Heptanal, oligomeric reaction products with aniline

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:

March 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 that the substance is significantly absorbed via the dermal route or the inhalation route, but for worst case risk assessment, 100% absorption is proposed. The results of an oral repeated dose toxicity study indicate that the substance may be absorbed orally. 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 within man.

Executive summary:

In conclusion, there is no evidence that the substance is significantly absorbed via the dermal route or the inhalation route, but for worst case risk assessment, 100% absorption is proposed. The results of an oral repeated dose toxicity study indicate that the substance may be absorbed orally. 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 within man.

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

Oral

Treatment related effects which were noted in the acute toxicity and reported dose toxicity studies via the oral route that resulted in the classification for exposure via this route is implicit that the substance is absorbed following oral ingestion, and hence oral availability of the substance is relatively high.

The test substance has a low water solubility (of < 0.16 mg/L) and log kow value (> 7.2). The absorption of highly lipophilic substances (log Kow ≥ 4) may be limited by the inability of such substances to dissolve in gastrointestinal fluids and therefore make contact with the mucosal surface. However, the absorption of such substances will be increased if they undergo micellular solubilisation by bile salts. As a worst case, for risk assessment purposes the oral absorption of the test substance is set at 100%.

Dermal

In the acute dermal toxicity study in rats at a dose level of 2000 mg/kg, no mortality occurred, however, flat posture, ptosis and/or chromodacryorrhoea (snout) were noted for all animals on Day 1 to 3. 

The in vivo skin irritation study rabbits treatment related effects were observed erythema, Scaliness and showed bald skin 14 days after exposure.

In an in vivo LLNA study, mice were observed to show very slight to well-defined erythema, scaliness and/or erythema between the ears throughout the dose groups, 10%, 25% and 50% between Days 2 and 6. Hunched posture and/or piloerection was also noted for most animals treated at concentrations of 25% (Days 4 - 5) and 50% (Days 3 -6). No Signs of systemic toxicity were noted for the 10% test item group or control group. Body weight loss was noted for the animals treated at concentrations of 25% and 50%. Body weights and weight gain of the animals at 10% remained in the same range as controls over the study period.

The log Kow value of the test substance > 7.2 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 < 0.16 mg/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.

As the molecular weight of the substance is seen to be < 500, the dermal absorption rate of 100% is used for the chemical safety assessment to factor in a worst case scenario.

Inhalation

The substance has a low vapour pressure (0.15 to 0.49 Pa at 25°C) therefore a significant inhalation exposure to vapours is 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 (>7.2) therefore it may be taken up by micellular solubilisation particularly as the substance is poorly soluble in water (< 0.16 mg/L). As a worst case, for risk assessment purposes the inhalation absorption of the test substance is set at 100%.