Octanoic acid, 1,1'-(1,3-propanediyl) ester

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
1,3 propanediol dicaprylate is predicted to be not bio-accumulating. It is predicted to be absorbed after ingestion, dermal application and inhalation. Metabolism is initiated by enzymatic ester hydrolysis. The acid part is treated as a fatty acid and will be degraded to CO2 via the Krebs cycle. For propanediol, renal elimination of the mostly unchanged substance is expected. Slow oxidation of 1,3-propanediol by liver homogenates in vitro was reported and considered to be a minor pathway in vivo.

Additional information

The toxicokinetic statement is based on the general knowledge of metabolism published in textbooks and in research publications. It is combined with information on target organ toxicity from animal studies of metabolites or related chemicals. 

 

Assessment:

The only functional group contained in the main product of 1,3-propanediol dicaprylate is the ester bond. Ester bonds are stable to acidic hydrolysis and so after ingestion, 1,3-propanediol dicaprylate is expected to enter the intestine unchanged. It is likely that lipases produced by the bile will initiate ester hydrolysis in the small intestine (Mattson, 1972). Any intact 1,3-propanediol dicaprylate ester that is absorbed will be rapidly cleaved by esterases in the blood (Testa, 2003). Enzymatic ester hydrolysis is also expected after dermal application or inhalation (Oesch, 2007; Zhang, 2006), especially since it is sufficiently small for uptake. Indeed, modeling skin permeability using the model of Fitzpatrick (Fitzpatrick, 2004) shows moderate permeability. Due to the low vapour pressure of 7.9 x 10-4 Pa at room temperature, exposure via inhalation is of low relevance. It may be relevant if the substance is handled at high temperature.

Ester hydrolysis yields the octanoic acid which is a slightly shorter version of a normal fatty acid. It will be coupled with coenzyme A and degraded via ß-oxidation in the microsomes and the Krebs cycle. The diol is probably sufficiently small and soluble to become eliminated via the kidney without further metabolic transformation. However, alcohols may also undergo oxidation to the carbonic acid via the aldehyde. It was reported that 1,3-propanediol can be metabolized to malondialdehyde by liver homogenate at a rate of 5.6 nmol/h/100 mg tissue protein in vitro (Summerfield, 1984). Limited information on the design (eg optimization of assay conditions) is given. Considering the high concentration of 1,3-propanediol in this in-vitro assay, the slow turnover rate and the high water solubility, malondialdehyde formation is not expected to be a major metabolic pathway in vivo. The experimental data on 1,3-propanediol consistently shows absence of significant systemic toxicity (DuPont, 1,3-propanediol Health and Environmental Data Summary). This is supportive of easy and rapid elimination.

 

 

Repeated-dose toxicity information:

Subchronic oral toxicity study with structural analogue Decanoic acid, mixed diesters with octanoic acid and propylene glycol (Pittermann, 1993) :

The subchronic toxicity study was performed according to guideline OECD 408 under GLP. Decanoic acid, mixed diesters with octanoic acid and propylene glycol was administered by gavage to each ten male and female rats at doses of 0, 100, 300 or 1000 mg/kg bw per day for 90 days. The NOAEL was 1000 mg/kg bw.

Prenatal development toxicity with structural analogue Decanoic acid, mixed diesters with octanoic acid and propylene glycol (Pittermann, 1994) :

The embryotoxicity study including teratogenicity was performed according to guideline OECD 414 under GLP. Female rats wre treated by oral gavage with 100, 300 or 1000 mg/kg bw from day 6 to day 15 of gestation. The NOAEL for both maternal toxicity and developmental toxicity was 1000 mg/kg bw, corresponding to the highest dose tested.

Subchronic oral toxicity study with 1,3-Propanediol (Gingell, 2000):

The subchronic toxicity study was performed according to GLP and the EPA Toxic Substances Control Act Health Effects Testing Guidelines. 1,3-Propanediol was given by gavage to groups of each ten male and female rats at doses of 0, 100, 300 or 1000 mg/kg bw per day. The no-observed-effect-level was 1000 mg/kg bw.

 

Teratogenicity study with 1,3-Propanediol (Leuschner, 1992):

The teratogenicity study was performed according to OECD guideline 414 and GLP. In this study, female rats were treated by oral gavage with 250 or 1000 mg/kg bw from day 6 to day 15 of gestation. All animals survived the treatment, and 250 mg/kg bw was identified as the no-observed effect level. At 1000 mg/kg bw, a slight decrease in body weight gain was noted. Teratogenic findings were not observed.

This study shows that pregnant female rats tolerate a 9-day treatment of 250 mg/kg bw without indication of toxicity.

 

Two-weeks inhalation study with 1,3-Propanediol (Scott, 1998):

The inhalation study was performed according and GLP. In this study, ten male rats were exposed nose-only to vapor only or a vapor /aerosol mixture in air at concentrations of 41, 650 and 1800 mg/m3 as analytically verified. During the two weeks, nine treatments of each 6 hours were performed and the following parameters were recorded: urinalysis at the last day of exposure, all standard haematology parameters, clinical signs of toxicity, body weight determination, organ weights of liver, kidneys, lung, testes and brain, as well as histopathology of nose, pharynx/larynx, lungs, livers, testes and gross lesions. All animals survived the treatment, and 1800 mg/m3 air was identified as the no-observed effect level.