Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Written assessment based on the available information

Adequacy of study:

key study

Study period:

October 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non-GLP assessment report

Materials and methods

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

453-480-2

EC Name:

-

Cas Number:

70851-04-6

Molecular formula:

Not available

IUPAC Name:

Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid.

Results and discussion

Any other information on results incl. tables

Summary and discussion of Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid CAS: 70851-04-6; EC: 453-480-2

This assessment of the toxicokinetic properties of Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid 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

·       repeated dose toxicity: oral

·       repeated dose toxicity: dermal

·       repeated dose toxicity: inhalation

·       developmental toxicity study

·       bacterial reverse mutation test

·       in vitro chromosome aberration test

·       in vitro mammalian gene mutation test

 

Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid is a UVCB substance. The most abundant species present in the substance have molecular weights between 917-1179 g/mol. The substance has an estimated water solubility of < 0.14E-3 g/l at 20 °C, vapour pressure of 0.17 Pa and a log Kow of ≥ 6.9.

 

Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid was administered to rats via oral gavage to 6 female Wistar rats at 2000 mg/kg bodyweight. Animals were subjected to daily observations and weekly determination of bodyweight. Under the conditions of the study mortality did not occur, body weight and pathology did not reveal treatment related effects. Clinical signs only consisted of hunched posture which was noted among the animals of the second group on day 1 which was reversible by day 2.

 

One acute dermal toxicity study from read-across substances are detailed below:

·              Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS: 71010-76-9) was applied to five Sprague-Dawley rats of each sex by dermal application to clipped skin of the dorsal area of the trunk at 2000 mg/kg bodyweight for 24 hours. Clinical observations were recorded immediately after dosing and at approximately 1, 2.5 and 4 h after dosing and daily thereafter through Day 15. Animals were weighed prior to dosing on Day 1 and on Days 8 and 15. During the study period there were no effects observed on the clinical parameters, body weight gain was within normal range, and necropsy did not reveal any changes relating to the application of the test substance. The dermal LD50 value in Sprague-Dawley rats was established to exceed 2000 mg/kg bw.

Three in vivo skin irritation studies from a read-across substance Fatty acids, C5-10, esters with pentaerythritol (CAS: 68424-31-7) are detailed below:

·             A single application of 0.5mL of the test substance was applied to the skin of 3 male New Zealand White rabbits for 4 hours using a semi-occlusive dressing with observations taking place at 30 - 60 min, 24, 48, 72, 96 hours and then on days 7, 8 and 12. Following the single 4-hour application, moderate to severe erythema (score 2 - 2.7) and moderate to severe edema (score 3 - 3.7)were observed for 2 or 3 days after application in all animals. This regressed and no signs of erythema or edema were evident 4 to 12 days after application. Thickening of the skin at the application site was seen on one animal between 4 and 7 days after application. Yellow staining was also observed at the application site of one animal following application. No other signs of irritations were observed.

·             A single application of 0.5mL of the test substance was applied to the skin of 3 male New Zealand White rabbits for 4 hours using a semi-occlusive dressing with observations taking place at 30 - 60 min, 24, 48, 72, 96 hours and then on days 7, 11 and 12. Following the single 4-hour application, very slight to well-defined erythema (score 1 – 1.3) and very slight to slight edema (score 1 – 1.7) were observed in all animals. This regressed and no signs of erythema or edema were evident 11 or 12 days after application. Slight desquamation at the application site of one animal was observed 7 days after application.

·             A single application of 0.5mL of the test substance was applied to the skin of 3 female New Zealand White rabbits for 4 hours using a semi-occlusive dressing with observations taking place at 30 - 60 min, 24, 48, 72, 96 hours. Following the 4-hour application, slight erythema (score 1.3 – 1.7) and virtually no signs of edema (score 0.3) was observed in all of the treated animals. The erythema was fully reversible within 4 days while edema was seen to be full reversible after 48 hours.

The conclusion of the three studies resulted in the substance not meeting the classification criteria for skin corrosion/irritation. 

 

Five skin sensitisation studies from a read-across substance Fatty acids, C5-10, esters with pentaerythritol (CAS: 68424-31-7) are detailed below:

·             (Q)SAR conducted with OECD Application Toolbox; Version 1.1.02 anticipated that the substance would not meet the criteria for skin sensitisation.

·             Three Mouse local lymph node assay (LLNA) studies were conducted on four mice per dose at concentrations of 1, 3, 10, 30%. All three studies were inconclusive.

·             Buehler test using 20 male guinea pigs, were induced for 6 hours twice on day 0 and day 7 over a 14 day period. The outcome of the study revealed no skin sensitisation with a challenge dose confirming this on day 28.

 

Two oral repeated dose toxicity studies from read-across substances are detailed below:

·             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).

·             The 90-day study with pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) dosing male and female Wistar rats with 100,300 and 1000 mg/kg bw. The results of the study show the following effects: deposition of intracellular fat and fatty degeneration of the hepatocytes, the increased weights of the liver, both in female only, and the increased activity of alkaline phosphatase correlate with each other and identify the liver as the target organ. However these effects can be seen as adaptive response. The NOAEL was determined to be≥1000 mg/kg bw.

One inhalation repeated dose toxicity study from read-across substances are detailed below:

·             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.

One dermal repeated dose toxicity study from read-across substances are detailed below:

·             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. Slight erythema and flaking; slight epidermal hyperplasia and chronic inflammation occurred in both treatment groups. The NOAEL was therefore determined to be 2000 mg/kg bw.

 

An Ames test using Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid was determined to be negative, with and without metabolic activation.

Two in vitro genetic toxicity studies from read-across substances are detailed below:

·             In vitro mammalian chromosome aberration test using Fatty acids, C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS: 189200-42-8) was conducted using 40, 80 and 160 µg/mL of the test substance with and without metabolic activation in Chinese hamster Ovaries. Negative results was observed in the aberration assay with and without metabolic activity

·             In vitro gene mutation study using mouse lymphoma L5178Y cells was conducted using 3-(pentanoyloxy)-2,2-bis[(pentanoyloxy)methyl]propyl valerate (non-preferred name) (CAS: 15834-04-5) with and without metabolic activation. . Negative results were observed in the study, with and without metabolic activity.

 

Two developmental toxicity studies from read-across substances are detailed below:

·            Fatty acids, C5-9, tetraesters with pentaerythritol (CAS: 67762-53-2) was applied daily to the skin of Sprague-Dawley rats in a prenatal developmental toxicity study at concentrations of 800 and 2000 mg/kg bw. Under the conditions of the study the following adverse effects relating to slight local dermal irritation was noted such as erythema and flaking of the skin. Other symptoms presented by the animals such as neck lesions, red nasal exudate, and chromodacryorrhea in all groups were not considered to be related to the test substance as these are common in parental animals that are collared.

Fetuses were observed to have a significant increase in laevocardia. Other reported effects such as malformations in lumbar and sacral vertebrae, tail, sternebrae, and ribs, bruising were considered to be non-treatment related due to the comparable statistics with the control fetuses.

·            2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS 11138-60-6) was tested in a prenatal developmental toxicity study. The test substance was percutaneously applied to Sprague-Dawley rats for 6 h/day under occlusive conditions. 25 animals per sex per dose were treated with 200, 600 or 2000 mg/kg bw/day in corn oil on Days 6-15 of gestation. Control animals (25 per sex per dose) received the vehicle. The middle and the high dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or food consumption. There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Therefore, a NOAEL ≥ 2000 mg/kg bw/day was derived for prenatal development and for systemic maternal toxicity. Due to the irritation effects on skin, the local maternal NOAEL was found to be 200 mg/kg bw/day.

 

Toxicokinetic parameters

Absorption

Oral

The acute and repeated dose toxicity studies that were conducted on the substance subject to registration and read-across substances did not reveal any significant effects relating to the exposure to the substances. Effects noted in the repeated dose studies appeared to be adaptive in nature and are not considered to be toxicologically relevant to humans. The information available suggests that the substances are not very well absorbed following ingestion.

The physicochemical properties of the substance will have a significant effect on the absorption of the substance in the gastrointestinal tract when ingested. The most abundant species that is present in the UVCB substance has a molecular weight between 917-1179, it is highly insoluble in water; which do not favour absorption or readily allow passage through aqueous pores in the epithelial barrier. Highly lipophilic compounds (log kow > 4) such as this one (log kow ≥ 6.9), especially those which are insoluble in water are limited due to the inability to dissolve into the gastro intestinal tract and therefore cannot make contact with the mucosal surface. However, the absorption of such substances could be enhanced if they undergo micellar solubilization by bile salts (Aungst 40 and Shen, 1986).

As a worst case, for risk assessment purposes the oral absorption of the test substance is set at 100%.

 

Inhalation

One acute toxicity and repeated dose toxicity studies via the inhalatory route are available; however there were no significant effects relating to the tested substances observed. Indicating a clear lack of absorption following exposure.

Inhalation is not attributed as being a route of exposure given the substances low vapour pressure (0.17 Pa at 20°C). Additionally, to be readily soluble in blood the vapour of the substance must be soluble in water and lipophilic to cross the alveolar and capillary membranes. As the substance is highly insoluble with a log kow of > 6.9, it is anticipated that the substance properties of the substance do not favour absorption unless it is taken up bymicellar solubilization. Lipophilic substances may reach deep into the lung where gas exchange may occur, however the rate of systemic uptake is limited by the rate at which the substance may partition out of the mucus lining of the respiratory tract and into the blood. It is expected that the substance may be transported out of the deposition region with the mucus and swallowed.

As a worst case, for risk assessment purposes the inhalation absorption of the test substance is set at 100%.

 

Dermal

The results from dermal studies including the acute/repeated dose dermal toxicity study, in vivo skin irritation studies, dermal developmental studies and Buehler skin sensitization tests do not provide much evidence to support significant dermal absorption. Acute studies revealed erythema, edema and desquamation being the most notable effects by the read-across substances, however these effects were seen to be fully reversible within 2–4 days. Repeated dermal toxicity studies showed the read-across substances inducing slight erythema and flaking; slight epidermal hyperplasia and chronic inflammation occurred in treated animals at 2000 mg/kg bw following daily exposure. These effects may be attributed to the minor local irritation effects which could have enhanced dermal penetration of the substance. The molecular weight of the majority of the constituents in the UVCB substance are > 500 and are likely to be too large to be absorbed. Additionally the substance is highly insoluble with a high partition coefficient (log Kow > 6.9) indicating that the rate of transfer between the stratum corneum and the epidermis will be slow and limit the absorption rate across the skin. Maximum dermal absorption is often associated with partition coefficient values between +1 and +2 (ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals Monograph No, 20; Percutaneous absorption. August 1993). In conclusion, dermal absorption of the test substance 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%.

Distribution

In the repeated dose toxicity studies and reproductive/developmental studies with read-across substances, only limited histopathological changed were observed, demonstrating a limited ability for the substances to distribute throughout the body. The UVCB substance constituents have a large molecular weight and are not water soluble, hindering wide distribution through the body, but will have the inclination to accumulate in the body. Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption. As discussed above, absorption of these substances is considered to be very low, based on their physico-chemical characteristics (poor water solubility and high molecular weight). Such esters may undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products alcohols and fatty acids. The available information indicates that the cleavage products, fatty acids and alcohol moiety will be distributed in the organism.

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 adipose tissues 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 the absorption for many polyol esters is considered to be very low, the potential of bioaccumulation is very low as well. Nevertheless, esters of alcohols and fatty acids are considered to undergo hydrolysis, leading to the cleavage products fatty acids and alcohol moiety. 

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

From the information on the substance subject to registration and read-across to the mutagenicity assays it appears that the substance would not metabolised toward genotoxic structures.

Conclusion

In conclusion, there is no evidence that would suggest that Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid is significantly absorbed via oral, dermal or inhalatory routes from the data available from the read-across substances and factoring in the physico-chemical properties of the substance. It is likely that the ester groups of the test substance would undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids. Following absorption, the substance can remain unchanged or can be metabolised or conjugated into polar compounds and excreted via the urine or faeces. Alternatively, following fatty acids cleavage and degradation by oxidation in the mitochondria, the substance can be expelled when exhaled as CO2.

Consequently, the substance is considered to have low bioaccumulation potential.

Applicant's summary and conclusion

Conclusions:

In conclusion, there is no evidence that would suggest that Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid is significantly absorbed via oral, dermal or inhalatory route from the data available from the read-across substances and factoring in the physico-chemical properties of the substance. It is likely that the ester groups of the test substance would undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids. Following absorption, the substance can remain unchanged or can be metabolised or conjugated into polar compounds and excreted via the urine or faeces. Alternatively following the fatty acids cleave and degradation by oxidation in the mitochondria and expelled when exhaled as CO2.

Consequently, the substance is considered to have low bioaccumulation potential.