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Toxicological information

Basic toxicokinetics

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

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Metabolism, Bioaccumulation and Incorporation of Diethanolamine into Phospholipids
Author:
Mathews JM, et al.
Year:
1995
Bibliographic source:
Chemical Research in Toxicology, July/August 1995 VOL. 8, No. 5,625-633
Reference Type:
secondary source
Title:
Metabolism, bioaccumulation and incorporation of diethanolamine into phospholipids, Chem. Res. Toxicol., 18, 625-633
Author:
Mathews JM, Gamer CR and Matthews RB
Year:
1995
Bibliographic source:
cited in: Report on Carcinogens (2002) Background document Diethanolamine, prepared by: Technology Planning and Management Corporation, Durham, NC, USA, Contract Number N01-ES-85421 for US Department of Health and Human Services, Public Health Service

Materials and methods

Objective of study:
distribution
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Metabolism and tissue distribution of DEA administered to male rats was studied.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC, USA)
- Age at study initiation: adult
- 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

Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
single and repeated exposure (8 weeks, 5 days/week)
Doses / concentrations
Remarks:
2-200 µCi plus an appropriate amount of unlabelled DEA in a total dose of 7 mg/kg bw
Control animals:
no
Positive control:
not done
Details on study design:
Metabolites were studied, and their concentrations in tissues, feces, and blood were measured by radiochemical assay. Human liver slices were incubated with carbon-14 labeled DEA for various periods, and radioactivity was partitioned and analyzed.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, brain, spleen, heart, kidney, liver
- Time and frequency of sampling: 48 hours

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Liver, kidney, heart, spleen and brain represent the major target organs for DEA accumulation. DEA was accumulated particularly to high concentrations compared to the levels observed in blood. DEA had a particularly high affinity for liver and kidney. As evidenced by the high tissue-to-blood-ratios of 150 to 200. Residues of kidney and blood accounted for nearly one third of the administered dose.
Within the individual organs DEA distributed mainly in the aqueous phase (>90%) and to a minor extent in chloroform extractable compartments.
Details on excretion:
Less than 30% of oral administered dose of DEA was excreted within 48 hours. Excretion was predominantly in urine and HPLC analysis demonstrated that virtually all the urinary radioactivity is present as the parent compound. Results of analysis showed that in rats DEA significantly accumulated in the liver, kidneys, brain, and spleen.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolism after oral administration revealed non-metabolized DEA and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline. After digestion 30% of the phospholipids were identified as ceramides and the remaining 70% as phosphoglycerides.

Any other information on results incl. tables

Tissue distribution:

Liver, kidney, heart, spleen and brain represent the major target organs for DEA accumulation. DEA was accumulatated particularly to high concentrations compared to the levels observed in blood. DEA had a particularily high affinity for liver and kidney. as evidenced by the high tissue-to-blood-ratios of 150 to 200. Residues of kidney and blood accounted for nearly one third of the administered dose.

Within the individual organs DEA distributed maily in the aquous phase (>90%) and only to 6 -9% in chloroform extractable compartments.

Tissue distribution of radioactivity 48h after oral administration of [14C]DEA (7 mg/kg bw) to rats (n=4)

Tissue

tissue/blood ratio

% dose in total tissue

µmol of DEA equiv/g tissue

blood

unity

0.18 ± 0.01

28.8 ± 0.6

brain

8.8 ± 0.4

0.27 ± 0.02

254 ±7

spleen

87 – 1

0.32 ± 0.01

1060 ± 40

heart

17 ± 1

0.19 ± 0.01

503 ± 22

kidney

200 ± 10

5.0 ± 1.0

5660 ± 290

liver

150 ±10

27 ± 1

4460 ±190

Metabolism:

Analysis of the aquous phases from liver and brain by HPLC determined that DEA accounted for 70 -80% of the total radioactivity. The remaining radioactivity in the aquous phase was distributed between three metabolites identified as N-methyl-DEA, N,N-dimethyl-DEA and one unidentified peak of about 1% of the total reactivity. PhosphoDEA was identified as the one minor metabolite present. Radioactivity present in in the chloroform extract of liver was equally distributed between two peaks that coeluted with phosphatidylethanolamine and phosphatidylcholine.

When these organic extracts were digested with sphingomyelinase in vitro, 30% of the DEA-derived phospholipids were identified as ceramides and the remaining 70% as phosphpglycerides. One third of the radioactivity in the liver is associated with ceramides contained methylated polar head groups and about 60% of that associated with phosphoglycerides was methylated.

Repeated dose experiments:

After repeated dosing for 8 weeks (5 days per week) similar tissue distributions were found. In liver 97% of the radioactivity were present in the aqueous phase. Approximately 2% of the tissue reactivity was present in chloroform extractions. In brain the chloroform extractable radioactivity increased from 6% of the total in brain after single exposure to 21% after repeated exposure.

Tissue distribution of radioactivity 72h after the final dose administered in an 8-week repeat oral dosing of [14C]DEA (7 mg/kg bw/day)

Tissue

tissue/blood ratio

% dose in total tissue

µmol of DEA equiv/g tissue

blood

unity

0.115 ± 0.021

604 ± 102

brain

5.6 ± 1.2

0.080 ± 0.011

3280 ± 290

liver

53 ± 10

4.12 ± 0.12

30900 ± 2300

Excretion:

Less than 30% of oral administered doses of DEA was excreted within 48 hours. Excretion was predominantly in urine and HPLC analysis demonstrated that virtually all the urinary radioactivity is present as the parent compound.

Cumulative excretion of radioactivity 48h after oral administration of [14C]DEA (7 mg/kg bw) to rats (n=4)

end of collection period (h)

% of dose appearing in

urine

faeces

24

9.0 ± 2.5

1.6 ± 0.2

48

22.0 ± 2.1

2.4 ± 0.3

Human liver slices.

After 4h and 12 h of incubation with 1 mM of DEA absorption was 11% and 29% respectively. Most of the radioactivity present in the media comprised with DEA with up to 4 metabolites present in low levels.

DEA -derived radioactivity in the organic extracts was predominantly comprised with phospholipid containing nonmethylated headgroups , although after 12h of incubation methylated radiolabeled phospholipids were detected.

Applicant's summary and conclusion