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Toxicological information

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additional toxicological information
Type of information:
experimental study
Adequacy of study:
supporting study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
no guideline followed
GLP compliance:

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
Details on test material:
Name: Di(2-ethylhexyl)adipate (DEHA) .
Other Names: Bis(2-ethylhexyl)adipate ; Kodaflex® DOA Plasticizer.
CAS No.: 103-23-1.
Lot No.: 910302.
Purity: >_99.8% .
Physical state at room temperature : Clear liquid .
Stability: Not specified by Sponsor .
Storage conditions : Stored in a secondary container at approximately 4°C
at SRI in Building T, Room 3 .
Date received: 11/5/91 .
Expiration date: Not specified by Sponsor.
Supplier: Eastman Chemicals Division
P.O. Box 43 1
Kingsport, TN 37662
Source: Eastman Kodak Co.
365 Ridge Road, Bldg 117, Door D
Rochester, NY 14615

Results and discussion

Any other information on results incl. tables

Di(2-ethylhexyl)adipate (DEHA) was administered via dosed feed to female Fischer-344 rats and B6C3F1 mice at levels ranging from 0 .025% to 2.5% for up to 42 days. A 14-day recovery group was included to evaluate effects in control and 2 .5% DEHA

animals on Day 56. WY-14,643 (0 .1%) was administered to a group of rats and mice as a positive control agent. Three days before each scheduled sacrifice, an osmotic pump loaded with 3H-thymidine was implanted in each animal to label all cells going through S-phase synthesis .

DEHA produced decreases in body weight and weight gain in both rats (1.2% and 2.5%) and mice (2.5%). Weights were the same as controls in the recovery groups. Food consumption in rats was slightly decreased in the 2.5% DEHA group but was not affected

in mice. Kidney-to-body-weight ratios were increased slightly at higher doses of DEHA in rats (1.2% and 2.5% on Day 42) and in all but the lowest DEHA dose group in mice (0 .12% through 2.5% on Day 14; 0.25% and 2 .5% only on Day 42). There was little effect on spleen-to-body-weight ratios, except for decreases in mice receiving WY-14,643 . Both DEHA and WY-14,643 produced significant increases in absolute liver weight and liver-tobody-weight ratios in both rats and mice . Blood samples collected at terminal sacrifice showed considerable variability in the levels of aspartate aminotransferase and alanine aminotransferase. Little or no effect was seen in rats for either enzyme . In mice, sporadic increases in both enzymes were observed in the 2 .5% DEHA and WY-14,643 groups. Hepatic palmitoyl CoA oxidation was measured for each animal as an indicator of peroxisome proliferation . Dose-related increases in activity were observed in both rats and mice treated with DEHA or WY-14,643 . This effect was highly time-dependent in mice, with increased activity observed at later time points for both compounds. Increased activity (based on palmitoyl CoA oxidation per gram tissue) peaked by Day 28 (p<0.01 at 0.25% through 2.5% in rats ; p<0 .01 at 0.025% through 2.5% in mice) and declined on Day 42. No increase in activity was observed in the 2.5% DEHA recovery group of either rats or mice. Liver, spleen, and kidney sections from all animals were evaluated for microscopic lesions. Increases in the incidence of karyomegaly and hypertrophy of hepatocytes were observed in both DEHA- and WY-14,643-treated mice at all time points except the 56-day recovery period. Increases in the incidence of hypertrophy of hepatocytes were observed in both DEHA- and WY-14,643-treated rats at all time points except the 56-day recovery period, but this effect was observed at lower doses than in mice . Unlike the case with mice, karyomegaly was not present in any rat livers . Hyperplasia was present in selected rats treated with DEHA or WY-14,643, but this effect was not dose-related and always occurred in only a single animal per dose group . In kidneys and spleens, no microscopic findings were clearly related to treatment with DEHA. Cell proliferation was evaluated in four separate lobes of the liver (large median, right lateral, left lateral, and caudate lobes). In rats, both DEHA and WY-14,643 produced significant dose-related elevations (approximately 2- to 3-fold over controls at 1 .2% or 2.5% DEHA) in the labeling index (LI) on Day 3 that declined on Day 7 and returned to control levels by Day 14. The LI was similar in all four lobes. In mice, DEHA produced little effect on the U. A single group (2.5% DEHA on Day 7) produced a statistically significant increase (approximately 2 .4-fold over control), and this effect was most pronounced in the left lateral lobe. In contrast to the DEHA results, WY-14,643 produced very significant increases (from 28- to 175-fold over control) in the LI at all time points.

In summary, these results indicate that DEHA produces numerous effects on the livers of treated female Fischer-344 rats and B6C3F1 mice, including increased liver weight, hypertrophy of hepatocytes, and peroxisome proliferation . Dose-related increases in cell proliferation were observed in rats (Day 3 only) treated with DEHA. A single dose group of DEHA (2.5%) yielded a statistically significant increase in cell proliferation in mice (Day 7 only).

Applicant's summary and conclusion