Sodium p-chloro-m-cresolate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification document provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Type:

absorption

Results:

91.54% / 92.96% (males /females) of dose excreted via urine while 6.69 / 4.35% (males / females) found in faeces; thus, the absorption rate is estimated to be 91.54 / 92.96% in males / females, respectively (source, CAS 59-50-7, key rel.1, Rudolph 2009)

Type:

distribution

Results:

< 1% of the administered dose was recovered in the carcass and GI tract (source, CAS 59-50-7, key rel.1, Rudolph 2009)

Type:

distribution

Results:

no recovery of the test material in the liver tissue at any time point or dose; isolated values above the detection limit in the fatty tissue (source, CAS 59-50-7, rel.1, Schmidt & Bomhard 1981)

Type:

metabolism

Results:

urine: at least 5 metabolite fractions (two major fractions 37-39% and 41-47% of the dose, respectively), 6-11% of dose unchanged parent compound; faeces: almost completely unchanged (3-5% of the dose) (source, CAS 59-50-7, key rel.1, Rudolph 2009)

Type:

metabolism

Results:

2 highly polar metabolites detected (source, CAS 59-50-7, rel.2, Schmidt 1980)

Type:

excretion

Results:

99.03% (males) and 98.94% (females) excreted via urine and faeces within 7 days after administration (source, CAS 59-50-7, key rel.1, Rudolph 2009)

Type:

excretion

Results:

mean excretion via urine was 60.5% (67.2% after correction by recovery rate) within 72 h; excretion via faeces was low (0.24% within 24 h (0.40% after correction by recovery rate), not detectable thereafter) (source, CAS 59-50-7, rel.2, Schmidt 1980)

Description of key information

Absorption, distribution, excretion and metabolism, oral, rat (OECD 417):

absorption: the test material is mainly excreted via urine and thus it is absorbed to a high extent

distribution: no retention of compound related residues in organs or tissues of the animals

excretion: rapid excretion during the first 24 h after administration; completed after 7 days; mainly via urine

metabolism: 4 and 5 metabolites in urine of males and females, respectively; 4 metabolites in faeces of males and females, respectively

Accumulation in liver tisue and/or fatty tissue:

Liver tissue: no retention of compound related residues in the liver detected

Fatty tissue: occasionally values above the detection limit without relation to the dose or the time of exposure

Excretion in urine and faeces, metabolism in urine:

rapid excretion via urine mainly during the first 24 h after administration (67.2%); low excretion via faeces (0.40%); 2 highly polar metabolites detected in urine

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no data available regarding toxicokinetic of sodium p-chloro-m-cresolate (CAS 15733-22-9). The assessment was therefore based on studies conducted with the analogue substance p-chloro-m-cresol (CAS 59-50-7) as part of a read across approach, which is in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

The toxicokinetic behaviour (absorption, distribution, excretion) and metabolism of the source substance p-chloro-m-cresol was investigated in the Wistar HanRcc:WIST rat according to OECD Guideline 417 (1984) and in compliance with GLP (Rudolph, 2009). The test compound was radiolabelled with 14C in the phenol moiety of the molecule. A group of 4 male and 4 female rats received the test substance at a single dose of 300 mg/kg bw orally via gavage suspended in polyethylene glycol (PEG 400) as vehicle. The excretion of radioactivity in urine, faeces and expired air was measured in daily intervals up to 7 days after administration. The animals were sacrificed 7 days after dosing and residues of the test material were determined in selected organs and tissues. The metabolite pattern was investigated in urine and faeces extracts.

Between 121.48% and 119.46% of the administered dose were recovered from measurement of the total radioactivity in males and females, respectively. All mean values were normalized to a recovery of 100%. Rapid excretion mainly via urine was observed after oral administration. Within 24 h 85.21% and 84.30% of the administered dose was excreted in urine of male and female rats, respectively. During the same period of time 3.70% and 1.44% was excreted via faeces of male and female rats, respectively. The radioactivity excreted in the expired air was low (< 1% of the administered dose). Almost the complete administered dose was excreted after 7 days (99.03 and 98.94% in males and females, respectively). Less than 1% of the test material was detected in the remaining carcass and GI-tract. Extensive metabolism of the test material was identified in urine and faeces and excretion of respective metabolites was mainly via urine. The urinary metabolite pattern consisted of at least 5 metabolite fractions dominated by 2 major fractions (37-39% and 41-47% of the dose, respectively). Unchanged parent compound accounted for 4.97% and 11.35% of the administered dose in urine of males and females, respectively. In the faecal metabolite pattern the major fraction was found as unchanged parent compound (3-5% of the dose) while 4 metabolites in negligible amounts (< 1%) were detected in both sexes. The metabolite pattern was very similar for both sexes with some quantitative differences. Thus, under the conditions of this study, after oral administration of the radiolabelled test material to male and female Wistar rats, the recovery of radioactivity in urine, faeces, expired air and cage wash was almost complete. The radioactivity was mainly recovered in urine and to a lower extent in faeces but to a negligible extent in the expired air.

In a further study the potential of the source substance p-chloro-m-cresol to accumulate in fatty tissue and /or liver tissue was investigated (Schmidt & Bomhard, 1981). Three groups of 12 male Wistar TNO/W74 rats received oral doses of 150, 500 or 1500 ppm of the test substance in the diet over 1, 4, 8 or 13 weeks. The liver as well as samples of fatty tissue from the abdominal cavity were removed from 3 animals per dose group 1, 4, 8 and 13 weeks after start of administration. The samples were homogenized and extracted with hexane before derivatisation with heptafluorobutyric acid anhydride for gas chromatography with electrochemical detection. Detectable concentrations of the test substance were not found in any of the liver samples (> 10 nmol/g). In the fatty tissue samples, concentrations of the test substance were occasionally above the detection limit of 4 nmol/g. No correlation was found between the applied dose and the amount of test substance in the samples. No cumulative effect was observed. Thus, under the conditions of the study, the test substance did not accumulate in liver and fatty tissues.

The excretion of the source substance p-chloro-m-cresol in urine and faeces of rats as well as the quantity of metabolites in urine was further assessed after single oral administration (Schmidt, 1980). Five male Wistar II rats received a single oral dose of 300 mg/kg bw via gavage and were housed individually in metabolism cages. Urine samples were taken at 4, 8, 24, 32, 48 and 72 hours after application and analysed by HPLC-UV. Faeces were collected at 24, 48 and 72 hours after application and measured by GC-ECD. In addition, the urine samples were analysed by TLC to identify potential metabolite. The major excretory route was via the urine with 67.2% recovery of the applied dose. The excretion was rapid within the first 24 h after application. Low concentrations were also detected up to 72 h. The faeces represent a minor excretory route, with only 0.40% recovery of the applied dose within 24 h post-dosing. Two highly polar metabolites were found in the urine samples after TLC analysis. Since these metabolites were not included in the calculation of the recovery they might be the explanation for the low recovery rate of around 68% and might account for the remaining 30%. Under the conditions of the study, the test substance is eliminated rapidly and extensively from the body; the urine was identified as the main way of excretion.

General Assessment of Toxicokinetics

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of sodium p-chloro-m-cresolate (CAS 15733-22-9) 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 physicochemical properties and studies in which the toxicokinetic behaviour has been investigated.

Sodium p-chloro-m-cresolate is a mono-constituent substance with a molecular weight of 164.56 g/mol. The substance is a solid, with a water solubility of 3.4 g/L at 20 °C (pH 7) and a vapour pressure of 3.2E-7 Pa at 25 °C. The log Pow is 2.73 at 25 °C (pH 7) and pH 12.3 at a concentration of 10 % (w/w as hydrate). Sodium p-chloro-m-cresolate dissociates in aqueous media, forming the corresponding sodium cation and 4-chloro-3-methylphenolate anion, therefore, the toxicokinetic data described above for p-chloro-m-cresol is relevant for assessing the toxicokinetic properties of the registered substance.

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 favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) which would otherwise be poorly absorbed (ECHA, 2017).

The physicochemical characteristics of sodium p-chloro-m-cresolate (log Pow and water solubility) are in a range suggestive of favourable absorption. Under aqueous conditions, such as in GI fluid, sodium p-chloro-m-cresolate dissociates into its conjugate acid, 4-chloro-3-methylphenolate, and sodium ion, which will subsequently be absorbed from the GI tract. The toxicokinetic data on p-chloro-m-cresol shows rapid and almost complete absorption after oral ingestion. Likewise, the available acute toxicity data on sodium p-chloro-m-cresolate and the acute and repeated dose toxicity data on p-chloro-m-cresols how a range of systemic effects, which again demonstrate absorption via the GI tract after oral ingestion. Overall, the available data supports rapid absorption after oral ingestion.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The physicochemical properties (log Pow and water solubility) and molecular weight of sodium p-chloro-m-cresolate are in a range suggestive of moderate to high absorption through the skin. Under aqueous conditions, such as in the moisture of the skin, sodium p-chloro-m-cresolate dissociates into its conjugate acid, 4-chloro-3-methylphenolate, and sodium ion, which will subsequently be dermally absorbed. Dermal uptake of the neat solid form is expected to be lower than that of formulated liquid products. There is limited dermal toxicity data available for sodium p-chloro-m-cresolate, however, data on p-chloro-m-cresol showed evidence of dermal absorption, with mortality and clinical findings observed in the acute dermal toxicity study. In addition, p-chloro-m-cresol was shown to be a skin sensitizer in a guinea pig maximization test, demonstrating penetration of the outer dermis of the skin.

Sodium p-chloro-m-cresolate causes irritant / corrosive effects on dermal application, which relate to the strong basicity of the substance. Therefore, damage to the skin surface may further enhance penetration.

In the absence of specific data on dermal absorption for either sodium p-chloro-m-cresolate or p-chloro-m-cresol, a worst-case approach is taken and it is assumed that the rate of oral and dermal absorption for sodium p-chloro-m-cresolate are equivalent (ECHA, 2012).

Inhalation

Sodium p-chloro-m-cresolate is a non-dusty solid with low vapour pressure (< 0.0001 Pa at 25 °C), thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2017).

Overall, systemic bioavailability is considered likely after inhalation of aerosols with aerodynamic diameters below 15 µm.

In the absence of specific data on inhalation absorption, a worst-case assumption is taken for the purposes of route-to-route DNEL calculation, with the rate of human inhalation absorption for sodium p-chloro-m-cresolate assumed twice that of rat oral absorption (ECHA, 2012).

Distribution and Accumulation

Distribution of a compound within the body depends on the physicochemical 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. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Under aqueous conditions, sodium p-chloro-m-cresolate dissociates into its conjugate acid, 4-chloro-3-methylphenolate, and sodium ion. Therefore, the available toxicokinetic data for p-chloro-m-cresol is representative for sodium p-chloro-m-cresolate. P-chloro-m-cresol has a low molecular weight and high water solubility, therefore is expected to be widely distributed in the body, however, the available toxicokinetic data shows minimal retention of compound related residues in organs and tissues, therefore it can be concluded that there is limited potential for bioaccumulation.

Metabolism

In the key study for p-chloro-m-cresol (2009), at least five metabolite fractions (two major fractions 37-39% and 41-47% of the dose, respectively) were detected in the urine, demonstrating that the substance underwent significant metabolism. Unchanged parent compound accounted for 6 - 11% of the excreted dose in the urine. In the faeces, the parent compound was excreted nearly completely unchanged. The metabolism profile of sodium p-chloro-m-cresolate is expected to be similar to that of p-chloro-m-cresol.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa).

Urinary excretion is the predominant route of excretion for substances of low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. Therefore, the dissociation products and subsequent metabolites of sodium p-chloro-m-cresolate are expected to be predominantly excreted via the urine. This is confirmed in the toxicokinetic studies for p-chloro-m-cresol, where urinary excretion was the predominant route of clearance, with >80% of the substance excreted in the urine, with <5% being excreted in the faeces and <1% in expired air.

Reference list:

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, November 2017. European Chemicals Agency, Finland.

ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012. European Chemicals Agency, Finland