Sodium anisate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behavior of sodium anisate (CAS 536-45-8) has been investigated. Also for the structurally related substance p-anisic acid (CAS 100-09-4) no information on the disposition and metabolism in experimental animals or humans is available. However, there is some information contained in the literature on the metabolism and excretion of p-anisic acid. This information is included in this statement in the appropriate sections.

Sodium anisate and p-anisic acid represent the sodium salt and the corresponding carbon acid. Therefore, under aqueous conditions at pH > 5.5, such as gastrointestinal fluids, the mucus of the respiratory tract, the skin surface moisture and blood, the cations will be dissociated from the anion and the common dissociation product is the anionic moiety. Based on this, comparable toxicokinetic behavior is expected for sodium anisate and p-anisic acid.

In accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behavior of sodium anisate (CAS 536-45-8) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

Sodium anisate is an organic solid at 20°C with a molecular weight of 174.129 g/mol. The measured water solubility and log Pow values are 135.0 g/L at 20 °C and -0.53, respectively. The vapour pressure for sodium anisate was determined to be 0.4 mPa at 20 °C.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favorable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Sodium anisate has a good water solubility of 135 mg/L, a molecular weight of 174.129 g/mol and the log Pow is – 0.53. Therefore, good absorption of the molecule from the gastrointestinal tract can be expected.

An acute oral toxicity study was performed with the analogue substance p-anisic acid indicating signs of systemic toxicity at high oral doses (5000 mg/kg bw) and resulting in an acute oral LD50 value of > 5000 mg/kg bw (7.2.1-1), demonstrating oral bioavailability of the substance.

Overall, taking into account the physical-chemical properties of sodium anisate (CAS 536-45-8) the oral absorption potential of the substance is anticipated to be high.

Dermal

A substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. However, if water solubility is above 10 g/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum (ECHA, 2017). Dermal uptake for these substances will be low. As sodium anisate (CAS 536-45-8) has a high water solubility (135 g/L) and a low Pow of -0.53, low dermal absorption is expected as the substance may not readily cross the lipid rich environment of the stratum corneum due to its hydrophilic character.

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2017). As the molecular weight of sodium anisate is 174.129 g/mol, dermal absorption of the molecule is likely. However, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake via the skin is possible (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

log Kp (cm/h) = -2.80 + 0.66 log Pow – 0.0056 MW

The calculated Kp for sodium anisate is 7.349 x 10E-5 cm/h and a dermal flux rate of 0.0275 mg/cm2 per h was calculated indicating a low dermal absorption potential for sodium anisate (please refer to Table 1).

Table 1: Dermal absorption value for sodium anisate (CAS 536-45-8) (calculated with Dermwin v 2.02, Epi Suite 4.1)

Component	Structural formula	Flux (mg/cm2/h)
sodium anisate	C8H7O3Na	0.0275

 

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). In vivo skin irritation studies with the analogue substance p-anisic acid (CAS 100-09-4) revealed no skin corrosive or irritation properties, thus no damage to the skin surface is expected to lead to an enhanced penetration (7.3.1-1).

Overall, based on the physico-chemical and the available toxicological data, dermal uptake of p-anisic acid is considered to be low.

Inhalation

In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2017). Based on the granulometry data (D10: 46 µm; D50: 154 µm; D90: 413 µm; Kintrup, 2017), exposure to sodium anisate via the inhalation route is in principle possible. The vapour pressure of sodium anisate was determined to be 0.4 mPa at 25 °C, thus being of low volatility (ECHA, 2017).

However, systemic exposure to sodium anisate after inhalation is regarded to be limited due to various reasons. More than 50% of the particles are > 100 µm and therefore not inhalable. The largest fraction of the particles with a size of < 100 µm will most probably be settling in the nasopharyngeal region, about 10% are likely to settle in the tracheo-bronchial or alveaolar regions. Particles depositing in the nasopharyngeal region will be coughed or sneezed out or swallowed, those depositing in the tracheo-bronchial region will mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. Phagocytosis and transport to the blood via the lymphatic system is the only way of uptake. Only few particles will reach the pulmonary alveoli and would mainly be engulfed by alveolar macrophages, either translocated to the ciliated airways or carried into the pulmonary interstitium and lymphoid tissues (ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 3.0 June 2017).

Overall, systemic bioavailability of sodium anisate cannot be excluded, e.g. after inhalation of dusts with aerodynamic diameters below 100μm, but is not expected to be higher than following oral exposure.

Distribution and Accumulation

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution (ECHA, 2017).

Sodium anisate has a low molecular weight and good water solubility. Based on the physico-chemical properties and the absorption potential, distribution within the body can be considered as very likely. After absorption, sodium anisate acid may enter the blood circulating system through which it will be distributed within the body.

Highly lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The low log Pow of -0.53 implies that sodium anisate has low potential to accumulate in adipose tissue (ECHA, 2017). This is confirmed by experimental data showing that 85% of an intraperitoneal p-anisic acid dose is excreted in rat urine within 24 h as conjugates of the mother compound (Cramer and Michael, 1971) and in a test in rabbits, about 75% of orally administered p-anisic acid is recovered in urine as the glucuronide conjugate (Adams, 2005).

Overall, the bioaccumulation potential of sodium anisate is considered to be low.

Metabolism

Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1, OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Three hepatic and the identical 3 dermal metabolites were predicted for the test substance. Up to 31 metabolites were predicted to result from all kinds of microbial metabolism for the test substance. Most of these metabolites were found to be a consequence of the degradation of the molecule by microbial metabolism.

In an in vivo study in rats (Lewis, 2016) as well as in an in vitro study in rat, mouse, rabbit and human hepatocytes (Harrison, 2012), it was demonstrated that p-anisic acid (the primary metabolite of anisaldehyde) was further metabolised by phase II enzymes to glycine conjugated anisic acid and glucuronide conjugated anisic alcohol.Further available data from publications indicate that intraperitoneally administered p-anisic acid is O-demethylated to p-hydroxybenzoic acid in rats, dogs and rabbits liver microsomes (Cramer and Michael, 1971; Axelrod, 1956).

Available genotoxicity data with the analogue substance p-anisic acid do not show any genotoxic properties of the test substance. An Ames-test, an in vitro HPRT and an in vitro micronucleus test were consistently negative with and without metabolic activation. Thus, there was no indication that the test substance may cause genotoxic reactivity.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the feces (via bile and directly from the GI mucosa). Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Low molecular weight (below 300 g/mol in the rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favorable for urinary excretion. Based on the good water solubility and low molecular weight, distribution within the body in the blood circulating system followed by excretion via urine is expected. This is supported by published data demonstrating the 85% of an intraperitoneal p-anisic acid dose is excreted in rat urine within 24 h as conjugates of the mother compound (Cramer and Michael, 1971). In a test in rabbits, about 75% of orally administered p-anisic acid is recovered in urine as the glucuronide conjugate (Adams, 2005).

 

Short summary:

There is only limited experimental data available on the toxicokinetic behavior of sodium anisate (CAS 356-45-8).

High oral absorption is likely for sodium anisate. Dermal and inhalation absorption is assumed to be low. Sodium anisate will be distributed in the body, mainly O-demethylated to p-hydroxybenzoic acid and predominantly excreted via urine. Its bioaccumulation potential is considered to be low.

 

References

Adams, T.B. et al. 2005: The FEMA GRAS assessment of hydroxy- and alkoxy-substituted benzyl derivatives used as flavor ingredients. Food Chem. Toxicol. 43: 1241–1271

Axelrod J. 1956: The enzymic cleavage of aromatic ethers. Biochem 63(4): 634-439

Cramer, M.B. and Michael, W.R. 1971: Metabolism of p-anisic acid by the rat. Life Sci. 10 (21):1255-1259.

ECHA (2017) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Harrison, R. 2012: p-Methoxybenzaldehyde: Comparative In Vitro Metabolism using Mouse, Rat, Rabbit and Human Hepatocytes (study report), Test laboratory: Huntingdon Life Sciences. Huntingdon, UK, Report No CAQ0001. Owner company: Research Institute for Fragrance Materials, Inc.,Woodcliff Lake, NJ, USA; Report date: Oct 02, 2012

Lewis, E.M. 2016: A 14-Day Percutaneous Study of p-Methoxybenzaldehyde in Rats, with an Oral (Gavage) Study Extension, Including an Evaluation of the Toxicokinetics of p-Methoxybenzaldehyde (study report), Testing laboratory: Charles River Laboratories, Inc. Horsham, PA, USA, Report no: 72608. Owner company: Research Institute for Fragrance Materials, Inc.,Woodcliff Lake, NJ, USA; Report date: Jun 24, 2016

NTP (2011): NTP Technical Report on the Toxicology and Carcinogenesis Studies of Diethylamine (CAS 109-89-7) in F344/NN Rats and B6C3F1 Mice (Inhalation Studies), NTP TR 556, October 2011.

OECD (2017). OECD QSAR Toolbox v4.0, April 2017, Laboratory of Mathematical Chemistry Oasis. Downloaded from https://qsartoolbox.org/ Prediction performed on 21 September 2017.

US EPA. 2012: Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.1.; Prediction of dermal flux rate: DERMWIN v.2.02 (September 2012); United States Environmental Protection Agency, Washington, DC, USA; Prediction performed on 05 May 2017.