Palmitoyl chloride

Endpoint summary

Description of key information

No experimental data on absorption, distribution and excretion are available for the target substance palmitoyl chloride. The toxicokinetic assessment is based on physicochemical properties of the substances. Additionally, the primary hydrolysis products can be used for the toxicokinetic assessment because of the rapid hydrolysis in aqueous systems and toxicokinetic data are available for the hydrolysis products HCl (CAS 7647-01-0) and palmitic acid (CAS 57-10-3). Therefore, the toxicokinetic of the target substance and the hydrolysis products is discussed below. 

Target substance and hydrolysis products
Based on the evidence of rapid hydrolysis, after oral administration of palmitoyl chloride the absorption of the hydrolysis products palmitic acid and HCl are considered.

The low vapour pressure of < 0.005 Pa @25°C indicates that palmitoyl chloride is non-volatile at room temperature and thus the exposure of the substances via inhalation route is unlikely. Therefore, absorption via inhalation is not further discussed.

Dermal absorption is expected to be low for the target substances based on the molecular weight of 274.9 g/mol and the high estimated Log Pow of 6.4. The substance is a skin irritant and was identified as a skin sensitizer, so some uptake via the skin surface may possible. However, as discussed above within aqueous systems hydrolysis occurs very rapidly. Thus, accumulation within the body is very unlikely.

Hydrolysis products
The hydrolysis of palmitoyl chloride was studied according to OECD 111 at pH 4, 7, and 9 at 10, 20, and 50°C. The hydrolytic half-life was determined to be t1/2 < 5 min at all pH values and temperatures. Palmitic acid and hydrochloric acid were determined as transformation products [BASF SE, 2020].

Palmitic acid is readily biodegradable while hydrochloric acid is inorganic. Therefore, a study on the hydrolysis is not provided.

a) Palmitic acid

Absorption
Due to the role as nutritional energy source, fatty acids are absorbed from the lumen of the intestine by different uptake mechanisms depending on the chain length. Long chain fatty acids (>C12) are absorbed into the walls of the intestine villi and assemble into triglycerides, which then are transported in the blood via lipoprotein particle (chylomicrons) (Jensen et al. 1986, ECHA).While an absorption of 99.9 % was found for C8 fatty acid, the long chain C18 fatty acid showed 64.4 % absorption (ECHA, 2021). Thus, and supported byits physico-chemical characteristics (MW = 256 g/mol), estimated log Know = 7.17),oral absorption of palmitic acid (C16) is considered to be high.

The dermal penetration of fatty acid is very variable based on the heterogeneous physico-chemical properties such as melting temperature, solubility and polarity. The polarity, for example, decreases with increasing chain lengths and/or the abolition of ionizable charged groups, so that they are less water soluble but more permeable through lipophilic membranes like the skin. Taken together fatty acids are almost completely absorbed after oral intake, whereas only limited dermal uptake has to be expected.

Metabolism and excretion
Medium and long chain fatty acids are esterified with glycerol and to triacylglycerides (TAGs) and packaged in chylomicrons (Spector, 1984; ECHA Dossier). These are transported via the lymphatic system and the blood stream to hepatocytesin the liver as well as to adipocytes and muscle fibers, where they are either stored or oxidized to yield energy (Hellerstein, 1999).

The quantitatively most significant oxidation pathway (ß-oxidation pathway) is predominantly located in the cardiac and skeletal muscle. In a first step, the fatty acids are converted to acyl-CoA derivates (aliphaticacyl-CoA) and transported into cells and mitochondria by specific transport systems. Then, the acyl-CoA derivatives are completely metabolized to acetyl-CoA or other key metabolites by the efficient enzymatic removal of the 2-carbon units from the aliphaticacyl-CoA molecule (Coppack et al., 1994). The complete oxidation of fatty acids via the citric acid cycle leads to H2O and CO2 (Coppack, 1994; MacFarlane, 2008). Other pathways for fatty acids catabolism also exist and include α- and ω-oxidation. The resulting main metabolites are acyl-carnitine, acetyl CoA, fatty acyl-CoA, propionyl-CoA and succinyl-CoA (Wanders et al., 2010).

Fatty acids are metabolized by various routes in the body to provide energy. Besides this, fatty acids are stored as lipids in adipose tissue, used as part of cellular membranes, as well as precursors for signaling molecules and even long chain fatty acids. Thus, fatty acids are not expected to be excreted to any significant amount in the urine or feces [ECHA 2021].

b)   HCl
Hydrogen chloride and its aqueous solution hydrochloric acid are corrosive and irritating and cause direct local effects on the skin, eye and gastro-intestinal or respiratory tract after direct exposure to sufficiently high concentrations. The chemistry of this substance is well understood; as an inorganic salt it dissolves in water to form hydrogen and chloride ions, both of which are physiological electrolytes [ECHA, 2021].

Reference:
BASF SE 2020: Hydrolysis as a function of pH of palmitoyl chloride, study number: 20L00159. 
ECHA REACH Dossier, https://echa.europa.eu/de/information‐on‐chemicals/registered‐substances; latest access 2021‐07‐17.