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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Metabolic and peroxisome proliferation studies with di- (2-ethylhexyl) phthalate in rats and monkeys.
Author:
Short RD, Robinson EC, Lington AW
Year:
1987
Bibliographic source:
Toxicol. Ind. Health 3, 185-195
Reference Type:
publication
Title:
Metabolism of DEHP:effects of prefeeding and dose variation, and comparative studies in rodents and the cynomolgus monkey (CMA studies)
Author:
Astill BD
Year:
1989
Bibliographic source:
Drug Metabol. Rev., 21(1), 35-53

Materials and methods

Objective of study:
excretion
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
: some data are missing (materials and methods mainly)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
DEHP non radiolabelled
- Purity: 99.8%

Di(2-ethylhexyl)phthalate [carbonyl-14C]
- Source: New England Nuclear Corporation
- Specific activity: 32.6 mCi/mmol
- Radiochemical purity of 97%
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Wilmington, MA
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: individually
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): free access to nutritionally adequate diet
- Water (e.g. ad libitum): free access to water
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg bw
No. of animals per sex per dose:
5 males
Control animals:
no
Positive control:
none
Details on dosing and sampling:
Urine and feces were collected over a 96 hour period.
Afterwards, animals were sacrificed by decapitation.
Tissue samples were taken for analysis.
Radioactivity was measured in excreta, blood, liver, lung, spleen, intestines, intestinal contents, fat, brain, kidney, adrenals, testes and urinary bladder by liquid scintillation counting.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Since the tissues contained less than 1% of the administered dose, DEHP appeared to be quickly eliminated with little tissue retention.
Details on excretion:
After a single dose of 100 mg/kg 14C-DEHP, rats excreted 32.9 (±4.8) % of the dose in urine, primarily during the first 24 hours after dosing.
In addition, 51.4 (±7.8)% of the dose was recovered in the feces within 48 hours after treatment. When the animals were sacrificed 4 days after dosing, the total recovery of radioactivity was 86.6 (±3.9)7%.

Metabolite characterisation studies

Metabolites identified:
yes

Any other information on results incl. tables

Percentage of the Dose Excreted as DEHP Metabolites in Urine in 0-24 h Male Fischer-344 Rats After Administration of14C-DEHP at 100 mg/kg p.o.

Metabolitea

Dose excreted (%)

MEHP

-

Phthalic Acid

0.6

I

3.2

II

0.3

III

-

IV

1.0

V

8.4

VI

3.2

VII

0.9

IX

5.2

X

1.1

XII

1.7

XIII

1.7

XIV

0.3

Unidentified

0.6

Total

28.7

aAlbro et al. convention.

Percentage of the Dose Excreted as DEHP and DEHP Metabolites in Feces in 0-24 h by Male Fischer-344 Rats After Administration of14C-DEHP at 100 mg/kg p.o.

Compound

Dose excreted (%)

DEHP

20.0

MEHP

8.2

Phthalic Acid

0.4

I

0.9

II, III

0.9

IV

0.9

V

2.2

VI

3.0

VII

0.9

IX

1.7

X

0.9

XII

1.3

XIII

0.9

XIV

0.4

Total

43.4

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:
A single oral dose of 100 mg/kg bw (carbonyl-14C)DEHP (radiochemical purity > 97%) in corn oil was adminstered by gavage to five male Fisher 344 rats. The study was using a method equivalent to a guideline study and conducted according to GLP. Urine and faeces were collected at intervals of 12, 24, 48, 72, and 96 hours after dosing. The animals were killed around 96 hours after dosing for tissue collection (liver, stomach, intestines, intestine contents, gall bladder wash and bile). Concentrations of radioactivity in urine, faeces were determined at the specified intervals and concentrations of radioactivity in selected tissues and other biological samples were determined by liquid scintillation at around 96 hours after dosing. Urine samples collected from 0-24 hours were pooled and were analysed for metabolites of DEHP by HPLC. Urinary metabolites were isolated and the major metabolites were analysed by GC/MS. Rats excreted 32.9% of the dose in the urine, primarily during the first 12 hours and 51.4% of the dose in the faeces, primarily during the first 24 hours. DEHP was detectable in some tissues. The mean concentrations detected, with the exception of intestinal contents, were less than 1 µg/g. The highest concentrations were detected in intestinal contents. Total recoveries of the radioactivity administered were 87 (82-92%). Radioactivity in 0-24 hour urine samples were resolved into 13 components. The components in urine were identified as phthalic acid, metabolites I, II, IV, V, VI, VII, IX, X, XII, XIII, XIV, and unidentified fractions. Major urinary components in rats were metabolites I, V, VI, and IX. Glucuronic acid conjugates are either absent or present in negligible quantities. Radioactivity in 0-24 hour faecal extracts were resolved into 11 components. The faecal components were identified as DEHP, MEHP, phthalic acid, metabolites I-IV, VI, VII, IX, X, XII, XIII, and XIV. DEHP and MEHP were the major faecal components.