Hexanedioic acid, 1,6-bis(2-propylheptyl) ester

Endpoint summary

Description of key information

Toxicokinetic data show that the read-across source chemical Diethylhexyladipat, administered orally to mice, rats, and monkeys, is readily absorbed, distributed to various tissues, metabolized and excreted in urine and to a lesser extent in feces and expired air. Dose-dependent changes in absorption, tissue uptake, metabolism, and elimination could be found. Sex differences were apparent in the hepatic uptake and metabolism. The data indicate little, if any, prolonged retention of Diethylhexyladipat or its metabolites in blood and tissue after oral administration in all three species. As metabolites the monoester, adipic acid, 2-ethylhexanol,  2-ethylhexanoic acid and their glucuronic acid conjugates were identified. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Summary

No toxicokinetic studies for Dipropylheptyladipat are available. However, the toxicokinetic behavior of Diethylhexyladipat, a structural analogue to Dipropylheptyladipat (for more details please refer to the read across statement in chapter 13), was examined in different species. The metabolism and disposition of Diethylhexyladipat were determined in rats, mice and monkeys in a study conducted by CMA (1984). B6C3F1 mice were treated with radiolabeled Diethylhexyladipat by oral gavage at dose level of 50, 500 or 5000 mg/kg bw. Elimination of radioactivity in urine, feces and expired air was determined and the animals sacrificed at 24 hours for measurement of residual radioactivity in blood and tissues. Similar studies were performed in mice treated with the high dose level and sacrificed at 48 hours, rats treated with the mid dose and sacrificed at 24 hours and in monkeys treated with the mid dose and sacrificed at 48 hours. In other studies, radiolabeled Diethylhexyladipat was administered to male and female mice at the three dose levels indicated above and the extent of Diethylhexyladipat hydrolysis and absorption was determined after 1, 3, or 6 hour. The metabolic profiles in livers and GI tracts of mice as well as urine of mice, rats, and monkeys were examined and reported below. In addition, results reported by Bergman and Albanus (1986), Takahashi at al. (1981) and Cornu et al. (1988) are presented as follows.

 

Absorption, Distribution and Elimination

Male rats and mice as well as pregnant mice were treated with radiolabeled Diethylhexyladipat. During the first 24 hours after iv or ig administration high levels of radioactivity were observed particularly in the body fat, liver and kidneys and in the intestinal contents (only after ig administration) of both species. Radioactivity was observed in the foetal liver, intestine and bone marrow during the first 24 hours after iv or ig administration to pregnant mice. There was very little accumulation in the mouse foetus but some was found on the urinary bladder, liver and intestinal contents as well as in the amniotic fluid (Bergman and Albanus, 1986). Takashi et al. (1981) showed after oral administration of radiolabeled Diethylhexyladipat that there was no evidence of accumulation of radioactivity in any organ or tissues. Almost all the dose was excreted within 48 hours predominantly in the urine and as respiratory carbon dioxide. The fetal excretion was low.

In the study determined by CMA (1984) radiolabeled (14C) Diethylhexyladipat ( and/or its metabolites was rapidly absorbed from the GI tract. The highest 14C levels were found in blood and liver 1 or 3 hour 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. Males mice show that after treatment with 50 and 500mg/kg bw 14C-DEHA, 95-102% was eliminated in urine, feces and expired air within 24 hours. After 5000 mg/kg bw, most of the 14C was excreted in 24 hours but ~12% were also recovered in the GI tracts. During studies with male and female mice (50, 500 and 5000 mg/kg bw 14C-DEHA) urinary elimination of 14C was rapid and extensive. About 91% of the low and mid doses were eliminated in urine in 24 hours; only 75% after 5000 mg/kg bw. 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 hours after dosing. Adrenals and livers showed the highest levels at low and mid dose, especially in males. After 5000 mg/kg bw, blood also contained high 14C levels; blood and liver content of the females were significantly higher than of males. At 48 hours, the skin (both sexes) and the fat (females) showed higher retention of 14C than other tissues.

Compared to mice, rats showed lower elimination in urine(~74%) and higher in feces(~20%). 14C elimination in the expired air was 1.4 to 2.1%. About 4% of the dose was recovered in the GI tract. 14C levels in livers and adrenals were higher than in other tissues. Males showed significantly higher tissue contents than the females. Tissue contents in rats were higher than in mice treated with 500 mg/kg bw (same conditions). The monkeys also showed rapid elimination of 14C in urine and to a lesser extent in feces. Absorption was rapid, as indicated by the fast rates of elimination and by the fast appearance of 14C in blood after 2 hr. Radioactivity disappeared faster from blood of male monkeys compared to females. At 48 hours following dosing, the skin, fat, and livers of males showed the highest levels. In females the 14C concentrations in livers were significantly higher than in other tissues.

Dipropylheptyladipat is not water soluble, possesses a logP value of 10.08 and a molecular weight of 426.68 g/mol. Therefore, dermal penetration is fairly limited.

 

Metabolism

Urine of mice, rats, and monkeys contained 2-ethylhexanoic acid (EHA), its glucuronic acid conjugate, a hydroxy acid (5-hydroxy-2-ethyl-hexanoic acid, 5-OH EHA), and the diacid (2-ethyl-l,6-hexanedioic acid, DiEHA). In monkeys, glucuronides of the monoester, MEHA, and the alcohol, EH, were also tentatively identified. Minor sex differences were demonstrated in mouse urine profiles. Female mice treated with the low dose appeared to form slightly more EHA glucuronide than the males. More EHA glucuronide was excreted by mice treated with the low dose of DEHA. Urine of mice receiving the high dose contained higher amounts of the hydroxy acid and diacid. The data show that DEHA is rapidly hydrolyzed to the monoester, then the alcohol and acid, without accumulation of MEHA. The alcohol is oxidized by ß-oxidation, W-, and W-l oxidation generating acids, ketones, keto-acids, hydroxy acids, and diacids. Metabolism appeared to be less extensive in monkeys, which mostly excreted MEHA and EH (as their glucuronides). In contrast, mice and rats mostly excreted products of faster oxidation, mainly EHA, 5-0H EHA and diEHA. In a study with human volunteers similar metabolites were found in urine and MEHA was found in fecal samples (Loftus, 1993).

Takahashi et al. (1981) identified adipic acid as main urinary metabolite, it was also detected in the digestive tract, blood and liver, when rats were orally administered to radiolabeled Diethylhexyladipat. In a study reported by Cornu et al. (1988) Diethylhexyladipat in dose levels of 0.665 and 1.5 g/kg were administered to rats for 5 days. Urine was collected each morning and extracted. Adipic acid was identified as main metabolite. Furthermore, 2-ethyl hexanedioic acid and 2 ethyl-5-hydroxyhexanoic acid and 2-ethylhexanol glucuronide were detected.