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EC number: 271-784-1 | CAS number: 68608-50-4
Dose responsive localized dermal effects at the test site (dorsal surface), consisting of scabbed post dose findings and elevated dermal scores. These findings were most pronounced at 1000 mg/kg/day and were seen most frequently at this dose level. The findings at 300 mg/kg/day were at a lower incidence and with lower dermal scores. Dermal scores and findings at 100 mg/kg/day were comparable to the controls.
In humans, lithium/ lithium carbonate has been used for decades in psychiatric therapy for the treatment of bipolar disorder. In case of long-term treatment, the recommended dose is 450 to 900 mg/day lithium carbonate and corresponding to a desired sustained therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. Based on experience with long-term application e.g. lithium carbonate for therapy in humans, there is no evidence that lithium is of concern with respect to repeated oral toxicity at medical doses as the ones indicated above.
The effect level (NOAEL) determined for lithium carbonate for repeated dose toxicity by the oral route is based on human data and can be calculated in two ways that complete one another:
One option is based on the therapeutic serum concentrations of 0.5 to 1.0 mmol lithium/L and the extracellular fluid (ECF) volume. Lithium has a large volume of distribution of 0.6 - 0.9 L/kg (42 L – 63 L for a 70 kg adult). It is distributed throughout the body water both extra and intracellularly. Lithium shifts into the intracellular compartments of cells because of its large volume of distribution. Although in long-term use, the intracellular concentration increases, the intracellular concentration is not reflected by the plasma level which measures only the extracellular fluid concentration. Therefore, a desired concentration of 1 mmol/L of lithium is expected to be sustained and reflected in the extracellular fluid (ECF) only and not in the intracellular fluid. Thus, the volume considered is of the ECF only which comprises of plasma, interstitial fluid (spaces between cells) and transcellular fluid (lymph, cerebrospinal fluid, synovial fluid, serous fluid, gastrointestinal secretions) and is typically 15 L (reported in different references to be between 14 – 19 L (for 70 kg adult)). Based on this data the derived NOAEL (considering a lithium concentration of 1mmol/L and an ECF volume of 15 L) is 1.5 mg lithium/kg bw/day equivalent to 7.98 mg lithium carbonate/kg bw/day. This NOAEL value can be considered as a conservative value as it is based on an bioavailable dose in humans after absorption and on a smaller volume than its actual distribution volume.
Another way to calculate NOAEL oral for lithium carbonate is based as well on data taken from the routine long-term treatment of bipolar disorder. Instead of calculating the NOAEL from the therapeutic serum concentration of lithium, the lithium carbonate NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 450 to 900 mg lithium carbonate/day (corresponding to the desired sustained concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing the oral doses 450 to 900 mg lithium carbonate/day to 70 kg, the following values are obtained respectively: 6.43 to 12.86 mg lithium carbonate/ kg bw/day or when dividing to 60 kg the following values are obtained respectively: 7.5 to 15 mg lithium carbonate/kg bw/day, representing the optional NOAEL values for lithium carbonate for the oral route.
In both ways of calculation, the values obtained are in same order of magnitude and similar to one another. As a worst–case value, a NOAEL repeated dose toxicity oral of 6.43 mg/kg bw/day was chosen. Further, this value could be used as a starting value for route-to-route extrapolation in calculation of the repeated dose toxicity for the dermal and inhalation routes.
See attached documents
This study was conducted for to evaluate the possible adverse effects of the test article, Fatty acids C18-(unsaturated) lithium salts
Additionally, two groups of five animals/sex/group at 0 (vehicle) or 1000 mg/kg bw/day were dosed for a total of 43 days and then began a 14-day recovery period. Observations of these animals included clinical signs, neurobehavioral observations, dermal irritation scores, body weights, food consumption, and clinical pathology parameters. At the end of the recovery period, necropsy examinations were performed, organ weights were recorded, and selected tissues were collected and preserved.
Observations of the P animals included clinical signs, neurobehavioral observations, behavioral indices, dermal irritation scores, body weights, and food consumption during the premating/mating, gestation, and lactation periods, clinical pathology parameters, and parturition and litter data. Observations of the offspring (F1) included survival at birth and during lactation, individual pup body weights, and gross abnormalities. At study termination, necropsy examinations were performed on all P animals, organ weights were recorded, and selected tissues were collected and microscopically examined. On LD 4, surviving F1pups were examined externally, euthanized, and discarded.
All animals on study survived to scheduled terminal and recovery necropsies. The most significant clinical observations consisted of dose responsive localized dermal effects at the test site (dorsal surface), consisting of scabbed postdose findings and elevated dermal scores. These findings were most pronounced at 1000 mg/kg bw/day and were seen most frequently at this dose level. The findings at 300 mg/kg bw/day were at a lower incidence and with lower dermal scores. Dermal scores and findings at 100 mg/kg bw/day were comparable to the controls. Mean body weight showed decreasing trends during the course of the study in males at 1000 mg/kg bw/day. For the remaining animals there were no consistent patterns of adverse effects on body weight or food consumption at the dose levels tested. The results of the neurobehavioral and behavioral evaluations did not reveal any definitive patterns consistent with treatment-related effects.
At termination, there were no adverse test article-related effects on hematology or clinical chemistry parameters evaluated.
The results at scheduled necropsy showed test article-related macroscopic findings that were limited to the dose site in the skin, consisting of minimal to moderate abrasion/scab formation at the dose site in both sexes. At the recovery necropsy, the incidence and overall severity of abrasion/scab formation was reduced at 1000 mg/kg bw/day, indicating partial resolution of this finding over the recovery period.
Possible test article-related organ weight differences at terminal necropsy included the increased spleen and adrenal gland weights (relative to body weight) of animals at 1000 mg/kg bw/day. The increased spleen/body weight ratio of males may have been associated with the lower mean body weight at this dose level and, possibly, increases in extramedullary hematopoiesis noted microscopically. There was no microscopic correlate for the increased adrenal gland/body weight ratio of females at this dose level.
Test article-related microscopic findings were present in treated skin at 300 and 1000 mg/kg bw/day, and possible test article effects were also noted in the thymus and spleen at 1000 mg/kg bw/day.
Test article-related findings in treated skin included an increase in the incidence and/or severity of erosion/ulceration, epidermal hyperplasia and exudate, acute to subacute/chronic inflammation, and edema. At recovery necropsy, test article-related microscopic findings in treated skin in animals at 1000 mg/kg bw/day were morphologically similar, although they occurred at a lower incidence and severity indicating partial resolution of these findings over the recovery period.
Minimal to mild cortical lymphoid depletion was noted in the thymus in animals of both sexes at 1000 mg/kg bw/day at the terminal necropsy. However, there were no statistically significant differences in the mean thymus weight. Thymic lymphoid depletion in animals at 1000 mg/kg bw/day may have been a secondary finding due to stress associated with the test article-related lesions in treated skin. Splenic extramedullary hematopoiesis was slightly increased in both sexes at 1000 mg/kg bw/day. The increased severity of splenic extramedullary hematopoiesis in control and treated females may have been due to recent parturition, but the slight increase in the incidence of this finding in animals at 1000 mg/kg bw/day may have also reflected an adaptive response secondary to test article-related inflammation in treated skin.
In conclusion, dermal application of Fatty acids C18-(unsaturated) lithium salts
The substances in the category are considered to be similar on the basis that they have common structures of a lithium ion varying only by the length of the fatty acid chain and the presence of unsaturated and/or hydroxyl functional groups. As a result, it is expected that the substances will have similar, predictable properties. REACH Annex V, Entry 9, groups fatty acids and their potassium, sodium, calcium and magnesium salts, including C6 to C24, predominantly even-numbered, unbranched, saturated or unsaturated aliphatic monocarboxylic acids. Provided that they are obtained from natural sources and are not chemically modified, the substances included in REACH Annex V, Entry 9 are exempt from registration, unless they are classified as dangerous (except for flammability, skin irritation or eye irritation) or they meet the criteria for PBT/vPvB substances. The fatty acid components of the category members are therefore not expected to be hazardous. As all category members are lithium salts, any toxicity is expected to be driven by the lithium ion. Due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, the repeated dose toxicity is expected to be similar across the category.
Although fatty acids C18 (unsaturated) lithium salts is not in the list of substances being registered, this substance falls within the definition of the lithium salts of fatty acids C14-C22 category (see Appendix 1 – Category Justification Document) by virtue of its chemical structure and therefore read across from data on fatty acids C18 (unsaturated) lithium salts to other members of the category is considered to be justified (see below).
A key subacute toxicity and reproductive toxicity screen, using the OECD 422 study design, was conducted in rats on fatty acids C18 (unsaturated) lithium salts via dermal administration. The test material was administered at dose levels of 0, 100, 300 and 1000 mg/kg bw/day nominal, equating to 111.25, 345 and 1089.75 mg/kg bw/day by analysis, and were based on local dermal effects from a dose range finding study. There was a 2-week post-dose observation period for satellite high dose level and control groups. No systemic toxicity directly related to the administration of the substance was observed, although dose-related local effects were seen in the skin of treated animals in the 300 and 1000 mg/kg bw/day groups. Since the highest dose of 1089.75 mg/kg bw/day was essentially equivalent to a ‘limit dose’ and was considered to be the systemic NOAEL, this lithium fatty acid salt is not considered to be systemically hazardous. A local NOAEL of 111.25 mg/kg bw/day was determined due to dermal changes seen at higher concentrations.
A number of supporting subacute or subchronic toxicity studies by oral or dermal administration on greases containing ca 5- 8% lithium 12-hydroxystearate in base oil have been published. These studies gave NOAEL levels between 500 and 2000 mg/kg bw/day of the grease. However, it should be noted that these greases also contained other additives and full experimental and analytical details were not presented. Therefore they can only provide an indication of potential toxicity rather than definitive NOAELs for the category of lithium fatty acid salts. Nevertheless, the results confirm the low toxicity potential for these substances.
Fatty acid lithium salts would be expected to dissociate into fatty acid anions and lithium cations. Since the fatty acid anions are not considered hazardous as described in the preamble to this endpoint and as in the category justification document, focus can be placed on the lithium cation as a potential toxicant. In humans, inorganic lithium salts (e.g. carbonate, acetate, sulphate) have been used for decades in psychiatric therapy for the treatment of bipolar disorder. These salts dissociate in biological fluids to yield the acid anions and the therapeutically active lithium cations. Like the fatty acid anions, the inorganic acid anions are considered not to be hazardous to humans. Because the source of ionic lithium is not relevant to its physiological activity, read across with respect to systemic toxicity is fully justified without restriction.
In case of long-term human treatment, the recommended dose is 450 to 900 mg/day of e. g. lithium carbonate, corresponding to a therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. Based on experience with long-term application of lithium carbonate in humans, there is no evidence that lithium is of concern with respect to repeated dose oral toxicity at the therapeutic doses indicated. The No Observed Adverse Effect Level (NOAEL) for the lithium fatty acid salts in the category for repeat dose toxicity by the oral route is therefore based on human data and can be calculated in two ways that complement each other.
One option is based on the therapeutic serum concentrations of 0.5 to 1.0 mmol lithium/L and the extracellular fluid (ECF) volume. Lithium has a large volume of distribution of 0.6 - 0.9 L/kg (42 L – 63 L for a 70 kg adult). It is distributed throughout the body water both extra- and intracellularly. Lithium shifts into the intracellular compartments of cells because of its large volume of distribution. Although in long-term use, the intracellular concentration increases, the intracellular concentration is not reflected by the plasma level which measures only the extracellular fluid concentration. Therefore, a desired concentration of 1 mmol/L of lithium is expected to be sustained and reflected in the extracellular fluid (ECF) only and not in the intracellular fluid. Thus, the volume considered is of the ECF only which consists of plasma, interstitial fluid (spaces between cells) and transcellular fluid (lymph, cerebrospinal fluid, synovial fluid, serous fluid, gastrointestinal secretions) and is typically 15 L (reported in different references to be between 14 – 19 L (for 70 kg adult)). Based on this data the derived NOAEL (considering a lithium concentration of 1 mmol/L and an ECF volume of 15 L) is 1.5 mg lithium/kg bw/day, equivalent to 50.68 mg/kg bw/day of lithium myristate (lithium myristate contains 2.96% lithium). Of the lithium fatty acid salts in the category, the myristate has the lowest number of carbon atoms (14) and hence the highest proportion of lithium. This represents the lowest NOAEL for the category and can be used for all the higher carbon chain category substances. This NOAEL value can be considered as a conservative value as it is based on a bioavailable dose in humans after absorption and on a smaller volume than its actual distribution volume.
An alternative way to calculate an oral NOAEL for lithium myristate is also based on data taken from the routine long-term treatment of bipolar disorder. Instead of calculating the NOAEL from the therapeutic serum concentration of lithium, the lithium myristate oral NOAEL can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: i.e. 450 to 900 mg lithium carbonate/day (corresponding to the desired sustained concentrations of 0.5 -1 mmol lithium/L in blood/serum). When converting the oral dose levels of 450 to 900 mg lithium carbonate/day to bodyweight based on a 70 kg human, the following values are obtained: 40.9 to 81.8 mg lithium myristate/kg bw/day. These values represent an optional NOAEL for lithium myristate for the oral route of administration.
Under both methods of calculation, the values obtained are in same order of magnitude and similar to one another. As a worst–case value, an oral NOAEL for repeated dose toxicity for lithium myristate of 40.9 (rounded to 41) mg/kg bw/day was chosen. Further, this value can be used as a starting value for route-to-route extrapolation from the oral repeated dose toxicity to the dermal and inhalation routes as necessary.
In another weight of evidence (Trautner, 1958), a 2-year study in rats administered lithium chloride in drinking water, resulted in a NOAEL of 13.9 mg lithium/kg bw/day. This result is higher than the human NOAEL derived (1.2 mg lithium/kg bw/day). Giving preference to human data, to the worst-case result, and to the most reliable data, the oral NOAEL value determined is 1.2 mg lithium/kg bw/day corresponding to 41 mg lithium myristate/kg bw/day.
The experimental results from the repeated dose dermal toxicity study on fatty acids C18 (unsaturated) lithium salts gave a NOAEL of 1089.75 mg/kg bw/day applied to the skin (equivalent to 26.26 mg lithium/kg bw/day) but the degree of absorption was not quantified. If a default absorption of 10% is assumed, then the systemic NOAEL is 2.62 mg lithium/kg bw/day. Again this is not significantly different to the human NOAEL of 1.2 mg lithium/kg bw/day as demonstrated above (with no requirement for an oral to dermal route extrapolation Assessment Factor).
The results from this study also permitted consideration of long term local effects on the skin. The NOAEL for this effect was 111.25 mg/kg/day, which converts to 0.86 mg/cm2based on the area of rat skin exposed in the subacute study (average weight of the rats in the study was 311g, the body surface area was calculated as being approximately 9.1 x bw(g)0.66, and the approximate surface area exposed was 10%).
All of the above data support a NOAEL based on human data for the lithium ion.
On the basis of the category justification for the C14 to C22 fatty acid lithium salts and supporting data, the lack of systemic toxicity when C18 (unsaturated) lithium salts was administered to rats in a subacute OECD 422 study can be read across to other members of the category, and no classification for specific target organ toxicity is required.
The human data on serum blood concentrations of lithium ion following long term therapeutic treatment with lithium carbonate for bipolar disease (see above) is protective of human exposure and sufficient to determine a human NOAEL and DNEL. Hence there is no scientific justification for conducting a subchronic toxicity study with a lithium fatty acid salt within the category. Such a study will not provide any further information on lithium ion toxicity that is not already available from human exposure. Thus the Annex IX requirement for a subchronic toxicity study is waived in accordance with Annex XI.
Trautner, E. M.; Pennychuik, P. R., Morris, R. J. H., Gershon, S., Shankley, K. H. (1958). The effects of prolonged subtoxic lithium ingestion on pregnancy in rats. Austral J Exp Biol. 1958;36:305-22.
Not classified for STOT systemic. No toxicologically significant adverse effects observed.
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