Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Assessment based on available information

Adequacy of study:

key study

Study period:

March 2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non-GLP assessment report

Data source

Reference

Reference Type:

other: Toxicokinetics Assessment

Title:

Unnamed

Materials and methods

Objective of study:

other: toxicokinetic assessment

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Assessment of all available data

GLP compliance:

no

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material: Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (DHOT)- CAS number: 68130-53-0- Physical state: Clear light yellow oily liquid

Test animals

Species:

other: none

Strain:

other: none

Administration / exposure

Details on exposure:

See assessment

Results and discussion

Any other information on results incl. tables

Summary and discussion of toxicokinetics

This assessment of the toxicokinetic properties of decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane 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

·       subacute (28 day) and subchronic (90 day) repeated dose toxicity studies

·       prenatal 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, octanoic acid and trimethylolpropane is a UVCB substance. The most abundant species present in the substance have molecular weights between 484.72 to 540.83 g/mol. The substance has an estimated water solubility of < 1.1 x 10^-5mg/L at 25 °C and an estimated log Kow of > 9.66.

 

Four acute oral toxicity studies have been conducted with read-across substances as detailed below:

·       The acute oral toxicity of decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS 11138-60-6) was evaluated conducted according to OECD Guideline 401. Upon treatment of male and female rats with 2000 mg/kg bw of the test substance, no mortality was observed during the 14 d observation period. Hypokinesia was observed 2 and 4 h after treatment; there were no other clinical signs. The animals had normal weight gain until the end of the observation period. The LD50 value was therefore determined to be > 2000 mg/kg bw.

·       In the second study conducted with CAS 78-16-0 in accordance with OECD Guideline 401, the oral LD50 value in Crl:CD (SD)BR rats was determined to be > 2000 mg/kg body weight. No mortality occurred during the study period. No clinical signs of toxicity were observed up to the end of the 14-day observation period. Necropsy revealed no substance-related findings.

·       In the third study conducted with CAS 91050-89-4 in accordance with OECD Guideline 401, the oral LD50 value in Crl:CD (SD)BR was determined to be > 2000 mg/kg body weight. No mortality occurred during the study period. No clinical signs of toxicity were observed up to the end of the 14-day observation period.

·       In the fourth study conducted with CAS 78-16-0 in accordance with EU Method B.1, the oral LD50 value in Wistar rats was determined to be > 5000 mg/kg body weight. No mortality occurred during the study period. No clinical signs of toxicity were observed up to the end of the 14-day observation period. Necropsy revealed no substance-related findings.

 

A single dermal application of >2000 mg/kg body weight of the test substance,decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropaneonto 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. 

 

Based on the results of an in vitro skin corrosivity study (OECD Guideline 431) and an in vitro skin irritation study (OECD Guideline 439), the test substance is not a skin irritant.

 

Three in vivo skin irritation studies have been conducted with read-across substances 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.

 

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

 

A 28 day repeated dose toxicity study by the oral route was conducted with read-across substance, pentaerythritol ester, tetrasubstituted (CAS 68424-31-7). The doses administered were 0 ppm, 1000 ppm, 5000 ppm, 12500 ppm (nominal in the diet). Repeated dietary administration of the test material to rats, up to and including a dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/d for female rats, did not produce any evidence of overt toxicity. There were no clinical signs indicative of neurological dysfunction or neuropathological changes in the brain related to treatment with the test material at any dose level. Treatment related histopathological changes in the kidney (including increased tubular hyaline droplet formation and tubular basophilia) and changes in kidney and liver weight in male rats at 5000 ppm and above were considered species-specific effects which are not relevant for humans and therefore not considered for NOAEL determination. The NO(A)EL for the read-across substance was therefore considered to be 12500 ppm in males (actual dose received: 1450 mg/kg/day) and females (actual dose received: 1613 mg/kg/day).

 

A 90 day repeated dose toxicity study by the oral route was conducted at the request of ECHA. Treatment with Hatcol 1510 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 Hatcol 1510 in Sprague Dawley rats following 90-day oral gavage dose is 1000 mg/kg/day, the highest dose level tested.

 

A 90 day repeated dose toxicity study by the oral route was conducted with read-across substance, CAS 403507-18-6; the substance was administered at doses of 5, 50, and 1000 mg/kg bw/day to male/female Sprague-Dawley rats. There were no treatment-related deaths during the 90-day study and no treatment-related effects on clinical chemistry and haematological parameters, body weight and organ weight. Increased salivation was detected immediately after dosing for 1000 mg/kg bw/day females from Day 17 and for 1000 mg/kg bw/day males from Day 18 onwards. Hunched posture was observed for individual 1000 mg/kg bw/day females from Day 37 with isolated incidents of tiptoe gait also observed on Days 37 and 38 and exophthalmia present in two females from Day 75 and 76 onwards. Exophthalmia was also evident in two 50 mg/kg bw/day females from Day 81 and hunched posture was observed for another 50 mg/kg bw/day female from Day 81 onwards. No such observations were detected for animals of either sex treated with 5 mg/kg bw/day. On necropsy, no treatment-related macroscopic abnormalities and no treatment-related histopathological changes were detected. The NOAEL was therefore determined to be ≥ 1000 mg/kg/day.

 

A 90 day repeated dose toxicity study by the inhalation route was conducted with read-across substance, CAS 67762-53-2; the substance was administered at doses of 0.05, 0.15, and 0.5 mg/L to male/female Sprague-Dawley rats.The NOAEC was therefore determined to be 0.5 mg/L air. No treatment-related effects were observed.

 

A 90 day repeated dose toxicity study by the dermal route was conducted with read-across substance, CAS 67762-53-2; the substance was administered at doses of 800 and 2000 mg/kg bw/day to male/female Sprague-Dawley rats.The NOAEL was therefore determined to be ≥ 2000 mg/kg/day. No toxicologically relevant symptoms/signs occurred; treated males gained slightly less weight than the controls (800 mg/kg bw: 7%, 2000 mg/kg bw: 10%). As the difference is low, the decrease in body weight was not interpreted as a sign for systemic toxicity.Sight erythema and flaking; slight epidermal hyperplasia and chronic inflammation occurred in both treatment groups.

 

A prenatal developmental toxicity study in the rat by the oral route was conducted at the request of ECHA. Treatment with Hatcol 1510 at doses up to 1000 mg/kg had no effect on mortality, physical examinations, cageside observations, maternal body weights, maternal body weight changes, food consumption, uterine data, fetal body weights or fetal examination data (external, visceral, and skeletal). Only one fetal malformation (short tail) was observed in this study in Group 3, which was not considered test substance related. All remaining fetal observations noted were variations. The total number of fetuses showing defects (malformations and variations) was 30 (9.6%) for Group 1, 21 (6.5%) for Group 2, 25 (7.9%) for Group 3, and 28 (10.0%) for Group 4. The majority of variations were noted during the skeletal examinations. All variations were considered within normal range and were not considered test-substance related.

 Based on the results from this prenatal developmental toxicology study in Sprague Dawley rats, the no-adverse-observed-effect-level (NOAEL) for maternal and embryo-fetal developmental toxicity when Hatcol 1510 was administered via oral gavage over the entire period of gestation (GD 5-20) is 1000 mg/kg, the highest dose level tested.

A prenatal developmental toxicity study in the rat by the dermal route was conducted with read-across substance, decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS 11138-60-6). The doses administered were 0 (control), 200, 600 and 2000 mg/kg body weight on each gestation day 6 to 15. Dermal application of 600 and 2000 mg/kg/day dosages of the test article caused local irritation at the site of application (statistically significant compared with control at 2000 mg/kg bw), but no decrease in material weight gain. There appeared to be no systemic effects. No adverse effects on embryo-fetal number, viability, sex ratio, body weight or morphology were observed at the highest dosage tested. Based on these results, the NOAEL for systemic maternal toxicity is 2000 mg/kg body weight/day and the NOAEL for local maternal toxicity is 200 mg/kg body weight/day.

 

In an Ames Test, the test substance was not mutagenic with or without metabolic activation. Three in vitro chromosome aberration tests with closely related read-across substances 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. Also, 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.

 

Toxicokinetic parameters

Absorption

Oral

In the four acute oral toxicity studies and the repeated dose toxicity studies with read-across substances, only minor clinical symptoms were observed in some of these studies; there were no treatment-related deaths. These results indicate that the oral bioavailability of each of the read-across substances is low or that the toxicity of each of the read-across substances is low. No treatment-related effects were observed in an oral 90 day study with either the substance itself or the read-across substance, CAS 403507-18-6. In a 28 day oral repeated dose toxicity study with read-across substance, pentaerythritol ester, tetrasubstituted, systemic effects were observed in rats indicating that this read-across substance is absorbed by the oral route in the rat. The test substance has an estimated water solubility of < 1.1 x 10^-5mg/L at 25 °C and a predicted log Kow value > 9.66. 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 of the acute dermal toxicity study with the test substance and the skin irritation and skin sensitisation studies provide no evidence to support significant skin absorption. In a prenatal development study with a read-across substance, CAS 11138-60-6, administered by the dermal route and in a 90 day dermal repeated dose toxicity study with read-across substance, CAS 67762-53-2, skin irritation was observed, however, no significant systemic effects occurred. The log Kow value of the test substance is predicted to be > 9.66 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 < 1.1 x 10^-5mg/L at 25 °C therefore dermal uptake is likely to be low. In conclusion, dermal absorption of decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane 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

A 90 day repeated dose toxicity study by the inhalation route was conducted with read-across substance, CAS 67762-53-2 and no significant treatment-related effects were observed. The substance has a low vapour pressure (7.55 x 10 E-6 Pa 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 (> 9.66) therefore it may be taken up by micellular solubilisation particularly as the substance is poorly soluble in water (< 1.1 x 10^-5mg/L at 25 °C). As a worst case, for risk assessment purposes the inhalation absorption of the test substance is set at 100%.

 

Distribution

In a 28 day oral repeated dose toxicity study with read-across substance, pentaerythritol ester, tetrasubstituted, effects were observed in the rat kidney and liver (effects not relevant to humans), suggesting distribution to these organs. 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.

Trimethylolpropane is water soluble therefore it is most probably excreted in the urine unchanged or in conjugated form.

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 thatdecanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropaneis significantly absorbed via the dermal route or the inhalation route. The results of an oral repeated dose toxicity study indicate thatdecanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropanemay be absorbed orally in the rat. It is likely that the ester groups indecanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropaneundergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids and trimethylolpropane. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. Trimethylolpropane is water soluble therefore it is most probably excreted in the urine unchanged or in conjugated form. Consequently, the substance is considered to have low bioaccumulation potential.

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
For risk assessment purposes the oral absorption is set at 100%
For risk assessment purposes the inhalation absorption is set at 100%
For risk assessment purposes the dermal absorption is set at 100%

Executive summary:

In conclusion, there is no evidence thatdecanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane is significantly absorbed via the dermal route or the inhalation route. The results of an oral repeated dose toxicity study with read-across substance, pentaerythritol ester, tetrasubstituted, indicate thatdecanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane may be absorbed orally. It is likely that the ester groups indecanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropaneundergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids and trimethylolpropane. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. Trimethylolpropane is water soluble therefore it is most probably excreted in the urine unchanged or in conjugated form. Consequently, the substance is considered to have low bioaccumulation potential.