Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Written assessment based on the available information

Adequacy of study:

key study

Study period:

November 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non-GLP assessmentreport

GLP compliance:

no

Species:

other: none

Strain:

other: none

 Summary and discussion of toxicokinetics

This assessment of the toxicokinetic properties of Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol is based on the results obtained with the test substance and read-across substances for the toxicological end‑points listed below and with reference to relevant physico-chemical data:

 ·      acute oral toxicity

·       acute dermal toxicity

·       skin irritation

·       skin sensitisation

·       subchronic (90 day) repeated dose toxicity studies

·       reproductive developmental toxicity study

·       bacterial reverse mutation test

·       in vitro chromosome aberration test

·       in vitro mammalian gene mutation test

Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol is a UVCB substance. The most abundant species present in the substance have molecular weights between 472.3 to 752.5 g/mol. The substance has an estimated water solubility of 0.51 ± 0.13 mg/L at 20 °C and a log Kow of > 6.5.

The acute oral toxicity of Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol was evaluated and conducted in accordance with OECD Guideline 423. The female rats were administered with 2000 mg/kg bw of the test substance, no mortality occurred and review of the clinical observations, body weight measurements, and necropsy did not reveal any adverse effects relating to toxicity. The LD50 value was therefore determined to be > 2000 mg/kg bw.

Dermal toxicity was assessed with the read-across substance,decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane. A single dermal application of >2000 mg/kg body weight of the test substance onto male and female rats (Wistar strain, Crl:WI (Han)) produced no deaths. Chromodacryorrhoea (snout) was noted for two males and two females on Day 1; one of these females also showed lethargy and ptosis on Day 1. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value was therefore determined to be >2000 mg/kg body weight. 

The results of the in vitro skin corrosivity study (OECD Guidelines 431) and skin irritation study (OECD Guideline 439) using reconstructed human epidermis revealed that the substance was not a skin irritant. Skin irritancy in vivo was assessed using three in vivo skin irritation studies as detailed below:

·       Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS 11138-60-6) was tested for its skin irritation potential according to OECD Guideline 404. The shaved back of each of three New Zealand White rabbits was exposed to 0.5 mL for 4 hours under semi-occlusive conditions. No cutaneous reactions were observed in any of the tested animals at any observation interval.

·       Read-across substance, 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 78-16-0), was tested for skin irritancy in accordance with EU Method B.4. Three New Zealand White rabbits was exposed to 0.5 mL for 4 hours under semi-occlusive conditions. Very slight erythema and edema were observed in all animals 24 h after treatment, however, these effects were fully reversible latest within 72 h. No signs of systemic toxicity were observed.

·       The third study was conducted with CAS 91050-89-4 in accordance with OECD Guideline 404. After 24 h, 3 animals (New Zealand White rabbits) showed erythema, which persisted in 1 animal for 48 h. 72 h after exposure, all animals were free of erythema. Therefore, it was concluded that the test substance is not irritating to the skin.

Skin sensitisation was assessed on the substance itself. Based on the results of a local lymph node assay in mice, the test substance is not a skin sensitiser.

  A 90 day repeated dose toxicity study by the oral route was conducted with read-across substance decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane at doses up to 1000 mg/kg had no effect on mortality, physical examinations, cageside observations, body weights, body weight changes, food consumption, ophthalmic examination findings, functional observational battery, locomotor activity, clinical pathology (clinical chemistry, hematology, coagulation, and urinalysis), gross pathology findings, absolute and relative organ weights, or histopathology findings.

All animals survived to the scheduled necropsies. On SD 92 (terminal necropsy), test substance-related alterations in clinical pathology parameters were minor and consisted of decreased mean chloride (CL) levels in males given ≥100 mg/kg/day, increased mean potassium (K) in males given 1000 mg/kg/day, increased mean red cell distribution width (RDW) in males given ≥300 mg/kg/day and females given 1000 mg/kg/day, and minimally increased mean activated partial thrompboplastin time (APTT) in males given 1000 mg/kg/day. All values were within the range for historical data controls, had recovered by the recovery necropsy, and were considered non-adverse. There were no test substance-related organ weight changes, macroscopic observations or microscopic findings at either necropsy (SD 92 or SD 120).

 Based on these results, the no observed adverse effect level (NOAEL) of the test substance in Sprague Dawley rats following 90-day oral gavage dose is 1000 mg/kg/day, the highest dose level tested.

In an Ames Test, the test substance was not mutagenic with or without metabolic activation.

In vitro chromosome aberration test with the read across substance 2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS 11138-60-6) provided negative results for structural and numerical chromosome aberrations, with or without metabolic activation. Regardless of dose level (from 625 g/ml to as high as 5000 g/ml) and dosing regimen, the test substance was concluded to be negative for structural and numerical chromosome aberrations, with or without metabolic activation.

In an in vitro mammalian cell gene mutation study, read-across substance, fatty acids, C8-18 and C18-unsatd., esters with trimethylolpropane (CAS 85186-89-6), did not induce mutations in mouse lymphoma L5178Y cells in the absence or presence of metabolic activation. Therefore, by read-across, the test substance is considered to be non‑mutagenic.

For reproduction toxicity, oral gavage administration of decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane at doses up to 1000 mg/kg/day from implantation through the end of gestation had no effect on maternal mortality, physical examinations, cageside observations, body weights, body weight changes, or food consumption.

There were no effects on fetal development. There was no difference between the control and treated groups in male and female fetal body weights or in external findings.

Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane given orally at doses up to 1000 mg/kg/day to pregnant female Sprague Dawley rats during prenatal development did not result in any adverse effects on the development of the embryo/fetus.

Based on these results, the dose levels of 100, 300, and 1000 mg/kg/day were considered appropriate for the decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane definitive prenatal developmental toxicity study in rats.

 

 

 

Toxicokinetic parameters

Absorption

Oral

The acute oral toxicity study conducted on Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol did not reveal any treatment related effects, with only one animal showing stagnation of body weight between the first and second week. This indicates that the oral bioavailability of the substance is low. This coincides with the 90-day repeated dose study conducted on decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane read-across substance. There were no test substance-related organ weight changes, macroscopic observations or microscopic, whilst minor alterations in clinical pathology were reported, they were seen to be within historical range and considered to be non-adverse.

The test substance has an estimated water solubility of 0.51 ± 0.13 mg/L at 20 °C and a log Kow value > 6.5. The absorption of highly lipophilic substances (log Kow ≥ 4) may be limited by the inability of such substances to dissolve in gastrointestinal fluids and therefore make contact with the mucosal surface. However, the absorption of such substances will be increased if they undergo micellular solubilisation by bile salts. As a worst case, for risk assessment purposes the oral absorption of the test substance is set at 100%.

Dermal

The results from dermal studies including the acute dermal toxicity study, in vivo / in vitro skin irritation studies and the LLNA study do not provide evidence to support significant skin absorption. The log Kow value of the test substance is > 6.5 therefore the dermal absorption of the substance is expected to be limited based on the high log Kow value. At log Kow values above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin and uptake into the stratum corneum itself may be slow. Maximum dermal absorption is often associated with values of log Kow between +1 and +2 (ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). Monograph No, 20; Percutaneous absorption. August 1993). In addition, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. The test substance has an estimated water solubility of 0.51 ± 0.13 mg/L at 20 °C therefore dermal uptake is likely to be low. In conclusion, dermal absorption of Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol is expected to be low. However, as a worst case, for risk assessment purposes the dermal absorption of the test substance is set at 100%.

Inhalation

Currently there are no studies associated with Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol that were conducted via the oral route. The substance has a low vapour pressure (1.60 x 10^-06Pa at 20 °C) therefore a significant inhalation exposure to vapours is not expected. Moderate log Kow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The test substance has a high log Kow value (> 6.5) therefore it may be taken up by micellular solubilisation particularly as the substance is poorly soluble in water (of 0.51 ± 0.13 mg/L at 20 °C). As a worst case, for risk assessment purposes the inhalation absorption of the test substance is set at 100%.

Distribution

In a 90 day oral repeated dose toxicity study with read-across substance, decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane, minor treatment related effects on the clinical pathology parameters were observed, indicating distribution throughout the body. The test substance is lipophilic therefore it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Short chain fatty acids released following hydrolysis of the test substance in the gastrointestinal tract are likely to be widely distributed in the body. Substances with high log Kow values tend to have longer half-lives unless their large volume of distribution is counterbalanced by a high clearance. There is the potential for highly lipophilic substances to accumulate in individuals that are frequently exposed to that substance. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance. However, as detailed below, the test substance is likely to undergo rapid hydrolysis following absorption so only low and transient exposure to the parent compound is expected.

Metabolism and excretion

The ester groups in the test substance are likely to undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids and trimethylolpropane so only low and transient exposure to the parent compound is expected. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells to carbon dioxide, acetate and ketones. Fatty acids are transported across the outer mitochondrial membrane by carnitine acyl transferases. Once inside the mitochondrial matrix, the fatty acyl-carnitine reacts with coenzyme A to release the fatty acid and produce acetyl-CoA. Fatty acids then undergo β-oxidation. During this process, two-carbon molecules acetyl-CoA are repeatedly cleaved from the fatty acid. Acetyl-CoA can then enter the citric acid cycle (Krebs cycle), which produces NADH and FADH2. NADH and FADH2 are subsequently used in the electron transport chain to produce ATP, the energy currency of the cell.

By read-across from the mutagenicity assays it appears that the substance is not metabolised toward genotoxic structures.

 Conclusion

In conclusion, there is no evidence Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol is significantly absorbed via the dermal route or the inhalation route. The results of an oral repeated dose toxicity study indicate that the substance may be absorbed orally in the rat, but with no effects. It is likely that the ester groups in Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. Consequently, the substance is considered to have low bioaccumulation potential.

 

 

Conclusions:

For risk assessment purposes the oral absorption is set at 100%
For risk assessment purposes the dermal absorption is set at 100%
For risk assessment purposes the inhalation absorption is set at 100%

Executive summary:

In conclusion, there is no evidence Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol is significantly absorbed via the dermal route or the inhalation route. The results of an oral repeated dose toxicity study indicate that the substance may be absorbed orally in the rat, but with no effects. It is likely that the ester groups in Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. Consequently, the substance is considered to have low bioaccumulation potential.

Description of key information

A toxicokinetic assessment has been conducted for Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritolf or risk assessment purposes. The assessment is based on the physico-chemical properties of the substance and on available toxicological studies for the substance and read-across substances.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

In conclusion, there is no evidence Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol is significantly absorbed via the dermal route or the inhalation route. The results of an oral repeated dose toxicity study indicate that the substance may be absorbed orally in the rat, but with no effects. It is likely that the ester groups in Decanoic acid, mixed esters with heptanoic acid, isovaleric acid, octanoic acid and pentaerythritol undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. Consequently, the substance is considered to have low bioaccumulation potential.