Ethyltriphenylfosfonium bromide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Objective of study:

toxicokinetics

Principles of method if other than guideline:

The data used for the toxicokinetic assessment are derived from measured physical chemical endpoints as well as from a single dose oral and dermaltoxicity study and a 28-day repeated dose toxicity study.

Conclusions:

Based on its physical/chemical properties, absorption factors for TEP are derived to be 50% (oral), 100% (inhalation) and 100% (dermal). The
dermal absorption is considered to be overestimated as it is generally accepted that dermal absorption is lower compared to oral absorption.
Absorbed TEP might be metabolized and is expected to distribute widely throughout the body; TEP is not expected to accumulate or to be retainedin the body and excretion will be mainly via urine.

Reference 2

Endpoint:

dermal absorption

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Principles of method if other than guideline:

The data used for the toxicokinetic assessment are derived from measured physical chemical endpoints as well as from a single dose oral and dermaltoxicity study and a 28-day repeated dose toxicity study.

Conclusions:

Based on its physical/chemical properties, absorption factors for TEP are derived to be 50% (oral), 100% (inhalation) and 100% (dermal). The
dermal absorption is considered to be overestimated as it is generally accepted that dermal absorption is lower compared to oral absorption.
Absorbed TEP might be metabolized and is expected to distribute widely throughout the body; TEP is not expected to accumulate or to be retainedin the body and excretion will be mainly via urine.

Description of key information

Experimental toxicokinetic studies are not available for Ethyltriphenylfosfonium bromide. Therefore, the toxicokinetic behaviour is assessed based on its physico-chemical and toxicological properties.

100% absorption by inhalation and via the gastrointestinal (GI) tract and 50% absorption by dermal exposure is assumed as worst case default for chemical safety assessment.

Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of Ethyltriphenylfosfonium bromide, are not available. Therefore, the toxicokinetic behaviour is assessed based on its physico-chemical and toxicological properties.

Absorption:

There are several studies available in which the systemic effects of Ethyltriphenylfosfonium bromide were investigated.

In an oral repeated dose toxicity study (28-days) according to OECD guideline 407, GLP compliant, administration of 15, 60 and 250 mg/kg bw Ethyltriphenylfosfonium bromide caused, beside changes in clinical biochemistry parameters and in organ weights, microscopic findings in several animals at 250 mg/kg/day in the stomach and thyroid gland consisting of hypertrophy of the parietal cells, foveolar hyperplasia and single cell necrosis in the glandular stomach, and diffuse hyperplasia/hypertrophy of the follicular cells of the thyroid gland. A No Observed Adverse Effect Level (NOAEL) for Ethyltriphenylfosfonium bromide of 60 mg/kg/day was established. In an oral acute toxicity study according to OECD guideline 423, GLP compliant, a LD50 > 300 < 500 mg/kg bw was determined. Macroscopic post mortem examination of the female (200 mg/kg body weight) that was found dead on day 2 revealed thickening of the limiting ridge at the stomach. No abnormalities were found at macroscopic post mortem examination of the remaining animals. In a dermal acute toxicity study according to OECD guideline 402, GLP compliant, a LD50 > 2000 mg/kg bw was determined. One male and one female were found dead at Day 2 of treatment. Dark red discolouration of the lungs was found in the male that died during the study, at macroscopic post mortem examination. No abnormalities were found at macroscopic post mortem examination of the female that died during the study and of the surviving animals at termination. Lethargy, tremor, flat or hunched posture, uncoordinated movements, quick or slow breathing, shallow respiration, piloerection, salivation, chromodacryorrhoea, ptosis and/or hypothermia were noted in all animals. The surviving animals had recovered from the symptoms by Day 5. Erythema, scales, scabs and/or scars were seen in the treated skin.

Additionally, in an eye irritation study conducted according to OECD guideline 405, GLP compliant, Ethyltriphenylfosfonium bromide resulted in effects on the cornea, iris and conjunctivae and was classified according to GHS criteria Category 1 to cause severe damage to the eye. No skin irritation was caused by 4 hours exposure to Ethyltriphenylfosfonium bromide in a in vivo skin irritation study according to OECD Guideline 404, GLP compliant.

- Oral:

Since systemic effects occurred after oral application, an absorption via the GI tract can be taken as granted. The absorption rate of Ethyltriphenylfosfonium bromide can only be assessed via its physico-chemical properties and effects on the GI tract.

Ethyltriphenylfosfonium bromide has a molecular weight of less than 500 g/mol (371.3 g/mol) and a log Kow of -0.446 and log P values between -1 and 4 are in general favourable for absorption subsequent to oral ingestion. As Ethyltriphenylfosfonium bromide will be present in its ionized form, this might limit the absorption as ionized substances do not easily pass the GI wall. On the contrary, Ethyltriphenylfosfonium bromide is a severe irritant to the GI tract and irritation or even corrosion is likely to enhance resorption. In the oral subacute study hyperplasia and single cell necrosis in the glandular stomach of the rats occurred. In the acute oral rat study thickening of the limiting ridge - a fold of the forestomach mucosa, which separates the forestomach from the glandular stomach - was seen.

For precautionary reasons, the oral absorption was stet to 100% by default.

- Inhalation:

There are no studies available with inhalative exposure. Ethyltriphenylfosfonium bromide is a solid at room temperature. The mass median diameter was determined to be 240.9 µm; D5, D10, D50, D90 and D95 were 530.3, 489.5, 240.9, 34.32 and 13.95 µm, respectively. Taking into account the melting point of 207-208°C together with a low vapor pressure of 0.10 ± 0.01 Pa at 20°C, substance evaporation and uptake of aerosols by inhalation is unlikely. However, the uptake after direct inhalation of substance dust particles may occur in humans due to D90 and D95 particle sizes of 34.32 and 13.95 µm, respectively which is below the threshold value for particles to reach the alveolar region (< 15 µm) and the thoracic region (< 50 µm) and which are definitively inhalable (inhalation threshold < 100 µm). As indicated by the negative log Kow and a moderate water solubility (89.2 mg/L) Ethyltriphenylfosfonium bromide is assumed to be readily dissolved into the mucous lining of the respiratory tract and is therefore unlikely to be coughed or sneezed out of the body. It will be taken up and possibly metabolised to excretable, hydrophilic derivatives. A deposition into lymphoid tissues is also rather unlikely.

Thus, for precautionary reasons absorption via the respiratory tract was set to 100% by default.

- Dermal:

After dermal exposure signs of systemic toxicity including death were observed in an acute study, thus absorption of Ethyltriphenylfosfonium bromide has obviously occurred. The absorption has probably been facilitated through skin damage. In an in vivo skin irritation study, no skin irritation was caused by 4 hours semiocclusive exposure to Ethyltriphenylfosfonium bromide but in the acute dermal toxicity study with 24 hours occlusive exposure erythema, scales, scabs and/or scars were seen in the treated skin area. The dermal LD50 of > 2000 mg/kg bw is definitely lower than the oral LD50 of > 300 < 500 mg/kg bw, which indicates on a lower absorption via the dermal route. From the physico-chemical properties of Ethyltriphenylfosfonium bromide dermal absorption may be rather unlikely due to its molecular weight > 100 g/mol (371.3 g/mol), its log Kow < 0 (-0.446) and its water solubility < 100 mg/L (89.2 mg/L).

Thus, in lack of detailed dermal penetration data and for precautionary reasons a dermal absorption rate of 50% is assumed as worst case default value.

 

Distribution:

Based on its relatively low molecular weight, high water solubility and its ionized form, Ethyltriphenylfosfonium bromide is expected to distribute widely throughout the body based on the assumption that small water soluble molecules and ions will diffuse through aqueous channels and pores. In the oral subacute study beside the glandular stomach, the thyroid gland was identified as target organ.

 

Metabolism:

There are no data on the metabolism of Ethyltriphenylfosfonium bromide. It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

Absorbed Ethyltriphenylfosfonium bromide might undergo hydroxylation of an aromatic hydrocarbon and conjugation by cytochrome P450 enzymes, as this is a common metabolism pathway for organic moieties. Hydrolysis is unlikely, as Ethyltriphenylfosfonium bromide is hydrolytically stable at pH 4, pH 7 and pH 9.

Excretion:

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. Excretion by exhalation does not seem to be relevant route of excretion based on the physico-chemical properties of the substance. However, since there is the possibility that several metabolites can occur due to metabolism renal and biliary excretion must be assumed. Some amounts may be excreted unchanged via the faeces.

Bioaccumulation:

Based on log Kow of -0.446 the substance is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.