Propanoic acid, 2-[4-[4,6-bis([1,1'-biphenyl]-4-yl)-1,3,5-triazin-2-yl]-3-hydroxyphenoxy]-, isooctyl ester

Endpoint summary

Description of key information

The test substance is a solid powder of low water solubility and high molecular weight. Based on its physico-chemical properties as well as the outcome of several experimental in vivo toxicity studies, a poor absorption is assumed. Single administration via the oral and dermal route did not overt acute toxicity. Repeated oral application did not induce signs of local or systemic toxicity as well. The test substance is expected to be stable under the conditions of stomach and duodenum. Due to the limited gastrointestinal absorption, the majority of the substance may be readily excreted via the feces. A bioaccumulation is considered unlikely, because the substance is poorly absorbed and offers hydroxy groups for phase II xenobiotic metabolism.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Additional information

1. Physico-chemical description

The test substance is a solid slightly yellow powder from the group of triphenyltriazines. In general, triphenyltriazines are large, bulky, non-polar organic compounds used as UV-filter in varnishes and plastics. The substance is characterized by one ether bond at the triphenyltriazine-system and a methyl methoxy acetate residue.

 

Description of the physico-chemical properties:

• physical state (20°C): solid: powder


• vapour pressure: measured: 0.00036 Pa at 49.5°C; extrapolated: 0.00011 Pa at 25°C


• molecular weight: 84 g/mol


• log Pow (25 °C): measured: >6; calculated: 10.7


• water solubility: <0.02 mg/L at 20 °C


• boiling point: n/a (decomposed at >288 °C without boiling)

 

2. Toxicokinetic assessment

No experimental data on absorption, metabolism, distribution and excretion are available for the substance. Therefore, the toxicokinetic behavior was evaluated based on the structure and the physico-chemical properties of the substance as well as data from experimental in vivo toxicity studies.

 

Absorption

Oral route:

The test substance has a low water solubility (<0.02 mg/L), which in combination with the high molecular weight of 677.84 g/mol, rather indicates a poor absorption within the gastrointestinal (GI) tract. The rigid triazine core determines the bulky shape of the molecule. Bulky substances may be taken up via Peyer’s Patches in the small intestine. However, this generally leads to their destruction in the macrophages. With regards to the calculated log Pow of 10.7, the substance is very lipophilic. Nevertheless, as the substance does not bear resemblance to fatty acids, uptake via micelles with bile acids is unlikely. Furthermore, the substance contains ether and ester bonds. Both are generally stable with regard to pH-dependent hydrolysis at pH values present in the GI tract. Ester bonds may undergo enzymatic cleavage, provided that the substance is taken up into cells.

In the acute oral toxicity study available for the substance, no toxicity was observed at the limit dose of 2000 mg/kg body weight. The same was true in a repeated 28-day oral dose toxicity study in rats, where the substance was administered by oral gavage. Here no adverse effects were observed up to the highest dose tested of 1000 mg/kg body weight/d. This is in support of the low absorption potential of the substance derived from its structure and the physico-chemical properties.

 

Dermal route:

Dermal uptake of the test substance is considered to be low, as it is a solid and has a low water solubility. Therefore, dissolution in skin surface moisture, which is necessary for dermal uptake in this case, is unlikely. Furthermore, the molecules may be too large for dermal uptake (molecular weight >500 g/mol) and the high lipophilicity limits the transfer rate across the different skin layers.

An acute dermal toxicity study revealed very slight to well-defined irritation (Grade 1 or 2 erythema and/or Grade 1 or 2 oedema) in 5 of 10 rats after topical application of the limit dose (2000 mg/kg bw) for 24 hours. As it has resolved completely by day 9 and no dermal irritation was noted in the remaining five animals throughout the study, the acute lethal dermal dose of the test substance was demonstrated to be greater than 2000 mg/kg bw in rats. In a further acute dermal irritation/corrosion study in rabbits, which received a single four-hour, semi-occlusive dermal administration of the test substance, no dermal reaction was observed within four days. In addition, experimental data from a mouse local lymph node assay showed no skin sensitizing potential of the test substance.

Overall, the physicochemical properties and the findings from the dermal toxicity, irritation and sensitization studies indicate that low absorption into the systemic circulation can be expected after dermal application and relatively non-toxic properties of the substance.

 

Inhalative route:

Based on the low vapor pressure (≤0.00011 Pa at 25 °C) and the fact that the test substance decomposes at >288 °C without boiling, exposure to vapor is unlikely under normal conditions. Inhalation of particles might be possible as the substance is a solid powder. However, only 4% by mass of the material has a particle size <15 µm and might reach the alveolar region of the respiratory tract. In addition, the substance exhibits low water solubility and a large molecular weight. Therefore, poor absorption in the respiratory tract is assumed.

 

Distribution and Accumulative potential

As mentioned above, no indication of uptake and systemic availability was observed in any experimental in vivo toxicity study. In combination with the large molecular size and the presence of functional groups for metabolism, these findings indicate that a potential for distribution as well as bioaccumulation is unlikely despite the high lipophilicity of the molecule.

 

Metabolism and Excretion

With regards to the physical-chemical properties of the test substance limited GI absorption in the form of micelles can be considered as likely and the vast majority may be readily excreted via the feces. With respect to a very small part of the substance that might be resorbed, potential metabolism in the liver involves the formation of glucuronic acid conjugates with the phenolic -OH groups, or with secondary carboxylic acids formed in the course of the metabolism along the aliphatic side chain. Glucuronidated metabolites are generally known to be rapidly excreted via the biles.