Lithium neodecanoate

Endpoint summary

Description of key information

No repeated dose toxicity study with lithium neodecanoate is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties lithium and neodecanoate.

In relevant and reliable oral repeated dose toxicity studies as well as supporting studies for the moiety neodecanoate, there were no toxicological findings reported. For the moiety lithium, a NOAEL for long-term oral toxicity of 6.43 mg lithium carbonate/kg bw/ day corresponding to 1.2 mg Li/kg bw/day was calculated based on human data obtained from long–term routine treatment of bipolar disorder with lithium carbonate. 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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No repeated dose toxicity study with lithium neodecanoate is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties lithium and neodecanoate

Lithium

Repeated oral toxicity

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.

 

In another weight of evidence (Trautner, 1958), a 2-year study in rat administered with 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 worst-case result, and to the most reliable data the NOAEL value determined is 1.2 mg lithium/kg bw/day corresponding to 6.43 mg lithium carbonate/kg bw/day.

Repeated dermal toxicity

Due to the chemical properties of lithium carbonate, the dermal absorption is considered to be very poor and therefore a dermal toxicity study with repeated dosing is not required and was waived. For CSA requirements a NOAEL for long-term dermal exposure was calculated. A NOAEL dermal of 64.3 mg lithium carbonate/kg bw/day was calculated based on the NOAEL long term oral of 6.43 mg lithium carbonate/kg bw/day and 10 % absorption through the skin (worst-case).

 

Neodecanoate

Repeated dose toxicity, oral:

Seven male and seven female rats were exposed to 0; 10; 30; 100, or 300 mg/kg/day propanoic acid, 2,2-dimethyl- (CAS# 75-98-9) by oral gavage for 28 consecutive days (Shell Research Ltd., 1990). No treatment related changes were observed in body weight, food intake, haematology, or histopathology. The only clinical signs seen in this study were a shaking of heads, sneezing, dark nasal discharge, immediately after dosing 100 and 300 mg/kg/day. This behaviour could result from a mild irritant effect of the volatile acidic test compound. Slight increase of alkaline phosphatise, cholesterol and bilirubin levels at the 100 and 300 mg/kg/day dose levels, and slight increase of alkaline phosphatise and cholesterol levels in the plasma of females at the 30 mg/kg/day dose level. Increase in kidney and liver weight was observed in the 300 mg/kg/day group. None of these changes correlated with histopathological effects. These findings were considered adaptive changes and not indicative of a treatment-related adverse effect. The no observed adverse effect level (NOAEL) in this study was 300 mg/kg.

 

Five male and five female rats were exposed to 0; 10; 55; or 300 mg/kg/day fatty acids, C9-C13 neo (CAS# 68938-07-8) by oral gavage for 28 consecutive days (Shell Internationale Petroleum Maatschappij, 1994). There were no mortalities. Increased salivation was observed after dosing in rats receiving 300 mg/kg. No treatment related changes were observed in body weight, food consumption, haematology, or clinical chemistry. In males receiving 300 mg/kg, kidney weight increased and necropsy revealed an abnormal appearance of the kidney. A dose-related hyaline droplet was noted in males at all treatment levels. The findings in the kidney of the treated males are species and sex specific and not considered relevant to humans. The NOAEL in this study was 300 mg/kg.

 

Repeated dose toxicity, dermal

In a repeated-dose dermal study, neodecanoic acid was applied repeatedly (once daily for 10 applications with a rest period on days 5 and 6) to the skin of rabbits at doses of 0.5 or 2.5 ml/kg (400 or 2280 mg/kg/day).  All animals survived the exposure.  Wheezing was noted in one animal at the 0.5 ml dose level.  Animals at the lower dose level generally showed an overall body weight gain while those at the high level showed terminal weight losses.  The low level animals generally showed slight erythema and moderate atonia and desquamation following the first or fourth application and during the remainder of the study.  At the high level, moderate erythema and moderate or marked atonia and desquamation were present in all animals.  In addition, slight edema was present following the fifth application and slight fissures or cracks were observed in several animals following the last seven applications.  The exposed skin also became hypersensitive to the touch.  There were no indications of systemic toxicity attributed to exposure.

 

A repeated dose dermal toxicity study was conducted for propanoic acid, 2,2-dimethyl- (CAS# 75-98-9) in male rabbits (Hazelton Laboratories Inc., 1964). Test material in isopropyl alcohol solution was repeatedly applied to the shaved intact skin of albino rabbits 5 days/week for two weeks (for a total of 10 applications) at doses of 30 or 300 mg/kg/day. Slight to moderate irritation at the low dose and moderate to marked irritation at the high dose was observed. Slight or moderate erythema, atonia, and desquamation were seen at the low dose. At the high dose, skin irritation consisted of moderate erythema, slight to marked edema, moderate or marked atonia and desquamation. Some dermal necrosis at the site of application was seen in three rabbits and persisted throughout the study. Control animals that received only the solvent (isopropyl alcohol) showed slight irritation. There were no signs of systemic toxicity attributable to dermal absorption of propanoic acid, 2,2-dimethyl-. The NOAEL for systemic toxicity in this study was 300 mg/kg.

 

Carboxylic acid, C6-8 neo (CAS# 95823-36-2) was applied at 55.4 mg/kg and 553.7 mg/kg to the shaved intact skin of rabbits for 10 applications (Hazleton Laboratories, Inc., 1964). No treatment related effects were observed on behaviour of clinical signs during the in-life phase of the study. Gross pathology of the animals in all dose groups did not reveal any abnormalities. Repeated application of carboxylic acid C6-8 neo did produce marked skin irritation with some dermal necrosis at the site of application in the high dose group. Since no systemic effects were observed in this study, the NOAEL for systemic effects following subchronic dermal application of carboxylic acid, C6-8 neo was 553.7 mg/kg.

Members of the Neo acid C5 to C28 Category have a low order of toxicity under conditions of repeat exposure by oral and dermal routes. In addition, they display a consistent degree of subchronic toxicity by either oral or dermal route of exposure. No classification for repeated dose toxicity is indicated according to the classification, labelling, and packaging (CLP) regulation (EC) No 1272/2008.

 

Lithium neodecanoate

Since no repeated dose toxicity study is available specifically for lithium neodecanoate, information on the individual moieties lithium and neodecanoate will be used for the hazard assessment and when applicable for the risk characterisation of lithium neodecanoate. For the purpose of hazard assessment of lithium neodecanoate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation.

In case of neodecanoic acid in lithium neodecanoate, the NOAEL of 75 mg/kg bw/day for the reproductive toxicity will be used. In case of lithium the NOAEL of 1,21 mg Li/kg bw/day derived from human data, repeated dose toxicity via oral route will be used.

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies for the moiety neodecanoate, there were no toxicological findings reported in oral toxicity studies. For the moiety lithium, a NOAEL for long-term oral toxicity of 6.43 mg lithium carbonate/kg bw/ day corresponding to 1.2 mg Li/kg bw/day was calculated based on human data obtained from long–term routine treatment of bipolar disorder with lithium carbonate.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.

According to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptions lithium neodecanoate does neither have to be classified and has no obligatory labelling requirement for repeated oral toxicity nor for specific target organ toxicity after repeated exposure (STOT RE).