6,6'-di-tert-butyl-2,2'-thiodi-p-cresol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Written assessment

Type of information:

other: Written assessment

Adequacy of study:

other information

Study period:

April 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Written assessment

Justification for type of information:

At the current level of registration, a written assessment is suitable.

Objective of study:

other: Written assessment of ADME

Qualifier:

no guideline required

Principles of method if other than guideline:

Written assessment based on available study data.

Details on absorption:

See attached background material below.

Details on distribution in tissues:

See attached background material below.

Details on excretion:

See attached background material below.

Details on metabolites:

See attached background material below.

Bioaccessibility (or Bioavailability) testing results:

See attached background material below.

Conclusions:

In conclusion, there is no evidence to suggest that the substance is significantly absorbed via any of the routes due to its physicochemical properties, this is coupled with the lack of effects shown in the in vivo studies, a 100% absorption rate is proposed as a worst case for oral, dermal and inhalation routes.
It is likely that the following ingestion, the substance undergoes conjugation with glucuronic acid and sulfate within the gastrointestinal tract. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. These solubilised metabolites are then most probably excreted in the urine in conjugated form. Consequently, the substance is considered to have low bioaccumulation potential.

Executive summary:

In conclusion, there is no evidence to suggest that the substance is significantly absorbed via any of the routes due to its physicochemical properties, this is coupled with the lack of effects shown in the in vivo studies, a 100% absorption rate is proposed as a worst case for oral, dermal and inhalation routes.

It is likely that the following ingestion, the substance undergoes conjugation with glucuronic acid and sulfate within the gastrointestinal tract. Following absorption, the fatty acids are transported to the tissues of the body including the liver where they undergo oxidation in the cells. These solubilised metabolites are then most probably excreted in the urine in conjugated form. Consequently, the substance is considered to have low bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Absorption

Oral

There have been no associated treatment related effects noted in the acute and repeated dose toxicity studies via the oral route which implies that the substance is not readily available following oral exposure. 

LOWINOX TBP-6 comprises of hydroxyl groups which indicate that it would be readily ionisable, which is not likely to diffuse across the biological membrane. The test substance is relatively large (molecular weight >200), has a very low water solubility of 8 µg/L and log kow value > 6.5. Therefore it is unlikely that LOWINOX TBP-6 will show a high systemic exposure after oral administration as the substance needs to be dissolved prior to being taken up via the gastro-intestinal tract. Nevertheless, a highly lipophilic character (log kow > 4) suggests that uptake by micellular solubilisation may take place by bile salts. For risk assessment purposes oral absorption of LOWINOX TBP-6 is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

 

Dermal

Acute dermal toxicity study in rats as a dose level of 2000 mg/kg, no mortality or treatment related effects occurred. Similarly an in vivo LLNA study in mice also revealed no signs of irritancy when applied to the dorsal surface of ears of the experimental mice.

The structure of the substance does not indicate The log Kow value of the test substance > 6.5 therefore the dermal absorption of the substance would expected to be limited based on the high log Kow value. At log Kow values 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. Maximum dermal absorption is often associated with values of log Kow between +1 and +2 (ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). Monograph No, 20; Percutaneous absorption. August 1993). In addition, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. The test substance has a water solubility of 8 µg/L therefore dermal uptake is likely to be low.

However in accordance with ECHA Chapter R.7c: Endpoint specific guidance, a default value of 100% skin absorption is generally used unless the molecular weight is above 500 and the log P/Kow is outside the range (-1, 4), in which case a value of 10% skin absorption is chosen.

The dermal absorption rate of 100% is used for the chemical safety assessment. Although the molecular weight of the substance would not defined as it being a large molecule, its low solubility, high log kow implies limited dermal absorbance. The results of the dermal studies do not provide an indication to deviate from the proposed absorption factor.

 

Inhalation

The large aerodynamic diameter (90% < 480.087 μm) implies that the substance will not reach the thoracic region. A very low vapour pressure (6.09 × 10^-4Pa at 20°C) and high boiling point (≥ 305°C) additionally infers that the substance will not reach the nasopharyncheal region or subsequently the tracheobranchial or pulmonary region. Consequently a significant inhalation exposure to vapours or dusts would not expected. Moderate log Kow value between -1 and 4 are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The test substance has a high log Kow value (>6.5) therefore it may be taken up by micellular solubilisation particularly as the substance is poorly soluble in water (8 µg/L). Overall, although it is unlikely that LOWINOX TBP-6 will become available via inhalation, for risk assessment purposes the inhalation absorption is set at 100%.