Phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: assessment

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The assessment was performed according to ECHA Guidance.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, R.7.12 Guidance on Toxicokinetics, November 2014.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide

EC Number:

423-340-5

EC Name:

Phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide

Cas Number:

162881-26-7

Molecular formula:

C26H27O3P

IUPAC Name:

[phenyl(2,4,6-trimethylbenzoyl)phosphoryl](2,4,6-trimethylphenyl)methanone

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption
The acute oral toxicity data showing the LD50 > 2000 mg/kg bw/day indicated that no signs of systemic toxicity is present. Clinical signs were confined to piloerection, seen in all rats and recovery was complete by Day 3. In the repeated dose toxicity study (28 day) there was no clinical observation noted that could be indicative of treatment to the substance. One female died in week 1 of an intubation error. Laboratory findings showed limited absorption took place orally. Since phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide is highly insoluble in water, it is considered to have low oral/GI absorption.

Respiratory absorption - Inhalation
Owing to its particle size (between 10 to 50 mm), phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide has potential to be inhaled. Considering it has very low water solubility, low volatility and low vapour pressure as well as effective control measure have been used, it is expected that the substance has limited potential to be inhaled (e.g. reach the human lungs). Inhalation is not a significant route of exposure.

Dermal absorption
Phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide is considered to have dermal absorption because it has been identified as a skin sensitizer according to CLP Regulation. With a log P value of 5.77 (experimental data) or 4.65 (estimated data) (both above 4 but below 6), the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Since cells in the outer layer (e.g. stratum corneum is the outermost layer of the eqidermis) are resistant to chemicals, also there are no blood vessels in the outer layer as well as there is no evidence of systemic toxicity reported in the 28-day oral toxicity study of phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide (Effects in organs: No treatment-related gross or microscopic changes were observed.), it is to be expected that uptake into the stratum corneum is probably but the substance will not manage to pass through the outer skin layer and therefore, it will not pass through the rest of the skin and not enter the circulation.

Details on distribution in tissues:

System effect were not observed in the 28-day oral toxicity study. It is therefore possible to conclude that the substance is not transported. As a highly lipophilic substance, phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide may penetrate the skin but probably reach the stratum corneum and is not well absorbed systemically because of no evidence of systemic toxicity records. After dermal absorption, this chemical may persist in the stratum corneum, but it will eventually be cleared as the stratum corneum is sloughed off. Accumulation in fat or in other tissues is unlikely.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

In view of its hydrophobicity, high lipophilic (log P between 4 and 6) and low volatility, oral and inhalation absorption of phenyl bis(2,4,6-trimethylbenzoyl)-phosphine oxide are considered limited. There is sufficient evidence that dermal absorption takes place and uptake into the stratum corneum will be high. In the case dermal absorption occurs, substance that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells. Accumulation in the body during prolonged exposure will be very low.

Applicant's summary and conclusion

Conclusions:

Thanks to its very low water solubility, the substance is considered to have negligible oral/ gastrointestinal absorption. It is expected this chemical has limited potential to be inhaled since it is highly insoluble in water, has low volatility and low vapour pressure. Based on the expected kinetic behaviour in the body, there is sufficient evidence that dermal absorption takes place and it is expected that uptake into the stratum corneum will be high. However, in view of no evidence of systemic toxicity in the 28-day oral toxicity study, this chemical shall not manage to pass through the outer skin layer and hence, it will not pass through the rest of the skin and not enter the circulation. The substance will hardly be absorbed after oral and inhalation administration due to its hydrophobicity and low volatility as well as low vapour pressure. If dermal absorption occurs, the substance that has penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.