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

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Written assessment

Type of information:

other: Written assessment

Adequacy of study:

other information

Study period:

21 May 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Written assessment

Justification for type of information:

At the current level of registration, a written assessment is suitable.

Objective of study:

other: Written assessment of ADME

Qualifier:

no guideline followed

Principles of method if other than guideline:

Written assessment based on available study data.

GLP compliance:

no

Details on absorption:

See attached background material below.

Details on distribution in tissues:

See attached background material below.

Details on excretion:

See attached background material below.

Details on metabolites:

See attached background material below.

Bioaccessibility (or Bioavailability) testing results:

See attached background material below.

Conclusions:

Oral, dermal and inhalation absorption of decanoic acid, mixed esters with heptanoic acid, octanoic acid and pentaerythritol appears to be low. This is based on the lack of significant toxicological relevance effects noted in the acute/repeated dose oral and dermal studies with the substance and the respective read across substances.
Following ingestion, it is likely that these substances undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids and pentaerythritol. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells.
Pentaerythritol is metabolised in the liver and plasma then excreted in the urine unchanged or in conjugated form.
Consequently, the substance is considered to have low bioaccumulation potential.

Executive summary:

Oral, dermal and inhalation absorption of decanoic acid, mixed esters with heptanoic acid, octanoic acid and pentaerythritol appears to be low. This is based on the lack of significant toxicological relevance effects noted in the acute/repeated dose oral and dermal studies with the substance and the respective read across substances.

Following ingestion, it is likely that these substances undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids and pentaerythritol. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells.

Pentaerythritol is metabolised in the liver and plasma then excreted in the urine unchanged or in conjugated form.

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

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

Absorption

Oral

In the acute oral study and the repeated dose toxicity studies with read-across substances, no treatment related deaths, body weight changes, systemic toxicity and clinical signs of significant toxicological relevance were not present. Indicating that the oral bioavailability of the read-across substance is low.

The test substance is poorly soluble in water (< 0.14 mg/L at 25°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 of the in vitro and in vivo skin irritation/sensitisation studies for decanoic acid, mixed esters with octanoic acid, pentaerythritol and valeric acid (read across substance) and decanoic acid, mixed esters with heptanoic acid, octanoic acid and pentaerythritol. Read across substance decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate did reveal signs of minor irritation, however no significant systemic effects were observed. Overall the studies 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 water solubility of < 0.14 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, 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

There are no studies which have utilised the inhalation route. Based on the physicochemical properties of the substance, the substance would not expected to be available. The substance has a low vapour pressure (1.93 x 10^-8Pa at 20°C), therefore significant inhalation exposure to vapours would not be expected. Moderate log Kow values favour(between -1 and 4)absorption directly across the respiratory tract epithelium via passive diffusion, indicating that the substance may be taken up by cellular solubilisation, especially for poorly water soluble substances (< 1mg/L). Therefore as a worst case scenario for the risk assessment the inhalation absorption value of the 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 andpentaerythritolso 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.

Pentaerythritolis not water soluble therefore it is most probably be metabolised in the liver and plasma then 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

Oral, dermal and inhalation absorption of decanoic acid, mixed esters with heptanoic acid, octanoic acid and pentaerythritol appears to be low. This is based on the lack ofsignificant toxicological relevanceeffects noted in the acute/repeated dose oral and dermal studies with the substance and the respective read across substances.

Following ingestion, it is likely that these substances undergo lipase-catalysed hydrolysis in the gastrointestinal tract, releasing fatty acids andpentaerythritol. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells.

Pentaerythritol ismetabolised in the liver and plasma then excreted in the urine unchanged or in conjugated form.

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