Silicic acid, lithium salt

Endpoint summary

Description of key information

Repeated dose toxicity studies with the structural analogue substances silicic acid, sodium salt or disodium metasilicate ranging from 4 weeks to 180 days have been conducted in rats, mice and dogs. From these studies a NOAEL (90d) of 227 - 237 mg/kg bw/day can be derived for rats. The  NOAEL (90d) for mice is 260 – 284 mg/kg bw/day. From a 2-year drinking water study in rats with lithium chloride a NOAEL of 15.3 mg lithium/kg bw/day corresponding to 219 mg silicic acid lithium salt (MR: 2.8)/kg bw/day was derived.

Additional information

No experimental repeated dose toxicity data are available for silicic acid, lithium salt. Therefore read-across was applied from soluble silicates, which have been tested for long-term toxicity via the oral route.

Ito et al. conducted a 90-day oral toxicity study similar to OECD guideline 408. Rats (5/sex/group) were administered disodium metasilicate via drinking water in concentrations of 200, 600 and 1800 ppm. No clearly treatment-related effects were found. Thus, a NOAEL of >=1800 ppm corresponding to >=227 mg/kg bw/day for males and >=237 mg/kg bw/day for females was determined.

 

In another subchronic study similar to OECD 408, male and female mice were exposed to disodium metasilicate in the drinking water at concentrations of 300, 900 and 2700 ppm (males) and 333, 1000 and 3000 ppm (females), respectively (Sawai et al., 1980). Parameters examined were mortality, body weight, urinalysis, clinical chemistry, haematology, organ weights and histopathology. The relative puitary gland weight was significantly increased in dose groups compared to the control, statistically significant only in the highest dose group. Other effects occasionally observed were single incidences and not dose-dependent. Under the test conditions, the NOAEL was determined to be 1000 ppm (corresponding to 260 – 284 mg/kg bw/day).

 

Silicic acid, sodium salt has been tested in repeated oral dose toxicity studies in rats and dogs with exposures ranging from 28 days to 180 days.

No adverse effects were observed in male and female rats administered the test substance via drinking water in concentrations of 79 and 159 mg/kg bw/day for 180 days (Smith et al., 1973). Body weight and mortality were the only parameters monitored. Statistically significant differences in body weight between dose and control groups were observed, but these were small (6% or less), not consistent and not dose related.

In a subacute study similar to OECD 407, the only treatment-related effects observed in rats were polydipsia, polyuria and soft stools at 2400 mg silicic acid, sodium salt/kg bw/day (Newberne and Wilson, 1970). Beagle dogs exhibited gross renal cortical lesions, polydipsia, polyuria and soft stools when receiving 2400 mg silicic acid, sodium salt/kg bw/day via feed for 4 weeks (Newberne and Wilson, 1970). In histopathological examination irritation of the renal tubular epithelium followed by degenerative and regenerative changes and inflammatory cell infiltration into the interstitium was noted.

 

In conclusion, repeated dose toxicity studies with disodium metasilicate and silicic acid, sodium salt revealed a low toxicity for soluble silicates.

 

Since silicic acid, lithium salt contains depending on its molar ratio 3.4 - 7% lithium (MR: 2.8 - 6.3), which is assumed to be bioavailable after ingestion, the repeated dose toxicity of lithium was also taken into consideration for assessment.

In a 2-year study by Trautner et al. (1958), rats were administered lithium chloride via drinking water in concentrations of 47, 93, 140 and 233 mg/kg bw/day (corresponding to 7.6, 15.3, 22.9 and 38.2 mg lithium/kg bw/day). In the highest dose group food and water intake fell to about 50% of the normal within a few days and the rats became progressively drowsy and asocial on the 3^rd to 5^th day. Their gate was staggering and hesitant and at resting a fine muscular tremor and trembling was observed. Simultaneously, the animals lost weight. Death occurred within 2-3 weeks. The plasma lithium levels increased steadily: mean plasma concentrations were about 3 mM when the first changes in behaviour became apparent and exceeded 8mM just before death. Except for gross dehydration and fat loss, gross pathology revealed no macroscopic damage. Some animals receiving 22.9 mg lithium/kg bw/day lost weight progressively, became ill and died within 3-4 weeks with the same systems as animals in the highest dose group. Other animals maintained a stable condition after an initial weight loss up to 20%. Later, usually within 2-4 weeks, these rats suddenly became ill, lost further weight and died. Rats of the 15.3 mg/kg bw/day dose group with a plasma lithium level of 1.5 – 2 mM no effects in health or behaviour could be determined significantly different from control animals. Thus under the conditions of the test, a NOAEL of 15.3 mg lithium/kg bw/day corresponding to 219 mg silicic acid, lithium salt (MR: 2.8)/kg bw/day was derived.

 

Human data:

Lithium is used as therapeutic drug for treatment of manic depressions and bipolar disorders. Therapeutic serum concentrations are normally about 3.5 - 5.6 mg/L (0.5 - 0.8 mM), at 10 mg/L of blood, a person is mildly lithium poisoned, at 15 mg/L they experience confusion and speech impairment and at 20 mg/L lithium there is a risk of death (Aral and Vecchio-Sadus, 2008). Toxic effects, that may appear after prolonged therapeutic use may include neurological symptoms, change in kidney function, hypothyroidism and leucocytosis.

The primary target organ for lithium toxicity is the central nervous system. Neurologic effects occurring during prolonged therapy often include minor effects on memory, motor activity and associate productivity. Hand tremor is the most common neurological side effect (Opresko, 1995).

Renal toxicity during lithium treatment includes the polyuria-polydipsia syndrome. Some patients develop nephrogenic diabetes insipidus (NDI), which in most cases seems to be reversible. However a small group of patients my develop chronic renal insufficiency (Lagerkvist and Lindell, 2002).

Lithium also produces many metabolic changes. In terms of mineral metabolism, lithium competes with sodium, potassium, magnesium and calcium and displaces them from intracellular and bone sites in this progression. Interaction of toxic metals and essential elements in the kidneys has been demonstrated in biological and toxic aspects (Aral and Vecchio-Sadus, 2008).

Gastrointestinal disturbances such as nausea or diarrhoea are other common side effects of lithium treatment (Aral and Vecchio-Sadus, 2008).

Justification for classification or non-classification

Based on available data on repeated dose toxicity from read-across or surrogate substances, silicic acid, lithium salt does not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.