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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Toxicokinetic Assessment of 2-phosphonobutane-1,2,4-tricarboxylic acid
Type of information:
other: Toxicokinetic Assessment of 2-phosphonobutane-1,2,4-tricarboxylic acid
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
2-phosphonobutane-1,2,4-tricarboxylic acid
EC Number:
253-733-5
EC Name:
2-phosphonobutane-1,2,4-tricarboxylic acid
Cas Number:
37971-36-1
Molecular formula:
C7H11O9P
IUPAC Name:
2-phosphonobutane-1,2,4-tricarboxylic acid

Results and discussion

Applicant's summary and conclusion

Executive summary:

Toxicokinetic Assessment of 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTC)


General


PBTC 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, PBTC is a good corrosion inhibitor for carbon steel. Moreover, the adsorption of the PBTC anion on inorganic particles suspended in water results in a negative charge on their surfaces and thus in an improvement in dispersibility. This is why neutralized PBTC is used as a dispersion agent / deflocculation agent for inorganic slurries and slips. PBTC is manufactured only as ca. 50% aqueous solution.


 


Toxicological Profile of  2-phosphonobutane-1,2,4-tricarboxylic acid (“PBTC”)


In aqueous media, PBTC and Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate (“PBTCNa4”) dissociate into the corresponding anion (2-phosphonatobutane-1,2,4-tricarboxylate ion) and the sodium ion and hydrogen ion (proton), respectively. The toxicological properties of PBTC and PBTCNa4 are thought to be an effect of the phosphonato-1,2,4-tricarboxylate 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.


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


PBTC (ca. 50% aqueous solution) was tested for acute oral toxicity in rats after a single dosage given by gavage of 5 mL/kg bw (equivalent to about >6500 mg/kg bw  or > 3250 mg/kg bw active ingredient). During 14 days of observation, no mortality and no intoxication symptoms were observed (Löser, 1979). The study result is supported by an acute toxicity study performed with PBTCNa4 (32.6% aqueous solution) in rats (Bomhard, 1990). The test substance 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.


In conclusion, the LD50 (oral, rat) of PBTC is >3250 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, 1990).


In conclusion, the LD50 (dermal, rat) of PBTC is >1300 mg/kg bw. Classification for the dermal route is not appropriate because no deaths or clinical symptoms were observed.


Acute inhalation toxicity was determined for the test substance, PBTCNa4 (41.4 % aqueous solution)) as aerosol generated by a dynamic inhalation apparatus. Rats were exposed for 4 hours to the test substance in analysed concentrations of 800, 1479, 1979 mg/m³air. 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; Kimmerle, 1976).


 


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


 


Following the mentioned results, PBTC is 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.


Based on the results of the in vitro skin corrosion and irritating studies and eye irritation studies with PBTC , the test substance is not to be considered as irritating to skin, but as irritating to  eyes. (Vohr 2011a, Vohr 2011b, Wingenroth 2011a und b.


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


PBTC was found to be non-mutagenic based on several in vitro tests: in Ames tests, performed with PBTC or with PBTC4Na (performed in 2021) a Mammalian Chromosome Aberration and V79 -HPRT Forward Mutation assay, both with and without metabolic activation. (Herbold, 1979) (Herbold, 1992) (May, 1996) (Brendler; Schwaab, 1997)


A 3-months feeding study in rats (Löser; Kaliner, 1976) 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, the test substance revealed low toxicity in case of subchronic exposure.


 


In a Prenatal Developmental Toxicity Study with PBTC in rats (Renhof, 1984), 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. Thus, the NOEL value for these effects is 1000 mg/kg bw/day.


 


Toxicokinetic Analysis of 2-phosphonobutane-1,2,4-tricarboxylic acid (“PBTC”)


2-PBTC has a molecular weight of 270 g/mol. The partition coefficient of 2-phosphono-butane-1,2,4-tricarboxylic acid (logPow = -1.66 at 25°C) was determined by calculation (using the software program EPISuite v4.11). The water solubility of the PBTC(655 g/L at 25°C ) was also calculated (program WSKOW v1.14). The vapour pressure of PBTC was calculated to be 8.07 x 10-9Pa at 25 °C (calculated by EPIWIN (v4.11)). The pKs values at 20°C were calculated by software ACD ChemSketch ACD/Labs 7.00 Release, Product Version 7.05. as follows:


 


Dissociation equilibrium


pKs


H5L/H+H4L = 0.66 to = 1.5


H4L/H+H3L= 3.78 to = 4.2


H3L/H+H2L= 4.34 to = 4.54


H2L/H+HL= 4.85 to = 5.13


HL/H+L= 8.09 to = 9.09


 


In conclusion, PBTC revealed a high water solubility, 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 logPow (equivalent to a very low lipophilic character), PBTC is not likely to penetrate the first skin barrier (stratum corneum).


Thus, upon dermal contact, the bioavailability of PBTC is expected to be very low and therefore negligible.


 


Resorption after uptake via inhalation


Due to its very low vapour pressure, PBTC 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 PBTC aerosols is expected to be very 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 pKs values, PBTC is either nearly not dissociated, in the stomach (pH 1 - 3), or is 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, PBTC  is 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 logPow of -1.66 at 25°C and the BCF of 3 (calculated by BCFWIN v2.15). As the substance is 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 PBTC and PBTCNa4 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  Ames tests, 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, the substance will most likely be excreted via the kidneys in the urine.


 


Conclusion


Depending on the high water solubility and the very low logPow, PBTC is not likely to penetrate the skin barrier. Thus, upon dermal contact, the bioavailability of PBTC is expected to be very low and therefore negligible. Due to its very low vapour pressure, 2-phosphonobutane-1,2,4-tricarboxylic acid is assumed to be 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 PBTC are of no toxicological relevance 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 logPow. This is also supported by the low calculated BCF. As the substance 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, the substance is most likely excreted via the kidneys in the urine.