Butyl (dialkyloxy(dibutoxyphosphoryloxy))titanium(trialkyloxy)titanium phosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Assessment report of toxicokinetic behaviour

Applicant's summary and conclusion

Conclusions:

The absorption rate of Butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate for oral, dermal and inhalation routes is considered as 30%. After absorption, the substance (or the degradation prodcuts) is expected to distribute widely in the body. The substance is expected to be vastly excreted by urine after metabolization to phosphoric acid and water soluble alcohols.

Executive summary:

The toxicokinetic behavior after exposure to butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate is assessed.

 

The substance is characterized as a UVCB substance where its stability is preserved by solvents. The variation of the alkyl chain derives different molecules in the UVCB which makes comprehensive toxicokinetic testing and analysis challenging. The substance is known to rapidly hydrolyze in water; therefore, the degraded substances are taken into consideration for toxicokinetics assessment.

 

To date, no relevant analytical toxicokinetic testing data has been generated for butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate. However, information on the physicochemical properties and toxicological data of the primary substance, together with the understanding of hydrolysis products can be used as a basis for the assessment of toxicokinetics.

 

Absorption

 

The substance is a liquid at room temperature and the measured vapour pressure is 5 482 Pa at 25°C. Inhalation of vapour of the substance would therefore be considered relevant to human exposure. However, the substance is a highly flammable liquid with a flash point of only 12°C and it is reactive with water requiring it to be preserved in solvents for stability and used in strictly controlled system. Occupational exposure via oral, dermal and inhalation routes is therefore mostly prevented by closed processes and adequate personal protection equipment.

 

Oral

 

The substance is reactive with water; therefore, the water solubility and Log Pow cannot be determined. It is expected that when entering the gastrointestinal tract, the registered substance will contact the digestive fluids and subsequently undergo rapid hydrolysis to degradation products of ethanol, 2-propanol, 1-butanol and alkyl phosphates. The oral absorption rate is therefore significantly increased by these molecules with smaller molecular weights and better solubility. To further assess the absorption potential via the oral route, several toxicology studies are taken into consideration. None of the acute and repeated dose toxicity studies (subacute and sub-chronic) showed any significant systemic toxicity. This is consistent with the low hazard of the expected degradation products i.e., simple alcohols and alkyl phosphates. However, given the moderate absorption of alcohols and short-chain phosphates, a default value for oral absorption of the substance is set as 30%.

 

Dermal

 

The key physical-chemical property that affects dermal absorption potential, i.e., Log Pow, is not available for butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate. The large molecular weight of typical structures is expected to limit dermal absorption. Due to the reactivity of the substance in water, it is not anticipated to be a surfactant; therefore, enhanced dermal uptake is not expected. Similarly, given that the integrity of the stratum corneum is an important factor affecting dermal absorption, skin irritation potential needs to be taken into account. The skin irritation study results showed the substance is considered to be not irritating to skin; therefore, dermal absorption contributed to impaired skin is not anticipated. As contact with skin is not normally associated with a water-abundant surface, significant hydrolysis is not expected for the substance. The degradation products are therefore not considered as relevant to the dermal absorption. 

In an acute dermal toxicity study of butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate the LD50 was determined to be greater than 2 000 mg/kg bw by a limit test. This indicates the substance may not be significantly absorbed via the dermal route. Based on the above information, the skin absorption rate of butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate is considered to be no higher than via the oral route and a default value for skin absorption is considered to be 30%.

 

Inhalation

 

In general, water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Lipophilic substances (Log Pow>0) would have the potential to be absorbed directly across the respiratory tract epithelium. However, the Log Pow is not available for butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate. There is also a lack of toxicology data via inhalation route.

The substance has a relatively high vapour pressure under normal conditions and hydrolysis is expected to happen when the vapour of the substance is inhaled and contacts the airway mucus. The degradation products such as alcohols and alkylphosphates have more potential to be absorbed via the respiratory tract due to a much lower molecular weight compared to the parent substance. Consequently absorption via inhalation is considered to be comparable to the oral route and a default value for inhalation absorption is set as 30%.

 

Distribution

 

Distribution of butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate is expected to be limited due to its relatively large molecular weight. However, when absorbed as degradation products, their lower molecular weights are expected to lead to a wide distribution in the organs such as the liver, kidney and spleen.

 

Metabolism and Excretion

 

As butyl(dialkyloxy(dubutoxyphosphoryloxy) titanium(trialkyloxy) titanium phosphate is known to be reactive with water, metabolism of the substance is expected to be a phase 1 hydrolysis process that breakdowns to inorganic parts such as titanium and organic parts such as simple alcohols (ethanol, 2-propanol and 1-butanol), alkyl phosphates and traces of hydrocarbons as impurities. The short-chain alkyl phosphates would be further hydrolyzed by phosphatase into alkanol and phosphoric acid. The water soluble phosphoric acid and alcohols can be excreted via the urine directly. The other hydrocarbons would further undergo oxidizing pathways to be excreted via water soluble metabolites.