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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert review and assessment derived from available information
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Expert review of available data
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled
EC Number:
700-991-6
Cas Number:
8007-24-7
Molecular formula:
Cardanol (saturated side chain): Formula: C21 H36 O Cardanol (monoene): Formula: C21 H34 O Cardanol (diene): Formula: C21 H32 O Cardanol (triene): Formula: C21 H30 O
IUPAC Name:
Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Absorbed via the gastro-intestinal tract (rate and extent of absorption cannot be elucidated from the data available)
Type:
absorption
Results:
Absorbed to a limited degree across the skin barrier (rate and extent of absorption cannot be elucidated from the data available). The irritancy of the test substance may affect the permeability of the skin barrier.

Any other information on results incl. tables

There are no toxicokinetic studies that have directly addressed the absorption, distribution, metabolism, or excretion of Distilled Grade, whichis a UVCB with the main components (comprising ~80% of content) being the four forms of the alkylphenol cardanol (i.e. the monoene, diene, triene and saturated side chain). Other alkylphenols (such as cardol and methylcardol) are present at lower levels. However, information on these processes have been inferred based upon the properties of the chemical and the results of reliable and relevant short- and longer-term mammalian toxicity tests based on guidance given in ECHA (2017).

Systemic availability of the different forms of cardanol depends on their ability to be absorbed across body surfaces (such as the skin, the gastrointestinal tract and the respiratory tract epithelium of the lungs). Physico-chemical parameters that affect toxicokinetic processes include water solubility, lipophilicity (characterized by the log of the octanol-water partition coefficient, log Kow), degree of ionization (as defined by the dissociation constant, pKa), and molecular size. The physical state of Distilled Grade is an oily liquid at ambient temperature which is very lipophilic, with an estimated log Kowof 6.2. Distilled Grade has a low measured water solubility of 0.3 mg/l, but the constituents of the test substance are not readily ionisable.

Absorption:The only likely route of absorption of the different constituents of Distilled Grade is via dermal exposure due to the industrial use patterns of the test substance identified in the Risk Characterisation Exercise. However, the lipophilicity of the different forms of cardanol (estimated log Kow values >8.31for all forms) and their molecular weights (298 to 304 g/mole) means that the expected rate of transfer of substances between the stratum corneum (the non-viable layer of corneocytes forming a complex lipid membrane that must be first penetrated) and the epidermis (which is resistant to penetration by highly lipophilic substances) will be slow and will limit absorption across the skin. In addition uptake of the Distilled Grade constituents into the stratum corneum itself may also be slow unless any damage to the skin surface caused by Distilled Grade (an identified irritant) enhances penetration (ECHA, 2017). Evidence for limited skin absorption is provided by an Acute Dermal Toxicity study (OECD TG402) where Wistar rats that were exposed to a single dose of 2000 mg/ kg body weight for 24 hours showed no signs of systemic toxicity throughout the 14-day observation period. Signs of systemic toxicity would be an indication that absorption has occurred. At the end of the test all animals were subjected to an external examination and opening of the abdominal and thoracic cavities. No abnormalities were noted at necropsy.

Absorption via the oral route of exposure is not likely to occur given the normal use patterns of Distilled Grade. The high log Kow’s and low water solubilities of the different forms of cardanol mean that they would be expected to be poorly absorbed across the gastrointestinal tract unless absorption was enhanced by the process of micellular solubilisation (ECHA, 2017). Repeated dose exposure studies have been conducted using the oral gavage route of exposure since the test substance is classified as a Category 2 Skin Irritant (H315) and it was not considered appropriate from an animal welfare viewpoint to conduct the studies using the dermal route of exposure. The data from a Combined Repeat Dose Toxicity Study with Reproduction/Development Toxicity Screening Study (OECD TG422), a Repeated Dose 90-day Toxicity Study (OECD TG408) and a Prenatal Developmental Toxicity Study (OECD TG414) all showed that there were local adverse histopathological changes in forestomach morphology in exposed rats at the highest test doses used in the studies. These are considered to be due to known irritancy of the test substance and could have affected the absorption of the different constituents of Distilled Grade. Furthermore, in these studies Distilled Grade has been dosed with a vehicle (arachis oil for the OECD TG422 study and propylene glycol for the OECD TG408 and TG414 studies) and the water solubility of the vehicle and the vehicle/water partition coefficient of the substance may affect the rate of uptake (ECHA, 2017).

In the oral exposure studies signs of toxicity can be taken as evidence that absorption has occurred. In the OECD TG408 study during macroscopic and histopathological examinations of animals at necropsy after 90 days exposure test substance-related effects were observed in the stomach, mesenteric lymph nodes, liver and thyroid gland. In the mesenteric lymph nodes, erythrophagocytosis was noted in males, which correlated to macroscopic dark discoloration and foci. The effects observed in the mesenteric lymph nodes may be secondary to the changes in the stomach. In the liver, minor increases in liver weight were noted in males and females, which may correlate with measured increases in the liver enzymes alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and alkaline phosphatase (ALP) noted in these animals. In the thyroid gland, diffuse follicular cell hypertrophy was noted in males, which was without any degenerative changes. The findings in the mesenteric lymph nodes, liver and thyroid gland were a common background finding, lacked any histopathological correlation or were without any degenerative changes, and therefore were not considered to be adverse. However, they are indicative to an extent of absorption (and distribution) of the test substance.

Distilled Grade only exists in liquid form and, based on the substance's low vapour pressure (0.00005 Pa at 25oC), the different constituents will not be present as an aerosol or vapour in the substances normal use pattern. Thus exposures via inhalation that lead to absorption through the respiratory system are unlikely given that the substance is unlikely to be inhaled. Furthermore the different constituents of Distilled Grade are not likely to be absorbed based on their lipophilicity and low water solubility, though uptake via the respiratory tract epithelium could be enhanced by the process of micellular solubilisation (ECHA, 2017).

Distribution:Given the low water solubility of Distilled Grade (and the different forms of cardanol, any absorbed chemical will probably be distributed through the body via the lipids rather than by circulation in the blood. In the OECD TG408 Repeated Dose 90-day Toxicity study the responses, though non-adverse, indicated that the different forms of cardanol had been distributed through the rats to the mesenteric lymph nodes, liver and thyroid gland. In the OECD TG414 Prenatal Developmental Toxicity study the absence of any observed effects on the foetuses in the study indicates that the test substance probably does not cross the placental barrier.

Metabolism:Given the test substances high measured partition coefficient (log Kow of > 6.2), it is expected that the bioavailability of the different constituents for metabolism will be reduced. The liver is expected to be the primary organ to receive and metabolize the different forms of cardanol, making them more soluble by oxidation and conjugation and releasing the more polar compound into the bile for elimination via the gastrointestinal tract. Any chemical which is not metabolized is expected to be excreted either through the urine or faeces. However, it is recognised that it is difficult to predict the metabolic changes that the different constituents of Distilled Grade may undergo on the basis of physico-chemical information alone (ECHA, 2017).

Excretion:There is no reported data available on the excretion of any absorbed constituents of Distilled Grade. The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via the bile and directly from the gastrointestinal mucosa). For constituents such as cardanol, which show low water solubility and a molecular weight of 298 to 304 g/mole, it is more likely that they will be excreted in the bile rather than in urine (ECHA, 2017)

Accumulation potential: Although the high log Kow values for the different forms of cardanol indicate they would be expected to accumulate in the body of organisms, low Bioconcentration Factors (BCFs) values were measured in an OECD TG305 Bioconcentration in Fish study. The individual BCF values obtained for the four forms of cardanol, both before and after lipid normalisation, were <2000 L/kg. A BCF of 2000 L/kg is the threshold for a test substance to be considered to be bioaccumulative meaning the different forms of cardanol should not accumulate within the body.

Applicant's summary and conclusion

Conclusions:
There are no toxicokinetic studies that have directly addressed the absorption, distribution, metabolism, or excretion of Distilled Grade. However, information on these processes have been inferred based upon the properties of the chemical and the results of reliable and relevant short- and longer-term mammalian toxicity tests based on guidance given in ECHA (2017).
Based on the lipophilicity of the different forms of cardanol (estimated log Kow values >8.31for all forms) and their molecular weights (298 to 304 g/mole), the expected rate of transfer of substances between the stratum corneum and the epidermis (which is resistant to penetration by highly lipophilic substances) will be slow and will limit absorption across the skin. The systemic toxicity observed in the mammalian studies are indicative to an extent of absorption and distribution of the test substance.
Given the test substances high measured partition coefficient (log Kow of > 6.2), it is expected that the bioavailability of the different constituents for metabolism will be reduced. Based on the low water solubility and a molecular weight of 298 to 304 g/mole, cardanol is more likely that they will be excreted in the bile rather than in urine. The individual BCF values for the four forms of cardanol, measured in an OECD TG 305 Bioaccumulation study (both before and after lipid normalisation), were <2000 L/kg, therefore, no bioaccumulation is expected.