Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
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

Reference
Name:
Unnamed

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 Technical Grade, whichis a UVCB with the main components (comprising ~81% of content) being the four forms of the alkylphenol cardanol (i.e. the monoene, diene, triene and saturated side chain) and larger size, higher molecular weight polymeric constituents. 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 cross biological membranes (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 Technical Grade is an oily liquid at ambient temperature which is very lipophilic, with an estimated log Kowof 6.2. Technical Grade has a low measured water solubility of 0.2 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 Technical Grade is viadermalexposure due to the typical use patterns of the test substance identified in the exposure scenarios given 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 Technical Grade constituents into the stratum corneum itself may also be slow unless any damage to the skin surface caused by the substance (an identified irritant) enhances penetration (ECHA, 2017). Technical Grade also contains a high proportion of larger size and higher molecular weight polymeric constituents which are expected to have more limited absorption through the skin than the different forms of cardanol. Evidence for limited skin absorption is provided by an Acute Dermal Toxicity study (OECD TG402) on another grade of CNSL (Distilled Grade) 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 theoralroute of exposure is not likely to occur given the normal use patterns of Technical Grade. The high log Kow’s and low water solubilities of the different forms of cardanol and the polymeric constituents mean that they would be expected to be poorly absorbed across the gastrointestinal tract unless absorption was enhanced by the process of micellular solubilisation, if this is relevant to the test substance (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 Repeated Dose 90-day Toxicity studies (OECD TG408) on the two other grades of CNSL in the category, Distilled and Distillation Residue Grades, showed that there were local adverse histopathological changes in forestomach morphology in exposed rats at the highest test doses used in the study. These local effects are considered to be due to known irritancy of the test substance and could have affected the absorption of the different constituents of the two grades. In these studies Distilled Grade has been dosed with the vehicle propylene glycol and Distillation Residue Grade has been dosed with the vehicle dried and deacidified corn oil and the water solubility and the water partition coefficient of the vehicle 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 both the OECD TG408 studies on Distilled and Distillation Residue Grades, during macroscopic and histopathological examinations of animals at necropsy after 90 days exposure, test substance-related, largely non-adverse, changes were observed in the stomach, liver, mesenteric lymph nodes and thyroid gland. The OECD TG408 data sets for Distilled and Distillation Residue Grades of CNSL indicate that Distilled Grade shows greater systemic and local toxicity compared to Distillation Residue Grade in terms of the derived NOAEL values. The greater comparative toxicity of Distilled Grade indicates that the higher proportion of low molecular weight non-polymeric constituents in this grade were responsible for the effects observed rather than the higher molecular weight polymeric content (which is present in greater levels in Distillation Residue Grade).

Technical Grade only exists in liquid form and, based on the substance's low vapour pressure (0.0002 Pa at 25oC), the different constituents will not be present as an aerosol or vapour in the substances normal use patterns. Thus exposures viainhalationthat lead to absorption through the respiratory system are unlikely

Distribution:Given the low water solubility of Technical Grade (and the different forms of cardanol and the polymeric constituents), 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 studies on Distilled and Distillation Residue Grades the responses, though largely non-adverse, indicated that the different forms of cardanol had been distributed to the liver, mesenteric lymph nodes and thyroid gland.

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 Technical 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 Technical 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 for another grade of CNSL (Distilled Grade). 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. It is anticipated that a similar result will be obtained in the test on Technical Grade given the presence of a significant proportion of larger size, higher molecular weight polymeric constituents that are not expected to bioaccumulate.

Applicant's summary and conclusion