Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Assessment from available information
Adequacy of study:
key study
Study period:
August 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
toxicokinetics
Qualifier:
no guideline required

TOXICOKINETICS EVALUATION

According to the Experimental Data

Acute studies

The substance, Semi Dry Absorption (SDA) Product, was applied to laboratory animals (rat, mouse, and rabbit) during studies with different way of entry into organism (e.g. stomach, respiratory tract - nose, skin and eye).

Only mild systemic effects (piloerrection 3 hours after application) were described after single oral application of the dose level 2000 mg/kg of the substance to rats.

After single application on skin of rabbit, no irritant or corrosive effects were observed. The substance is not irritant. No symptoms of systemic toxicity were observed in rabbits after application on skin.

Examination of eye after single application of substance to the conjunctival sac demonstrated, that Semi Dry Absorption (SDA) Product, is mild irritating for eye of rabbit; the changes observed were of mild character and they were reversible (redness and chemosis of conjunctivae and lacrimation – till the 4th day of study). No corrosive effects were observed on eyes of rabbit and no clinical signs of systemic intoxication were detected.

The substance, Semi Dry Absorption (SDA) Product, elicited negative response after topical application to the mouse ear in LLNA. No clinical signs of systemic intoxication were detected in study of sensitization. The substance did not show a tendency to increase ear weight.

Long-term studies

The oral administration of the substance, Semi Dry Absorption (SDA) Product, to rats by gavage for a period of 90 consecutive days at dose levels 160, 400 and 1000 mg/kg/day affected haematological parameters. Parameters were significantly affected by treatment at the dose level 1000 mg/kg/day but had prolongated effect (was recorded after recovery period). These changes consisted of effect on red blood cells in males and females (increased levels of haemoglobine together with correlated parameters) and effects on clotting parameters in males (increased protrombin time and concentration of fibrinogen, decreased partial thromboplastin time). These changes are an indication for increased erythrocyte turnover. Effect on white blood cells (significantly increased level of granulocytes and slight increased leukocyte count) was recorded only in females also after recovery period.

Clinical biochemistry parameters were significantly affected by treatment at 1000 mg/kg/day. For males, statistically significantly decreased value of urea and decreased activity of AST were observed after application period and decreased concentration of glucose and increased levels of phosphorus and sodium ions were measured after recovery period. On the contrary in females increased concentration of calcium after application period and decreased level of total protein and creatinine after recovery period were recorded. In absence of a treatment-related distribution they were considered changes of no toxicological significance.

Histopathological examination revealed significant changes in stomach (erosions, haemorrhages or other focal changes) and in heart (haemorrhages or myocardititis). These affections were found out only in males at the highest dose level after application period and probably correlated with application of the test substance. Males of the lowest and middle groups and all groups of females showed only sporadically changes without toxicological significance.

In Reproduction/Developmental Toxicity Screening Test the following dose levels: 160, 400 and 1000 mg/kg/day were administered. The test substance Semi Dry Absorption (SDA) Product had negative effect on mating and reproduction parameters. The test substance did not affect number of pups.

Number of females achieving pregnancy, durations of mating and pregnancy, number of pups, sex ratio, average weight of litter, average body weight and postnatal development of pups were unaffected by the test substance treatment.

The test substance administered at the dose levels 160, 400 and 1000 mg/kg/day did not show toxicologically significant treatment-related effects in Prenatal Developmental Toxicity Study. Reproduction parameters were unaffected and detailed necropsy of foetuses did not reveal increase of external and visceral variations and malformations.

 

The test substance showed no genotoxic properties in the In-vivo Mammalian Alkaline Comet Assay. The test substance was administered orally at the dose levels 400, 1000 and 2000 mg/kg/day. Treatment with the test substance did not increase the tail intensity for the liver, stomach and duodenum cells.

According to the Literature Data

Calcium chloride

(component of substance Semi Dry Absorption (SDA) Product)

Toxicity

Dry calcium chloride reacts exothermically when exposed to water. Burns can result in the mouth and esophagus if humans or other animals ingest dry calcium chloride pellets.

Acute Toxicity

Inhalation of dust may cause irritation to the respiratory tract, with symptoms of coughing and shortness of breath.

Ingestion may cause serious irritation of the mucous membrane due to heat of hydrolysis. Large amounts can cause gastrointestinal upset, vomiting, abdominal pain.

Solid is mild irritant for dry skin; strong solutions or solid in contact with moist skin may cause severe irritation, even burns.

Eye irritant – can caused burns from heat of hydrolysis and chloride irritation.

Long-term toxicity

No literary data.

 

Calcium carbonate

(component of substance Semi Dry Absorption (SDA) Product)

Acute Toxicity

After inhalation of excessive concentrations of a nuisance dust, nuisance condition such as coughing, sneezing, and nasal irritation can be observed.

Ingestion – non toxic.

Is not expected to be a health hazard from skin exposure.

No information about eye contact were found, but presumed to cause mechanical irritation.

Long-term toxicity

Excessive oral doses of calcium carbonate may produce alkalosis and hypercalcemia.

 

Calcium sulphite

(component of substance Semi Dry Absorption (SDA) Product)

Acute Toxicity

Single large oral doses of sulphites produced gastro-intestinal disturbances in man. A moderate acute oral and injection toxicity was indicated in laboratory animals.

Sulfites are counted among the top nine food allergens. It may cause breathing difficulty within minutes after eating a food containing it, or migraines. Other symptoms include sneezing, swelling of the throat, and hives can be observed.

No data about reaction on skin and eye (irritation/corosion) were found.

Long-term toxicity

On repeated oral administration, the main site of toxic attack in rats, pigs and rabbits was the gastro-intestinal tract.

After inhalation - mild lung changes occurred in rats and nasal and respiratory tract effects were reported in dogs exposed repeatedly to a sodium sulphite aerosol.

Fairly low reproductive toxicity has been seen in a number of laboratory animal species exposed orally.

 

 

According to the Database Data

Calcium chloride

Acute Toxicity – animal exposure

LD50 rat oral: 1000 mg/kg

LD50 rat intraperitoneal: 264 mg/kg

LD50 mouse oral: 1940 mg/kg

LD50 mouse intraperitoneal: 210 mg/kg

Application of 2% to 10% solution to rabbit eyes after removal of the cornea epithelium, or injection into the corneal stroma, causes no permanent damage. Calcium chloride has been admin systemically to rabbits (50-500 mg/kg) to induce acidosis. This has been shown to reduce intraocular pressure temporarily.

Calcium chloride (280 mg/kg) provokes arrhytmia, heart fibrilation and death of mice.

Repeated dose toxicity – animal exposure

No data.

Acute Toxicity - human exposure

Calcium chloride has powerful irritant action on skin and mucous membranes. Erythema, peeling of facial skin, lacrimation, eye discharge, burning sensation, pain in nasal cavities occasional nose bleeding and tickling in the throat were recorded. Cases of perforation of the nasal septum have also been reported.

Injected subcutaneously or intramusculary – calcium salts are intensely irritating. Injected ionized calcium salts may cause slowing of the heart rate and sinus arrythmia; in toxic doses heart block, extrasystoles and ventricular fibrilation are discrabed.

 

Calcium carbonate

Acute Toxicity – animal exposure

LD50 rat oral: 6450 mg/kg

LD50 mouse oral: 6450 mg/kg

Acute Toxicity – animal exposure

Calcium carbonate in form of powder has no toxic effect when applied to surface of rabbit eyes. Injecting 8 mg of calcium carbonate powder into aterior chamber of rabbit caused

moderate rise of intraocular pressure lasting less than 24 hours.

Repeated dose toxicity – animal exposure

Developmental or Reproductive Toxicity: Rats were fed up to 1.25% dietary calcium carbonate for 6 weeks prior mating and during gestation; no adverse effects have been found.

Human Toxicity

A healthy, 36-year-old woman developed severe hypercalcemia several days after beginning breast-feeding her second child. During and after this pregnancy, she supplemented a high calcium diet with moderate amounts of calcium carbonate in an attempt to avoid an osteoporotic fracture that occurred while she was breast-feeding her first child. Because the metabolic changes that occur during lactacion predispose a woman to hypercalcemia, the daily recommended daily allowances for calcium should not be exceeded during breast-feeding.

The release of CO2 from bicarbonate and carbonate-containing antacids can cause belching, occasional nausea, abdominal distention and flatulence. Belching may cause exacerbation of gastroesophageal reflux.

 

Calcium sulphite

No data were found.

Conclusions:
Interpretation of results
The systemic effect (disappeared shortly after administration) was described after single oral administration of the substance Semi Dry Absorption (SDA) Product to rats. It is not possible to confirm absorption of the test substance from digestive tract. The clinical symptoms found (piloerection) could be related with total reaction of organism to application of the test substance.
After single application of test substance to the skin of rats, rabbits, systemic toxic effects were not detected – the substance obviously does not penetrate through the skin after acute exposure. Although the substance contains calcium chloride, it is not irritating to the skin. No irritation potential was found out after application on ears of mice.
The test substance is not a skin sensitizer.
After single application of the substance to conjunctival sac of the rabbit eye the local reversible effects (redness, chemosis and lacrimation) appeared – the substance is irritating to the eye (probably due to content of calcium chloride). Systemic toxic effects were not detected – the test substance does not penetrate to the body after acute eye exposure.

Based on results of 90-day study in rats it could be deduced that the test substance is absorbed from gastrointestinal tract and it is distributed throughout the body of experimental animals to relatively distant compartments (what is demonstrated by the effects on blood haematological and biochemical parameters and on urine parameters). These changes are probably caused by other main components of the test substance rather than by the calcium carbonate (which effect is instant, through the release of CO2 from carbonate-containing antacids can cause belching, occasional nausea, abdominal distention and flatulence).
Histopathological examination revealed significant changes in stomach (site of first contact) – erosions, haemorrhages and other focal change. These findings could be due to one of the test substance components - calcium chloride (Calcium chloride has powerful irritant action on skin and mucous membranes).

Results of Reproduction/Developmental study in rats revealed that the test substance Semi Dry Absorption (SDA) Product did not affect reproduction organs of parents and did not impair the fertility and development of pups. There was no evidence that the substance could get through placenta and affect the embryo or foetus.

The test substance did not show a teratogenic effect after evaluation of results of Prenatal Developmental Toxicity Study.

The In-vivo Mammalian Alkaline Comet Assay showed no genotoxic properties of the test substance.

Absorption of Semi Dry Absorption (SDA) Product from the digestive system and their distribution throughout the body of experimental animals to relatively distant compartments was confirmed during oral repeated dose studies, but it could be presumed, that the substance is not able to get through placenta and affect the embryo or foetus.

No information was found about excretion of Semi Dry Absorption (SDA) Product.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There was an assessment performed from available information without experimental toxicokinetics.

Toxicokinetics of the test substance was evaluated from three sources:

Experimental data (unpublished)

Free literature data from internet

Data from toxicological databases (STN - Scientific and Technical Information Network).

 

The systemic effect (disappeared shortly after administration) was described after single oral administration of the substance Semi Dry Absorption (SDA) Product to rats. It is not possible to confirm absorption of the test substance from digestive tract. The clinical symptoms found (piloerection) could be related with total reaction of organism to application of the test substance.   

After single application of test substance to the skin of rats, rabbits, systemic toxic effects were not detected – the substance obviously does not penetrate through the skin after acute exposure. Although the substance contains calcium chloride, it is not irritating to the skin. No irritation potential was found out after application on ears of mice.

The test substance is not a skin sensitizer.

After single application of the substance to conjunctival sac of the rabbit eye the local reversible effects (redness, chemosis and lacrimation) appeared – the substance is irritating to the eye (probably due to content of calcium chloride). Systemic toxic effects were not detected – the test substance does not penetrate to the body after acute eye exposure.

 

Based on results of 90-day study in rats it could be deduced that the test substance is absorbed from gastrointestinal tract and it is distributed throughout the body of experimental animals to relatively distant compartments (what is demonstrated by the effects on blood haematological and biochemical parameters and on urine parameters). These changes are probably caused by other main components of the test substance rather than by the calcium carbonate (which effect is instant, through the release of CO2 from carbonate-containing antacids can cause belching, occasional nausea, abdominal distention and flatulence).

Histopathological examination revealed significant changes in stomach (site of first contact) – erosions, haemorrhages and other focal change. These findings could be due to one of the test substance components - calcium chloride (Calcium chloride has powerful irritant action on skin and mucous membranes).

 

Results of Reproduction/Developmental study in rats revealed that the test substance Semi Dry Absorption (SDA) Product did not affect reproduction organs of parents and did not impair the fertility and development of pups. There was no evidence that the substance could get through placenta and affect the embryo or fetus.

 

Absorption of Semi Dry Absorption (SDA) Product from the digestive system and their distribution throughout the body of experimental animals to relatively distant compartments was confirmed during oral repeated dose studies, but it could be presumed, that the substance is not able to get through placenta and affect the embryo or foetus.

No information was found about excretion of Semi Dry Absorption (SDA) Product.