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Toxicokinetic Assessment of Bayhibit AM

 

General

 

Bayhibit AM is a corrosion inhibitor and an additive for industrial cleaners.

 

Bayhibit AM is produced at an EU manufacturing site (Germany) in closed systems.

 

Bayhibit AM 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, Bayhibit AM 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 Bayhibit AM is used as a dispersion agent / deflocculation agent for inorganic slurries and slips.

 

Bayhibit AM is a multi-constituent substance that contains of ca. 43% (w/w) 2-phosphonobutane-1,2,4-tricarboxylic acid ("PBTC"), ca. 49% (w/w) water and several very  low-concentrated impurities. For this reason, the main focus of this toxicokinetic statement is on toxicokinetic of 2-phosphonobutane-1,2,4-tricarboxylic acid ("PBTC") in aqueous solution. This approach is in line with OECD SIDS "PBTC" and BUA report 182 on 2-phosphonobutane-1,2,4-tricarboxylic acid. Both reports refer to the aqueous solution of PBTC (respectively Bayhibit AM) or of its sodium salts.

 

 

Toxicological Profile of Bayhibit AM

 

In acute toxicity testing, Bayhibit AM (respectively Bayhibit AM -Tetra-sodium salt, containing about 60% - 65% water) revealed very low acute toxicity (oral, dermal and inhalation route):

Bayhibit AM 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). During 14 days of observation, no mortality and no toxication symptoms were observed (Löser, 1979). The study result is supported by an acute toxicity study performed Bayhibit AM-Tetra-sodium salt (containing ca. 65% water) in rats (Bomhard, 1990). The test substance was applied one-time by gavage to a final amount of 4000 mg/kg bw. After 14 days of observation no mortality occurred and no toxication symptoms appeared.

In conclusion, the LD50 (oral, rat) of Bayhibit AM is >6500 mg/kg bw and therefore >2000 mg/kg bw.

A limit test at a dose level of 4000 mg/kg bw of the test substance Bayhibit AM-tetra-sodium salt (containing about 65% water) 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 Bayhibit AM is >4000 mg/kg bw and therefore >2000 mg/kg bw.

Acute inhalation toxicity was determined for the test substance, Bayhibit AM-tetra-sodium salt (containing about 60% water) 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 LC50can be estimated as >1979 mg/m3(Mihail; Kimmerle, 1976).

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

Following the mentioned results, Bayhibit AM 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 one skin irritation and one eye irritation study with Bayhibit AM, supported by three studies performed with the respective tetra-sodium salt of 2-phosphonobutane-1,2,4-tricarboxylic acid, the test substance is not to be considered irritating to skin or eyes. (Mihail; Kimmerle, 1977) (Mihail; Kimmerle, 1976) (Hoffmann, 1971)

A guinea pig maximisation test with Bayhibit AM-tetra-sodium salt (consisting of 64.7% water, 32.6% Bayhibit AM-tetrasodium salt, 1.3% Bayhibit AM-trisodium salt) did not reveal skin sensitising properties. (Diesing, 1990)

Bayhibit AM was found to be non-mutagenic based on four in vitro tests: An Ames tests, performed with Bayhibit AM or with Phosphonosuccinic acid (a structural analogue substance), 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 Bayhibit AM-Na salt 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). 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 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 Bayhibit AM /kg bw/day. 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 Bayhibit AM

 

Bayhibit AM is a multi-constituent, aqueous substance that is liquid at room temperature and completely miscible in water. Its main constituent (beside water) at about 43% is 2-phosphonobutane-1,2,4-tricarboxylic acid with a molecular weight of 270 g/mol. The partition coefficient of 2-phosphono-butane-1,2,4-tricarboxylic acid (logPow = -1.36 at 25°C) was determined by calculation (using the software program EPISuite v. 3.20). The water solubility of the main constituent (655 g/L at 25°C ) was also calculated (program WSKOW v1.14). The vapour pressure of 2-phosphonobutane-1,2,4-tricarboxylic acid was calculated to be 8.08 x 10-9Pa at 25 °C (calculated by EPIWIN (v3.12)). 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 ¿ = 1.5

H4L/H+H3L

= 3.78 ¿ = 4.2

H3L/H+H2L

= 4.34 ¿ = 4.54

H2L/H+HL

= 4.85 ¿ = 5.04

HL/H+L

= 8.09 ¿ = 9.09

 

 

 

In conclusion, 2-phosphonobutane-1,2,4-tricarboxylic acid revealed a high water solubility, is very hydrophilic, and has a very low vapour pressure. Moreover, it is (nearly) non-dissociated at very low pH values and is not completely dissociated at higher pH values.

The pH value of 1% aqueous solution of Bayhibit AM was determined to be 1.9, of the undiluted substance 0.0.

 

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), 2-phosphonobutane-1,2,4-tricarboxylic acid is not likely to penetrate the first skin barrier (stratum corneum).

 

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

 

Resorption after uptake via inhalation

 

Due to its very low vapour pressure,2-phosphonobutane-1,2,4-tricarboxylic acidis 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 Bayhibit AM 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, 2-phosphonobutane-1,2,4-tricarboxylic acid 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, Bayhibit AM 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 -1.36 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 2-phosphonobutane-1,2,4-tricarboxylic acid is 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 two 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.

 

Final remark on impurities

The impurities in Bayhibit AM are mainly phosphoric or phosphono carboxylic acids that are ¿ also due to the very low content - completely miscible with or soluble in water and therefore are expected to behave similar to 2-phosphonobutane-1,2,4-tricarboxylic acid in respect of absorption, distribution and excretion. Moreover their toxicological potential is also investigated by the studies described before. Thus, the impurities are not relevant for considerations on toxicokinetics of Bayhibit AM.

Conclusion

 

Depending on the high water solubility and the very low logPow 2-phosphonobutane-1,2,4-tricarboxylic acid is not likely to penetrate the skin barrier. Thus, upon dermal contact, the bioavailability of Bayhibit AM 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 Bayhibit AM are of no toxicological relevance due to the high water-solubility and low toxicity revealed in acute and subchronic oral toxicitystudies. 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. Impurities (mainly phosphoric or phosphono carboxylic acids) are regarded as not relevant for considerations on toxicokinetics of Bayhibit AM as their toxicological behaviour is expected to be similar to 2-phosphonobutane-1,2,4-tricarboxylic acid and is also covered by the available in vitro and in vivo studies with Bayhibit AM.

 

References

1. Brendler; Schwaab, 1997: Mutagenicity study for the detection of induced forward mutations in the V79-HPRT assay in vitro, Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

2. Bomhard, 1990: Bayhibit AM-Tetra-Natriumsalz Versuchsprodukt AC 4030 Untersuchungen zur akuten dermalen Toxizität an männlichen und weiblichen Wistar-Ratten [Bayhibit-AM-Tetrasodium salt product AC4030 Examination of acute dermal toxicity in male and female Wistar rats], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

3. BUA-substance report 182 (Sep 1994): 2-Phosphono-1,2,4-butantricarbonsäure, issued by the German Chemical Society (GDCh)

 

4. Diesing, 1990: Bayhibit AM-Tetra-Natriumsalz Untersuchung auf hautsensibilisierende Wirkung beim Meerschweinchen [Maximierungstest nach Magnusson und Kligman) (Bayhibit AM-tetra-sodium salt examination of skin sensitization effect in guinea pigs], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

5. ECHA, 2008:

Guidance on Information requirement and chemical safety assessment, R 7c

 

6. Goodman & Gilman¿s The Pharmacological Basis of Therapeutics

6thedition, Chapter 66, p. 1572-1573

 

7. Hawkins D.R., 1988: The importance of bioavailability in toxicity testing. In: HRC (eds.) Newer Methods in Toxicity Testing: Kinetic Monitoring, Bartham Press Ltd. London

 

8. Herbold, 1979: BAHIBIT AM Salmonella / Mikrosomen-Test zur Untersuchung auf Punktmutagene Wirkung [BAYHIBIT AM Salmonella / Mikrosome assay for point mutations], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

9. Hoffmann, 1971: Hautverträglichkeit (Kaninchenrücken) "patch test" [Skin tolerance (rabbit's back) "patch test"], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

10. Löser; Kaliner, 1976: PBS-AM Subchronische toxikologische Untersuchungen an Ratten (Fütterungsversuch über 3 Monate) [PBS-AM subchronic toxicological investigation in rats (3 months-feeding study )], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

11. Löser, 1979: Akute orale Toxizität [Acute toxicity, oral route], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

12. Marquardt, H., Schäfer S.G., McClellan R.O., Welsch, F. , 1999:

Toxicology, Academic Press

 

13. May, 1996: Prüfung exemplarisch ausgewählter Altstoffe auf eine cytogenetische Wirkung in vitro: Induktion von Chromosomenaberrationen [Examination of selected existing chemicals for cytogenetic effects in vitro: Induction of chromosomal aberrations], Herausgeber: Bundesanstalt für Arbeitsschutz, Friedrich-Henkel-Weg 1-25, 44149 Dortmund [Editor: Federal institute for occupational safety, Friedrich-Henkel-Weg 1-25, 44149 Dortmund, Germany], ISBN 3-88261-019-0

 

14. Mihail; Kimmerle, 1976: Bestimmung der Inhalationstoxizität und Untersuchung auf Haut- und Schleimhautreizung [Determination of the inhalation toxicity and examination of the skin and mucosa irritation effect], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

15. Mihail; Kimmerle, 1977: Bayhibit AM Untersuchung auf Haut- und Schleimhautreizwirkung [Bayhibit AM examination of the skin and mucosa irritation effect], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

 

16. Mutschler, E., 1986: Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie.

Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1986

 

17. OECD SIDS "PBTC" (Jul 1996),

via:http://www.inchem.org/pages/sids.html

 

18. Renhof, 1984: Untersuchung auf embryotoxische Wirkungen an Ratten nach oraler Verabreichung [Examination of embryotoxicitiy effects in rats following oral administration of Bayhibit-AM], Lanxess Deutschland GmbH. Chemiepark Leverkusen, Germany.

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