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Physicochemical and toxicological data were evaluated for the toxicokinetic assessment of tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic Assessment of Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate

 

Preface

Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate ("PBTCNa4") is a highly effective scale and corrosion inhibitor. Main fields of application are the treatment of cooling and process water as well as the area of cleaning formulations.

PBTCNa4 has proved highly effective as a threshold inhibitor. Very low additions (ppm range), i.e. in far less than sub-stoichiometric concentrations (calculated on the hardness of the water), prevent the formation of scale and incrustations, respectively. Under the conditions found in cooling water, PBTCNa4 is a good corrosion inhibitor for carbon steel. Moreover, the adsorption of the 2-phosphonatobutane-tricarboxylate ion on inorganic particles suspended in water results in a negative charge on their surfaces and thus in an improvement in dispersibility. This is why PBTCNa4 is used as a dispersion agent / deflocculation agent for inorganic slurries and slips.

 

Toxicological profile of Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate ("PBTCNa4")

 

In acute toxicity testing, PBTCNa4 revealed very low acute toxicity (oral, dermal and inhalation route):

PBTCNa4 was tested for acute oral toxicity in rats. PBTCNa4 (32.6 % aqueous solution) was applied one-time by gavage to a final amount of 4000 mg/kg bw (ca. 1300 mg/kg bw active ingredient). After 14 days of observation no mortality occurred and no intoxication symptoms appeared (Bomhard E, 1990).

 

In a second study ten male rats each received a single dose of 10 - 30 ml of PBTCNa4 (41.8 % aqueous solution) per gavage. The animals were observed for mortality and clinical signs through day 14. A gross pathological examination was performed on animals which died during the observation period or were killed after termination of the study.

Signs of intoxication were ruffle fur, decreased motility, prone position, accelerated and irregular breathing, cyanosis and after 24 hours diarrhoea. The section of the animals which died revealed a diffuse reddening of the mucosa of the stomach and intestine.

For male and female rats a LD50 = 20.1 ml/kg bw (ca. 8300 mg/kg bw) was found for PBTCNa4 (Hoffmann, 1971).

In conclusion, the LD50 (oral, rat) of PBTCNa4 is ca. 8300 mg/kg bw.

 

A dose level of 4000 mg/kg bw PBTCNa4 (32.6% aqueous solution) of was examined for acute dermal toxicity in rats. No mortality occurred during 14 days of observation (Bomhard E, 1990).

In conclusion, the LD50 (dermal, rat) of PBTCNa4 is >1300 mg/kg bw.

 

Acute inhalation toxicity was determined for PBTCNa4 (41.4 % aqueous solution) as aerosol generated by a dynamic inhalation apparatus. Rats were exposed for 4 hours to PBTCNa4 (41.4 % aqueous solution) in analysed concentrations of 800, 1479, 1979 mg/m³ air. After 7 days of observations, no mortality occurred, no clinical symptoms were observed and no significant difference was found in haematological parameters which were examined before and after exposure. The LC50 can be estimated as >1979 mg/m³ (Mihail F, Kimmerle G, 1976).

In conclusion, the LC50 (inhalation, rat) of PBTCNa4 is >1979 mg/m³ (>1.979 mg/L).

 

Following the mentioned results, PBTCNa4 has not to be classified as acute toxic via inhalation as at the highest achievable concentration (1979 mg/m³) no clinical symptoms were observed and no significant difference was found in haematological parameters which were examined before and after exposure.

  

For the evaluation of the skin corrosion/irritating properties of PBTCNa4 an artificial 3D-skin model test according to OECD TG 431/439 was used. In these tests PBTCNa4 was neither corrosive nor irritant.

Additionally several in vivo tests with a 40-50% solution of tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate ("PBTCNa4") in rabbits are available. The test solution was applied on the inner surface on rabbit ears. In these tests PBTCNa4 was not irritating.

In an in vitro study for assessing ocular irritation of compounds using a human epithelial corneal cell model was conducted. In this test PBTCNa4 was not irritating.

Additionally an in vivo assay in rabbits equivalent or similar to OECD TG 405 is available. In this assays a 41.4 % solution of PBTCNa4 in water was used. PBTCNa4 was not irritating.

Based on the results of the skin and eye corrosion/irritation studies with PBTCNa4, PBTCNa4 is not irritating to skin or eyes. (Mihail F, Kimmerle G, 1976) (Hoffmann, 1971) (Wingenroth M, 2012).

 

A guinea pig maximisation test with PBTCNa4 (32.6% aqueous solution) did not reveal skin sensitising properties (Diesing L, 1990).

 

PBTC was found to be non-mutagenic based on three in vitro tests: An Ames tests, a Mammalian Chromosome Aberration and V79 -HPRT Forward Mutation assay, both with and without metabolic activation (Herbold B, 1979) (Herbold B, 1992) (May C, 1996) (Brendler-Schwaab S, 1997).

 

In aqueous media, PBTCNa4 and PBTC dissociate into the corresponding anion (2-phosphonatobutane-tricarboxylate ion) and the sodium ion and hydrogen ion (proton), respectively. The toxicological properties of PBTC and its tetrasodium salt are thought to be an effect of the phosphonato-carboxylate ion rather than of the sodium ion or the hydrogen ion (proton), which are normal constituents in body fluids and have no relevant toxic properties in low concentrations. Therefore a read-across between PBTCNa4 and PBTC acid is justified.

 

A 3-months feeding study in rats with technical PBTCNa4 results in a NOAEL equal or higher than 5000 ppm (equivalent to about 424 mg/kg bw/day for male rats and 632 mg/kg bw/day for female rats) (Löser E, Kaliner G, 1976). All applied doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (Na, K, Ca), Ferrum and Phosphorus were not affected. The same was proven for the kidneys by urinalyses, clinical chemistry and pathological and histopathological examinations. Gross necropsy and histological examinations did not reveal any adverse effects due to the test substance. Thus, PBTCNa4 revealed low toxicity in case of subchronic exposure.

 

In a Prenatal Developmental Toxicity Study with PBTC in rats no maternal toxicity (by means of death, weight loss, changes in appearance and behaviour), embryotoxicity or teratogenicity in respect of resorption, placenta weight, any skeletal and internal malformation was recorded up to the highest administered dose of 1000 mg/kg bw/day (Renhof M, 1984). Moreover, female mother rats were proved later to be fertile. Thus, the NOEL value for these effects is 1000 mg/kg bw/day.

 

Toxicokinetic Analysis of Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate ("PBTCNa4")

 

PBTCNa4 is solid at room temperature. The molecular weight is 358.1 g/mol. Regarding the water solubility no individual examination was performed with PBTCNa4, but it can be deviated from the corresponding parent acid PBTC by read-across that PBTCNa4 is highly water soluble. The partition coefficient of PBTCNa4 (log Pow = -5.45) was determined by calculation (using the software program EPISuite v4.10). The vapour pressure of PBTCNa4 was calculated to be 2.38 x 10E-8Pa at 25 °C (calculated by MPBPIWIN v4.10).

In conclusion, PBTCNa4 can be assumed to be highly water soluble, is very hydrophilic and has a very low vapour pressure.

 

Dermal absorption

Dermal absorption, the process by which a substance is transported across the skin and taken up into the living tissue of the body, is a complex process. The skin is a multilayered biomembrane with particular absorption characteristics. It is a dynamic, living tissue and as such its absorption characteristics are susceptible to constant changes.

The barrier properties of skin almost exclusively reside in its outermost layer, the stratum corneum, which is composed of essentially dead keratinocytes.

Upon contact with the skin, a compound penetrates into the dead stratum and may subsequently reach the viable epidermis, the dermis and the vascular network. During the absorption process, the compound may be subject to biotransformation.

The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to highly lipophilic compounds.

Depending on the high water solubility and the very low log Pow (equivalent to a very low lipophilic character), PBTCNa4 is not likely to penetrate the first skin barrier (stratum corneum).

Thus, upon dermal contact, the bioavailability of PBTCNa4 is expected to be low.

 

Resorption after uptake via inhalation

Due to its very low vapour pressure, PBTCNa4 is assumed to be toxicologically relevant for inhalation exposure primarily in the form of aerosols released.

Non-polar substances are easily resorbed by the lungs. Opposed to that, water-soluble substances are mainly excreted by the nasal and bronchiolar mucosa before reaching the alveolar region.

Thus, the bioavailability of PBTCNa4 aerosols are expected to be low after inhalation.

 

Resorption after oral uptake

After oral uptake, water as such is absorbed by the small intestine, is retained in the liver and then transported to and excreted via the kidneys. The same is for salts, other nutrients and substances that are resorbed analogously, i.e. can pass the membranes of body cells.

In the gastrointestinal tract, the degree of resorption of substances that dissociate depends on the pH value.

Based on the pKa values, PBTCNa4 is either nearly fully protonated (= PBTC) in the stomach (pH 1.3) or dissociated to a large extent in the small intestine (pH 7.6). Consequently, absorption takes place mainly in the stomach due to the pH environment.

 

Distribution and Metabolism

After resorption, PBTCNa4 and the corresponding parent acid PBTC respectively are believed to be fast distributed in the body (due to the high water solubility). Bioaccumulation is not to be assumed due to the very low log Pow (PBTC = -1.66, PBTCNa4 = -5.45) and the BCF of 3.16 L/kg wet-wt (calculated by BCFBAF v3.01). As PBTCNa4 and PBTC respectively are already highly water soluble metabolising is not necessary to achieve water soluble / excretable metabolites (phase I and II reactions are not likely). If any metabolising occurs, decarboxylating of the carboxylic acid group might be possible (as observed for acetic acid).

Thus, it is unlikely that PBTCNa4 and PBTC respectively are metabolised or degraded to more reactive (toxic) products. This assumption is supported by results obtained in oral toxicity studies and different in vitro tests. In acute and subchronic in vivo studies the toxicity was rather low. In an Ames test, a Mammalian Chromosome Aberration and V79 -HPRT Forward Mutation assay no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites or degradation products is rather unlikely.

 

Excretion

Based on molecular weight (< 500 Da) and water solubility, PBTCNa4 will most likely be excreted via the kidneys in the urine.

 

Conclusion

Depending on the high water solubility and the very low log Pow PBTCNa4 is not likely to penetrate the skin barrier in high quantities. Thus, upon dermal contact, the bioavailability of PBTCNa4 is expected to be low. Due to its very low vapour pressure, PBTCNa4 is assumed to be inhaled only as aerosols, and excreted by the nasal and bronchiolar mucosa due to its high water solubility. After oral uptake (preferably in the stomach), resorption and bioavailability of PBTCNa4 are assumed to be low due to the high water solubility and low toxicity revealed in acute and subchronic oral toxicity studies. Bioaccumulation is not to be assumed because of the very low log Pow. This is also supported by the low calculated BCF. As PBTCNa4 is highly water soluble, metabolising is not necessary to achieve water soluble / excretable metabolites and therefore the formation of more reactive (toxic) products is not likely. This assumption is supported by results obtained in acute and subchronic oral toxicity studies and different in vitro tests. Based on molecular weight and water solubility, PBTCNa4 is most likely excreted via the kidneys in the urine.

 

References

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