Tributyl citrate

Dermal absorption

Administrative data

Endpoint:

dermal absorption

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An extensive Assessment of the toxicological behaviour of tributyl citrate was performed, taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

no guideline required

Test material

Test material information

Constituent 1

Reference substance name:

Tributyl citrate

EC Number:

201-071-2

EC Name:

Tributyl citrate

Cas Number:

77-94-1

Molecular formula:

C18H32O7

IUPAC Name:

tributyl citrate

Test material form:

other: liquid

Details on test material:

not applicable in this expert statement

Radiolabelling:

other: not applicable in this expert statement

Test animals

Species:

other: not applicable

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable in this expert statement

Administration / exposure

Type of coverage:

other: all routes of administration are discussed in the expert statement

Duration of exposure:

not applicable in this expert statement

Doses:

not applicable

No. of animals per group:

not applicable

Details on study design:

not applicable

Results and discussion

Any other information on results incl. tables

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight (MG) below 100 are favourable for penetration of the skin and substances with a MG > 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal). Above 4, 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. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound may be subject to biotransformation.

In case of tributyl citrate, the molecular weight is above 100 and below 500, which indicates a low potential to penetrate the skin. Even though the water solubility of tributyl citrate is intermediate, absorption through the lipophilic stratum corneum is possible. The LogPow value is not optimal (values 2-3), but still favour absorption via the skin (between 1 and 4). The amount of tributyl citrate, which is absorbed following dermal exposure into the stratum corneum is however unlikely to be transferred into the epidermis, due to its molecular weight and LogPow. The systemic toxicity via the skin is assumed to be low.

 

Applicant's summary and conclusion

Conclusions:

An extensive Assessment of the toxicological behaviour of tributyl citrate was performed (expert statement), taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Executive summary:

In order to assess the toxicological behaviour of tributyl citrate, the available experimental and predicted physico-chemical data have been evaluated. The substance is expected to be absorbed well (based on molecular weight of 360.442 g/mol, water solubility and LogPow value of 3.5 and experimentally derived data). The absorption of any metabolite of hydrolysis of the substances of interest is, however, fast and complete. Concerning the absorption after exposure via inhalation, as the chemical has a low vapour pressure, it is clear, that the substance is poorly available after inhalation. Given its lipophilicity (LogPow 3.5) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium. Tributyl citrate is expected to be also poorly absorbed following dermal exposure into the stratum corneum and to a certain extent into the epidermis, due to its molecular weight of 360.442 g/mol and its LogPow of 3.5. In addition, the systemic toxicity via the skin is assumed to be low. Concerning the distribution in the body, tributyl citrate is expected to be available in the circulatory system and to be distributed into the cells, since it is a more lipophilic substance. The experimentally determined or calculated LogPow values, the water solubility and predicted behaviour concerning absorption, the substance does not indicate a potential for accumulation. Tributyl citrate is expected to be extensively metabolised by esterases and cytochrome P450 enzymes and break-down in the beta-oxidation or citric acid cycle or in cases subsequent glucuronidation. The substance is assumed to be excreted (if not metabolised completely in beta-oxidation and citric cycle) as metabolites (i.e. conjugates with glucuronic acid)via urine and to a lower extent via bile.