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Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, inhalation and dermal absorption occur. Widely distribution within the water compartment of the body after systemic absorption is because of lipophilicity of the test substance is not expected. Based on its log Pow the test substance is not considered to accumulate. The test substance might be metabolized after absorption. Excretion predominantly via the urine is expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.


Additionnal information

The test substance is a slightly yellow limpid liquid at 20°C under atmospheric pressure with a molecular weight of 300 g/mol and a water solubility of 791 mg/L at 20 °C. The substance has a low vapour pressure of 2.5E-3 Pa at 25 °C and the log Pow is -0.06 at 25 °C.


The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2017).



In general, low molecular weight (MW≤500) and hydrophilic (log Pow values <0) are not favourable for membrane penetration and thus absorption. The molecular weight of the test substance with 300 g/mol is favouring oral absorption of the compound. This is supported by the determined log Pow value of -0.06, being advantageous for oral absorption. Moreover, water-soluble substances will readily dissolve in the gastrointestinal fluids which favour oral absorption. Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

In an acute oral toxicity study conducted with the test substance in rats (Weisz, 2017) at 2000 mg/kg body weight. In a stepwise procedure three additional groups of three females were dosed at 300 and 50 mg/kg body weight as active ingredient. All animals treated at 2000 and 300 mg/kg were found dead on Day 2. At 2000 mg/kg, lethargy, hunched posture, abnormal gait, piloerection and/or ptosis were noted on Day 1. At 300 mg/kg, hunched posture and piloerection were noted on Day 1. At 50 mg/kg, hunched posture and/or piloerection were noted on Day 1. At 2000 and 300 mg/kg, abnormalities of the stomach (irregular surface, hardened and/or watery clear contents (only 300 mg/kg)) were found at macroscopic post-mortem examination. Under the test conditions of this study, the oral LD50 value of Phosphonium, tetrakis (hydroxymethyl)-sulphate (2:1); polymer with urea in Wistar rats was established to be within the range of 50 -300 mg/kg body weight (as active ingredient).

In a 13 week toxicity study performed according to OECD 408 guideline and in compliance with GLP (Dinsha, 2013), Tetrakis (hydroxymethyl) phosphonium chloride, oligomeric reaction products with urea (THPC-urea), an analogue of the registered substance was administered continuously by gavage to three groups, each of ten male and ten female Wistar rats, for 90 consecutive days, at dose levels of 6.54, 13.1 and 39.2 mg/kg bw/day (incorporating a correction factor for 65.4% purity). A control group of ten males and ten females was dosed with vehicle alone (Distilled water). Two recovery groups, each of ten males and ten females, were treated with the high dose (39.2 mg/kg bw/day AI) or the vehicle alone for 90 consecutive days and then maintained without treatment for a further twenty-eight days.

No treatment-related effects were detectedon Behavioural Assessment, Functional Performance Tests, Sensory Reactivity Assessments, Body Weight, Food Consumption, Oestrous Cycle Assessments, Ophthalmoscopy, Haematology, Urinalysis, Organ Weights and sperm analysis. However, the males treated with 39.2 mg/kg bw/day AI showed increases in alanine aminotransferase and aspartate aminotransferase levels compared to controls.Females treated with 39.2 mg/kg bw/day AI showed a reduction in total protein, albumin and calcium levels, with the reductions in albumin and calcium extending into the 13.1 mg/kg bw/day AI dose group. Calcium values were also lower at the lowest treatment level. Males treated at all dose levels also showed a reduction in total protein and calcium levels.

At necropsy,mottled appearance and pallor of the liver was recorded for three males treated at 39.2 mg/kg bw/day AI. One female treated with 39.2 mg/kg bw/day AI also showed a mottled appearance of the liver. No further treatment-related macroscopic abnormalities were detected.

Histopathological findings show treatment-related changes in the liver.Hepatocellular eosinophilic cytoplasmic vacuoles were observed in animals of either sex treated with 13.1 and 39.2 mg/kg bw/day AI, and males treated with 6.54 mg/kg bw/day AI. Among these animals, hepatocellular single cell necrosis andmicrovesicular hepatocellular degeneration were observed in males treated with 13.1 mg/kg bw/day AI and animals of either sex treated with 39.2 mg/kg bw/day AI. In the recovery animals, hepatocellular eosinophilic cytoplasmic vacuoles were still present for animals of either sex treated with 39.2 mg/kg bw/day AI. Increased incidence and/or severity of inflammatory cell foci were recorded in animals of either sex treated with 39.2 mg/kg bw/day AI. This was not evident in the recovery high dose animals.One male and three females treated with the high dose level showed minimal periportal hypertrophy observed in hepatocytes not containing eosinophilic vacuole, and minimal bile duct proliferation was recorded in three males and two females treatedwith 39.2 mg/kg bw/day AI. This was not evident in the recovery high dose animals.

Under the test conditions of this study, the administration of Tetrakis (hydroxymethyl) phosphonium chloride, oligomeric reaction products with urea by oral gavage for a period of ninety consecutive days resulted in treatment-related effects at all dose levels. The effects were confined to blood chemical changes and microscopic changes detected in the liver. Based on the results of this study, a ‘No Observed Adverse Effect Level’ (NOAEL) was established at 6.54 mg/kg bw/day active ingredient for males and 13.1 mg/kg bw/day active ingredient for females.

In a teratogenic study (L. Barker, 1992), according to OECD 414 and in compliance with GLP, pregnant rabbits received consecutive daily oral doses of Tetrakis (hydroxymethyl) phosphonium chloride oligomeric reaction products with urea (THPC-urea), an analogue of the registered substance at dose levels of 6.5, 19.5 and 65 mg Active Ingredient (AI)/kg bw/day in water from the 7th to 19th day of gestation. The animals employed were a New Zealand White strain rabbit and 16 pregnant rabbits were used in each group. A similar group of 16 rabbits given the vehicle (distilled water) by the same route and over the same period served as controls. There were no treatment related mortalities at any dose tested. Maternal effects were noted at 65 mg AI/kg bw/day and included coloured urine (11/16), reduced body weight gains and reduced food consumption. No toxicological significant changes in foetal weight were noted. Decreased mean litter weight was observed at 65 mg AI/kg bw/day, but was considered to be due to a lower number of foetuses due to increased pre-implantation loss. No clear treatment related changes in the number of foetuses showing external, visceral or skeletal malformations were noted. However, at 65 mg AI/kg bw/day, one foetus showed retinal dysplasia, absent forelimb phalanges, brachydactyly and fused sternebrae. At 19.5 mg AI/kg bw/day, one foetus presented multiple malformations including open eye, Iris malformed, Eye socket reduced in size and zygomatic arches malformed. In the high dose groups, an increased incidence (statistically significant) in foetuses showing external and visceral variations was noted, and included abnormal common carotid and agenesis of the intermediate lobe, in addition, a slightly increased incidence of bilateral and unilateral insertion of pelvic girdle on the second sacral vertebra was noted at 19.5 and 65 mg AI/kg bw/day. The slightly increased incidence of extra thoraco-lumbar ribs noted at all dose levels tested was considered to be due to a low incidence in control animals, when compared to historical control data.

Under the test conditions of this study, the NOAEL (maternal): 19.5 mg AI/kg bw/day based on decreased body weight and food consumption in females and the NOAEL (teratogenicity): 19.5 mg AI/kg bw/day based mainly on eye and/or limb malformations.

The malformations (oligosyndactyly, microphtalmia and retinal displasia (1 foetus/65 mg AI/kg bw/day), and oligosyndactyly, brachymelia, microphtalmia and retinal dysplasia (4 foetuses/97.5 mg AI/kg bw/day) observed in a range finding study in rabbits (See: tox. repro V2 1991 Bark) were considered to be secondary non-specific effects (for explanation, see summary in the Head Chapter of this section).

The developmental toxicity study in the rabbit is judged as acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rabbit.



The dermal uptake of liquids and substances in solution is generally expected to be higher than that of dry particles. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for the molecular weight level of the test substance dermal uptake can be seen to be moderate. The log Pow value of the test substance is not optimal for dermal absorption. For dermal uptake sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, if the water solubility is between 100 and 10000 mg/L the dermal absorption is anticipated to be moderate to high (ECHA, 2014). Data from an acute dermal toxicity limit test (Weisz, 2017) at 2000 mg/kg bw on the test substance revealed no particular signs of toxicity, except very slight erythema which disappeared 14 days after the treament period. No mortality or gross abnormal findings were also observed. Against the background of the demonstrated toxic potency after oral exposure, the dermal toxicity seems to be of lower magnitude, presumably due to a much lower dermal uptake in contrast to oral absorption.



Tetrakis [hydroxymethyl]phosphonium chloride oligomeric reaction products with urea, an analogue of the test substance has a low vapour pressure of 0.0025 Pa at 25 °C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible.



Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Since the test substance is hydrophilic (log Pow -0.06) the distribution into cells is not likely and the intracellular concentration may not be higher than extracellular concentration. Substances with log P values of -0.06 would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

In the the 90 day rat toxicity study provided evidence of systemic distribution of the substance or its metabolites with microscopic findings in the liver. These changes supported this assumption that liver is the target organ.



No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. There was evidence for differences in genotoxic potencies due to metabolic changes in elicited in vitro genotoxicity tests. Two studies performed on genotoxicity in L5178Y (Mouse Lymphoma Assay and Micronucleus in vitro) were positive with and without metabolic activation (Chevallier, 2017). Another genotoxicity study (Ames) was negative (Vers, 2015).


Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol) and the water solubility of the molecule are properties favouring excretion via urine. Coloured urine described in the teratogenic study confirmed the excretion of the test substance and/or its metabolites via the urine.



ECHA (2017): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, HelsinkiLiterature

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