	53 ± 10	4.12 ± 0.12
spleen	55300 ± 1100	9.9 ± 1.7	0.06 ± 0.00

Values are means ± SD of four to six rats

Tissue distribution of radioactivity 4 weeks after the final dose administered in a 4-week repeated dose study with [¹⁴C]DEA (7 mg/kg bw/day)

Tissue	eq.DEA per g tissue (in ng)	Half life in tissue (days)
blood	2860 ± 840	54.0
brain	2690 ± 270	8.3
liver	12800 ± 2900	6.2
spleen	4210 ± 560	7.3

Metabolism:

Single oral and iv doses of the test compound were excreted predominantly as unchanged DEA. The profile of metabolites changed following 8 weeks of repeated oral dosing. DEA was still the major metabolite, but there were also significant amounts of poorly retained metabolites, as well as N-methyl DEA and a late eluting presumably more cationic metabolite.