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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Basic assessment using phys.-chem. properties and available toxicological data
Adequacy of study:
supporting study
Study period:
Assessment date - 15 August 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Qualifier:
according to guideline
Guideline:
other: according to the requirements of Annex VIII of the EC Regulation 1907/2006
GLP compliance:
no
Specific details on test material used for the study:
Identification: FAT 40851/A TE
Batch Number: TZ 5891 / BOP 02-09
Purity: 69.9 % all coloured components
Appearance: Orange powder
Expiry Date: July 31, 2014
Storage Conditions: At room temperature at about 20 °C
Details on absorption:
Absorption:
Before any signs of toxicity appear, the substance must traverse across cell membranes whichever site is involved from an environment (Lehman-McKeeman, 2008). The substance may cause a local effect at the site of administration on initial exposure, but it must penetrate the biological barriers to give rise to have a systemic effect. Cell membranes are built as layers and basically composed of phospholipids and proteins. The most important feature of membranes is selectively permeable. Therefore, only certain compounds which meet specific criteria are able to pass through. Physicochemical characteristics including size, shape, solubility and hydrophobicity/hydrophilicity are key factors in estimating the absorption of substance. The major routes of entry into body for xenobiotics are via the gastrointestinal tract, lungs and the skin (Timbrell, 2000). The absorbability of FAT 40851 through oral, inhalation and dermal route will be discussed below based on the available physicochemical properties data and toxicological studies.

Oral (Gastrointestinal Tract):
The gastrointestinal tract can be considered as a tube traversing through the body (Lehman-McKeeman, 2008). Absorption of compounds can take place through the entire GI tract from mouth to rectum, but the small intestine is particularly important because of the large surface area for absorption. Transportation of xenobiotics across the GI tract is mainly by passive diffusion under certain environments that have low pH value and full of water and other secretions (ECHA Chapter R.7c, 2008). That means the GI tract greatly favors the absorption of hydrophobic over non-hydrophobic chemicals and thus of non-ionized over ionized species. The FAT 40851 will readily be dissolved into the GI fluids due to it’s highly water solubility. The components which have ionisable groups, such as sulphonate, hydroxyl and amines are potentially ionized in the GI tract. It is generally thought that ionized substances do not readily diffuse across biological membranes. Furthermore, large molecule substances (molecular weights above 1000) which are organic anions would be poorly absorbed. Small water soluble molecules (molecular weight below 200) which dissociate and form inorganic ions can be easily absorbed in the GI tract via aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1994). The Log POW value of FAT 40851 is -4 at 22 °C and therefore it is not favorable for absorption by passive diffusion (Log POW values between -1 and 4 are preferred) in the GI Tract. The ions have low molecular weights, e.g. sodium/potassium sulfate, dipotassium hydrogen orthophosphate, sodium/ potassium chloride and sodium/ potassium fluoride will be absorbed and pass across the cell membranes into plasma rapidly. Considering the low Log POW value (-4 at 22 °C), ionisable potential and large molecular weights, the main constituents of organic anions are not be expected to have high absorption rate in humans or rats via oral exposure. This hypothesis of absorption behavior described above is supported by the available oral toxicity studies. In a 28-day oral toxicity study, the mean potassium level was significantly increased in males at 1000 mg/kg/day (p<0.05) group when compared with the controls. Brownish pigment was recorded in the tubular epithelia in kidneys of rats at 1000 mg/kg/day indicating that the absorption of azo dyes from GI tract has occurred. The inflammatory changes of the glandular submucosal region in the stomach were observed indicating that the test substance has a potential for irritation of the stomach and damage to cell membranes, so the absorption may be enhanced at this site of GI tract. Moreover, in an in vivo micronucleus assay, 500, 1000, 2000 mg/kg bw testing substance were applied on mice by oral route and all treated animals showed discolored urine (orange) after treatment with 1000 and 2000 mg/kg bw, which could be also a sign of oral absorption. Discoloration of multiple organs was also reported in the Reproduction/Developmental toxicity screening test. All the evidences listed above indicated the absorption in rats has occurred in the gastrointestinal tract. However, the systemic toxicity of FAT 40851 is considered to be slightly or mildly based on the oral toxicity studies (e.g. LD50 oral, rat >2000 mg/kg; NOAEL= 1000 mg/kg in the reproductive screening test; NOAEL= 750 mg/kg in the prenatal assay) and this phenomenon may be due to low absorption rate or low systemic toxicity of testing item. However, the GI absorption may be enhanced if exposure continues based on the 28-days study, displayed irritation effects in the stomach. Overall, the inorganic salts in FAT 40851 may be taken up rapidly in the GI tract but they are not expected to cause significant systemic toxicity to humans. The organic anions may be absorbed into the body based on their physiochemical properties and available animal data. Therefore, a default value of 100 % oral absorption for prolonged exposure is appropriate for conservative considerations.

Inhalation:
The lungs have a large surface area, around 50-100 m² in humans. The barrier between the air in the alveolus and the blood stream is only two cell membranes thick (Timbrell, 2000). Hence, absorption from the lungs is usually rapid and efficient. The main process of absorption is passive diffusion through the cell membrane of respiratory system and then the substance will dissolve in the blood and may react with plasma proteins. After that the substance in the blood flow will be transferred from lungs to other organs or tissues. The vapor pressure of FAT 40851 is 2.70 x 10 -37 Pa at 25 °C (estimated) which displays its extremely low volatility property and indicates that the inhalation of substance as vapor is quite unlikely. However, the FAT 40851 may generate dust due to its small particle size which are found from approximately 0.3 μm to 20.0 μm in the granulometry test and consequently the dust can be breathed and enter into lungs if no protective measure is applied. The particles with aerodynamic diameters below 50 μm may enter the thoracic region and those below 10 μm may reach the alveolar region of the respiratory tract. Furthermore, the larger particles which are around and above 20 μm tend to be retained in the upper parts of the respiratory system, whereas the smaller particles which are around 5~6 μm, described as “course particles” are deposited in the nasopharyngeal region. The particulate matters with diameters of approximately 2.5 μm, referred to as “fine particles” mainly deposit in the tracheo-bronchiolar regions of the lungs (Lehman-McKeeman, 2008; US EPA, 1994).
The “course particles” generated by FAT 40851 may deposit on the unciliated anterior or rostral portion of the nose and tend to remain at this site until being removed by action of clearance mechanisms, such as nose wiping, blowing, or sneezing. The particles may dissolve in the mucus due to the high water solubility (88.3 g/L at 20 °C) and then will be carried to the pharynx and may be absorbed through the nasal/ pharynx epithelium into the blood. The mucus containing the dissolved particles can also be transported out of the respiratory tract and consequently be swallowed. The “fine particles” of FAT 40851 may deposit on the tracheo-bronchiolar regions of the respiratory tract and will be cleared by retrograde movement of the mucus layer in the ciliated portions of lungs. Same as “course particles”, coughing and sneezing can greatly increase the movement of mucus and particulate matter toward the mouth. Particles with diameters of 1 μm or less may penetrate to the alveolar sacs of the lungs and these extremely small particles may be absorbed into blood or cleared through the lymphatics
after being scavenged by alveolar macrophages (Oberdorster et al., 2005). The rate of cilia-propelled movement of mucus varies in different parts of the respiratory tract but it is always a rapid and efficient transport mechanism. However, the FAT 40851 was found to be slightly irritating to mucosa (slightly irritating to eyes in the in vitro assay), thus it may damage the cilia and impair the efficiency of the removal process. In addition, cell membrane damage in this site will enhance the absorption rate of foreign compounds. Most water soluble inorganic cations/anions (molecular weight below 200) might be absorbed through aqueous pores or be retained in the mucus and transported out of respiratory tract. There is no inhalation toxicity data available, however the absorption via GI tract in the oral toxicity studies was observed (see more details in section 3.1.1) indicating the substance can also be absorbed if it is inhaled. A part of FAT 40851 particles which were inhaled in the respiratory tract will be exhaled or transported and swallowed. However, the swallowed substance will be absorbed from GI tract and contribute to the total systemic burden. Overall, the inorganic ions in the FAT 40851 may be taken up rapidly in the respiratory system but are expected to have insignificant systemic toxicity in humans at small dose level. The inhaled organic particles have the potential to reach the deep lungs and, once there, may be absorbed or retained for prolonged periods. Therefore, in the absence of data it is assumed that 100% absorption is possible based on conservative considerations.

Dermal:
Human skin is the largest body organ, around 18000 cm² for adults and provides a relatively good barrier for separating organisms from their environment (Timbrell, 2000). The skin comprises two major layers, the epidermis and dermis. The outermost layer of epidermis is stratum corneum comprising of several layers of keratinocytes which can limit the absorption of foreign compounds. The dermis is situated beneath the epidermis and consists primarily of fibroblasts. This region is more permeable and vascularized and will carry absorbed compounds into blood. The stratum corneum represents its greatest barrier function to prevent the absorption of xenobiotics. Absorbed components that already passed the stratum corneum need to traverse the other several layers of cells too before entering into the blood and then reach the systemic circulation. Absorption through the skin is mainly by passive diffusion through the stratum corneum which is the rate-determining step. Foreign compounds may also be absorbed via sebaceous glands and hair follicles but the overall absorption quantities may be limited as these appendages only account for less than 1 % of the total human skin surface area (Lehman-McKeeman, 2008). The organic constituents of FAT 40851 may not be absorbed due to their large molecular weight (above 1000). In contrast, uptakes of small ingredients stand a good chance. The water solubility of FAT 40851 is far beyond 10 g/L (88.3 g/L at 20 °C) indicating it has potential for uptake by dermal exposure. But considering its low log POW value (-4 at 22 °C), the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and therefore dermal absorption of organic fractions is likely to be low (Flynn, 1985). The surface tension of FAT 40851 in an aqueous solution is far beyond the 10 mN/m (66.7 mN/m at 20 °C). Therefore, it is not considered as a surfactant and may not enhance the potential of dermal uptake. FAT 40851 was found neither irritating nor corrosive to rabbit skin, thus it will not damage the epidermis and dermis when it is applied to the surface of skin. So, the penetrability caused by tissue damage will not be enhanced. The acute dermal toxicity study in rats showed that the LD50 is greater than 2000 mg/kg and there were no systemic toxicity signs although discolored urine and faeces were observed during this test. As a result, the skin absorption of the substance may be considered to be very low. On the other hand, the substance has been identified as a strong skin sensitizer in a LLNA test; hence it shows that at least some fractions of applied test material have been absorbed after repeated exposure and reacted with immune system. Overall, the inorganic salts in the FAT 40851 may be taken up into vascular system but these components will be expected to have insignificant systemic toxicity in humans at low dose level. The organic salts will be poorly absorbed into the body based on their physico-chemical properties. Therefore, a default value of 10% skin absorption is recommended (de Heer et al, 1999).
Details on distribution in tissues:
Distribution and Bioaccumulative Potential:
Following the absorption by oral, inhalation and dermal routes, foreign compounds will enter the blood and distribute to tissues/organs throughout the whole body. The rate of distribution to organs or tissues is dependant on blood flow and the rate of diffusion out of the vascular system into the cells of a particular organ or tissue. In a general way, the initial phase of distribution is dominated by blood flow, whereas the eventual distribution is determined largely by affinity (Lehman-McKeeman, 2008; Timbrell, 2000). The inorganic salts of FAT 40851 which have water-soluble molecules and ions in the blood will diffuse through aqueous channels or pores into the cells. The organic anions being large molecules will pass out of the plasma very slowly, possibly by pinocytosis. Therefore, the distribution areas of such compounds are limited in the body.
In a 28-day oral toxicity study, brownish pigment in the kidneys was observed particularly in the tubular epithelia of males and females at 1000 mg/kg/day indicating that the distribution in this site has occurred. In addition, one male treated at 100 mg/kg/day and one female treated with 1000 mg/kg/day had dilation of the renal pelvis. There were no treatment related effects and discoloration observed in the liver, so bioaccumulation in this organ is unlikely. The substance with log POW is unlikely to be accumulated in the adipose tissue with repeated exposure. Certain small ions such as fluoride can interact with ions in the matrix of bone and may be accumulated there within continuous exposure (Rozman and Klaassen, 1996). The neurobehaviors were also evaluated at week four in this study via Functional Observational Battery (Screen) method and there were no test related changes in all treated group, indicating the substance and/or its metabolites may not have the ability to cross the blood-brain barrier (BBB) and finally accumulate in the central nervous system (CNS) (Rozman and Klaassen, 1996). Gross pathology and histopathology were investigated in a reproduction/developmental toxicity screening test after the animals were sacrificed and yellowish discoloration of epididymides, testes, kidneys and uterus/oviduct/cervix were noted. However, the signs discoloration were contributed to test item deposition and no adverse effects were noted in these organs, thus specific target organ toxicity caused by substance deposition may be considered as insignificant under the limited exposure duration. Only poorly water and lipid soluble particles have the potential to deposit in the deep respiratory system and FAT 40851 is not considered having such potential. However, the substance has slightly irritating effects to mucosa, thus it may damage the alveolar cells and
therefore cause inflammation and reduce the efficiency of the removal process. So the bioaccumulation of the large molecular organic fractions in lungs cannot be excluded if exposure is continuous.
Details on excretion:
Excretion
The major routes of elimination of compounds from the body are urine and/or the faeces. Other potential excretion routes are expiration and secretion into the fluids such as milk, saliva, tears, sweat and semen (ECHA Chapter R.7c, 2008). The renal excretion processes involve three mechanisms: filtration from the blood through the pores in the glomerulus, diffusion from the bloodstream into the tubules and active transport into the tubular fluid. The inorganic/organic salts and their metabolites that have water-soluble and low molecular weights (below 500-700 in humans, 300 in rats) are likely to be excreted in the urine. In an in vivo micronucleus assay, discolored urine (orange) was found in the treated animals, indicating urinary excretion of small parts of the test material has occurred at least. Therefore, the excretion of FAT 40851 via urine also can be expected in humans, especially when the bile excretion was saturated. The biliary route of elimination is the most significant excretion route for FAT 40851, especially for those components/derivatives which have high molecular weights (above 500-700 in humans, over 300 in rats) or conjugated with glucuronides or glutathiones (Renwick, 1994). Orange faeces were noted for all treated animals in oral toxicity studies, indicating bile excretion of FAT 40851 or its metabolites may take place. However, this phenomenon may also be attributed to unabsorbed ingredients of FAT 40851 which were removed from body directly. The other potential routes of excretion such as expiration to air and secretion into breast milk are unlikely owing to the available physico-chemical data.
Metabolites identified:
not measured
Details on metabolites:
Metabolism:
Metabolism is the biotransformation of a foreign compound into one or more different chemical entities which are called metabolites. Xenobiotic biotransformation is the process of converting lipophilic chemicals into hydrophilic chemicals, which are readily excreted in urine or bile (Lehman-McKeeman, 2008; Timbrell, 2000). Biotransformation can be divided into phase I (oxidation, reduction and hydrolysis) and phase II (conjugation). However, it is very difficult to predict the metabolic changes and potential metabolites. The hypotheses listed below are based on deduction from physico-chemical information and may only be used as references for further investigations. Some of absorbed organic anions that are azo dyes may be catalysed by reductases of cytochromes P450 in the gastrointestinal tract after oral exposure in a phase I process. Then these metabolites or fractions in the blood will be delivered into the liver through the portal vein for further metabolization, such as oxidation reactions being catalyzed by mono-oxygenase. After that, phase II metabolism may participate and a part of metabolites or even the origin components of FAT 40851 may conjugate with glucuronic acid, sulphate, glutathione and other endogenous groups and then become excreted via bile or urine.
Conclusions:
Considering the physico-chemical properties of FAT 40851, [i.e., high molecular weight for organic salts (above 1000), small log POW value (-4), and low vapor pressure of 2.70 x 10E -37Pa at 25 °C (estimate)], absorption of FAT 40851 from various routes of exposure, such as oral, dermal or inhalation is expected. However, absorption of FAT 40851 is expected to mainly occur via oral (100% absorption rate and inhalation routes (100 % absorption rate), but with limited potential for dermal absorption (10 % absorption rate can be expected). The results of the 28-day repeated oral toxicity study also provide evidence that the organic components of FAT 40851 may not cross the blood-brain barrier (BBB) upon oral exposure to cause CNS effects. Additionally, fluoride ions may interact with ions in the matrix of bone and may be accumulated there if exposure is continuous. Brownish pigment in the kidneys indicated that distribution and deposition have occurred and therefore kidneys may be considered as a target organ if exposure continues. Bioaccumulation of small particles in the deep lungs via inhalation exposure route may also not be excluded due to the substance physicochemical properties. Following absorption, FAT 40851 is anticipated to be distributed at the very least to the liver and kidneys, based on the systemic effects noted in these organs in animals following repeated oral exposure. The constituents having large molecular weight may be metabolized in the liver and consequently excreted via bile. On the other hand, the inorganic salts/ions may be excreted mainly through urine.
Executive summary:

Considering the physico-chemical properties of FAT 40851, [i.e., high molecular weight for organic salts (above 1000), small log POW value (-4), and low vapor pressure of 2.70 x 10E -37Pa at 25 °C (estimate)], absorption of FAT 40851 from various routes of exposure, such as oral, dermal or inhalation is expected. However, absorption of FAT 40851 is expected to mainly occur via oral (100% absorption rate)and inhalation routes (100 % absorption rate), but with limited potential for dermal absorption (10 % absorption rate can be expected). The results of the 28-day repeated oral toxicity study also provide evidence that the organic components of FAT 40851 may not cross the blood-brain barrier (BBB) upon oral exposure to cause CNS effects. Additionally, fluoride ions may interact with ions in the matrix of bone and may be accumulated there if exposure is continuous. Brownish pigment in the kidneys indicated that distribution and deposition have occurred and therefore kidneys may be considered as a target organ if exposure continues. Bioaccumulation of small particles in the deep lungs via inhalation exposure route may also not be excluded due to the substance physicochemical properties. Following absorption, FAT 40851 is anticipated to be distributed at the very least to the liver and kidneys, based on the systemic effects noted in these organs in animals following repeated oral exposure. The constituents having large molecular weight may be metabolized in the liver and consequently excreted via bile. On the other hand, the inorganic salts/ions may be excreted mainly through urine.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Considering the physico-chemical properties of FAT 40851, [i.e., high molecular weight for organic salts (above 1000), small log POW value (-4), and low vapor pressure of 2.70 x 10E-37 Pa at 25 °C (estimate)], absorption of FAT 40851 from various routes of exposure, such as oral, dermal or inhalation is expected. However, absorption of FAT 40851 is expected to mainly occur via oral (100 % absorption rate)and inhalation routes (100 % absorption rate), but with limited potential for dermal absorption (10 % absorption rate can be expected). The results of the 28-day repeated oral toxicity study also provide evidence that the organic components of FAT 40851 may not cross the blood-brain barrier (BBB) upon oral exposure to cause CNS effects. Additionally, fluoride ions may interact with ions in the matrix of bone and may be accumulated there if exposure is continuous. Brownish pigment in the kidneys indicated that distribution and deposition have occurred and therefore kidneys may be considered as a target organ if exposure continues. Bioaccumulation of small particles in the deep lungs via inhalation exposure route may also not be excluded due to the substance physicochemical properties. Following absorption, FAT 40851 is anticipated to be distributed at the very least to the liver and kidneys, based on the systemic effects noted in these organs in animals following repeated oral exposure. The constituents having large molecular weight may be metabolized in the liver and consequently excreted via bile. On the other hand, the inorganic salts/ions may be excreted mainly through urine.