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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
equivalent or similar to guideline
OECD Guideline 417 (Toxicokinetics)
urine and fecal excretion was not measured
Principles of method if other than guideline:
Yes, see description of method below.
GLP compliance:
yes (incl. QA statement)
Midwest Research institute

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(2-ethylhexyl) adipate
EC Number:
EC Name:
Bis(2-ethylhexyl) adipate
Cas Number:
Molecular formula:
bis(2-ethylhexyl) adipate
Test material form:
Specific details on test material used for the study:
- Name of test material (as cited in study report): DEHA
- Analytical purity: >99.7%
- Impurities (identity and concentrations): no data
Radiolabeled material was prepared by NEN (Boston), and supplied through the CMA. Lot No. 1679-109, specific activity 32.2 mCi/mmol. Radiochemical purity 98.9% (TLC). HPLC analysis by MRI showed >97%.

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Lab. (Wilmington, Massachusetts).
- Age at study initiation: 50-57 days
- Weight at study initiation: 14-24 gram
- Fasting period before study: 18 hours prior to dosing
- Individual metabolism cages: yes
- Diet: ad libitum
- Water :ad libitum
- Acclimatisaton period: at least 7 days

- Temperature (°F): 68-72:
- Humidity (%): 40-60
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
The mice were dosed orally with 14C-DEHA at the low, mid, or high dose (50, 500 and 5000 mg/kg).
Duration and frequency of treatment / exposure:
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
5 000 mg/kg bw/day
No. of animals per sex per dose / concentration:
hydrolysis and absorption: 6 animals per sex and dose group
hydrolysis and absorption repeat: 3 animals per sex and dose group
preliminary disposition (only males): 2 males per dose group
disposition: 4 animals per sex for the low and high dose group, 8 animals per sex for the high dose group
Control animals:
Positive control reference chemical:
no data
Details on study design:
Three groups of four male and four female mice each were treated orally with the low, mid, or high dose levels of 14C-DEHA
(50, 500 and 5000 mg/kg) and were placed in individual glass metabolism cages (Delmar-Rath type).
Expired air, urine, and feces were collected during 0-6, 6-12, and 12-24 hr intervals following dosing.
The expired 14 C02 was trapped with 5-Methol-amine in 2-methoxyethanol. Other volatile products were collected in
methanol:water (50:50).
Urine was collected in containers kept on dry ice. After each collection, the cages were rinsed and the cage washings were measured
and analyzed.
At 24 hr, the mice were anesthesized with ether, blood was withdrawn by cardiac puncture, and the following tissues and organs were
removed, weighed, and assayed for 14-C content: Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, ovaries and uterus.

Portions of blood were centrifuged to separate plasma and red blood cells (RBC's). Bladder contents were removed and the bladder was
washed thoroughly with 0.9% saline. The contents and washings were combined with the final urine samples and analyzed.
Blood and tissues were kept on ice during the necropsy procedures. Sample preparatian and analyses were performed immediately after collection, or the samples were frozen until analyzed. The remaining tissue and excreta were stored frozen.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : Expired air, urine, and feces, cage washes, and:
blood, Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, and ovaries and uterus.
- Time and frequency of sampling: Expired air, urine, and feces and cage washings during 0-6, 6-12, and 12-24 hr intervals following dosing.
Other tissues at sacrifice after 24 hrs.

- Tissues and body fluids sampled : urine, GI-content
- Time and frequency of sampling: 24 hrs
- From how many animals: samples pooled
- Method type(s) for identification: HPLC-MS-MS

The means ± standard errors were calculated for each test group with a programmable calculator. Data were subjected to analysis of variance.
Significant F-ratios were then analyzed by Dunnett's procedure. Significant differences were indicated when p < 0.05.

Results and discussion

Preliminary studies:
A preliminary study in males only:
dose mg/kg: 50, 500, 5000
Urine +expired air : 81% 86% 67%

excretion (24 hr)
dose mg/kg: 50, 500, 5000
Urine +expired air+ feces : 94% 101% 75%

Toxicokinetic / pharmacokinetic studies

Details on absorption:
At 24 hr
dose mg/kg: 50, 500, 5000
Urine +expired air: 92-94% 98-100% 67- 76%

Details on distribution in tissues:
Levels in organs were low (< 0.3%) . From all tissues examined the liver and kidneys showed the highest level ( 0.1-0.2% and 0.03-0.086% resp.).
Also in the GI-tract the levels were relatively high, and highest in 5000 mg/kg group (12%).
Details on excretion:
At 24 hr
dose mg/kg: 50, 500, 5000
Urine +expired air+ feces : 97-98% 98-100% 69-81%

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
The GI tract contained the diester, monoester, and the alcohol, and traces of the polar material.
The liver contained primarily the oxidation products.
The urine contained major amounts of the oxidation products and their conjugated derivatives. Although the liver
profiles did not contain appreciable amounts of the less polar metabolites, these products may have been excreted shortly following formation.

Metabolites identified:
MEHA : monoethylhexyladipate
EH: ethylhexanol and EH glucuronide
EHA: ethylhexanoic acid, and EHA glucuronide
DiEHA: ethylhexanedioic acid

Any other information on results incl. tables

Hydrolysis and Absorption: 14C-DEHA and/or its metabolites was rapidly absorbed from the GI tract. The highest 14C levels were found in blood and liver 1 or 3 hr after dosing. In the GI tracts large amounts of the diester (DEHA) , monoester(MEHA)and alcohol (EH) were found. The quantities of DEHA decreased with time while other products increased. The major metabolites in the livers were more polar than EH. In general, only small amounts of DEHA, MEHA and EH were found. The livers of male mice also contained large amounts of an early eluting metabolite which was found in female livers in only small quantities. The extent of the two major metabolites recovered in livers of female mice differed significantly.



Preliminary studies with males: after treatment with 50 and 500mg/kg 14C-DEHA, 95-102% was eliminated in urine, feces and expired air within 24 hr. After 5,000 mg/kg, most of the 14C was excreted in 24 hr but ~12% were also recovered in the GI tracts.

Definitive studies with male and female mice (50, 500 and 5,000 mg/kg 14C-DEHA): urinary elimination of 14C was rapid and extensive. About 91% of the low and mid doses were eliminated in urine in 24 hr; only 75% after 5,000 mg/kg. Elimination in feces was 7-8% at the low and mid doses and 4% at the high dose. The latter group showed high recovery in the GI tract. Only 0.8 to 1.2% in males and 1.5 to 3.8% in females were eliminated in the expired air. Respiratory elimination was highest in the female low dose group. Only small amounts were found in blood and tissue 24 and 48 hr after dosing. Adrenals and livers showed the highest levels at low and mid dose, especially in males. After 5,000 mg/kg, blood also contained high 14C levels; blood and liver content of the females were significantly higher than of males. At 48 hr, the skin (both sexes) and the fat (females) showed higher retention of 14C than other tissues.

The high recovery in the GI tract following the high dose (12%) may account for the lower elimination in feces.

Applicant's summary and conclusion