4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco

Endpoint summary

Description of key information

Assessment of the Toxicokinetic Behaviour

 

4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco (CAS-No. 115640-85-7; EC-No. 500-303-2)

 

There are no studies available in which the toxicokinetic properties of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco were investigated.

 

Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco was conducted based on the relevant available information.

This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to ‚Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance‘ (ECHA, 2012).

 

4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco (molecular weight of a multi-constituent is not available, but estimated to 538 – 822 g/mole) is a yellowish clear liquid, which is practically insoluble in water (< 1 mg/L;key study; see chapter 4.8 water solubility).

 

The calculated log Po/w is 9.01 (QSAR estimation KOWWIN v1.68, see chapter 4.7 partition coefficient), indicating high lipophilie and that a general accumulation of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is possible. The vapour pressure of 0,00065 Pa at 20 °C (key study, see chapter 4.6 vapour pressure) is very low.

 

Absorption

 

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

 

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2012). As the molecular weight of more than 90% of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is above 530 g/mol absorption of these molecules in the gastrointestinal tract is not very likely. The smaller molecules will be taken up but their content is only about 7%.

In the gastrointestinal tract (GIT), metabolism prior to absorption via enzymes of the microflora may occur. In fact, after oral ingestion, coco fatty acid esters with 4,4'-Isopropylidenediphenol, ethoxylated are hydrolised by ubiquitously expressed esterases to fatty acids and 4,4'-Isopropylidenediphenol, ethoxylated. Those will be almost completely absorbed (Mattson and Volpenhein, 1969, 1972a,b) and might undergo biotransformation.

The available data on oral toxicity of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco are considered for assessment of oral absorption.
In an acute oral toxicity study, female rats were administered to 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco by gavage. No mortalities were observed at the dose of 2000 mg/kg bw. Adverse effects such as Ataxia and Decrease reaction were observed in the animals of the 2000 mg/kg bw dose group in the first six hours. Later on to day 14 of the observation period no adverse effect was observed in all the test animals (key study, see chapter 7.2.1 acute oral toxicity). Therefore, bioavailability of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco after oral administration is indicated.

 

No systemic toxicity was reported in the oral 28-day Repeated Dose Toxicity in rats with daily oral administration of up to 1000 mg/kg with the test substance 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco. The NOAEL for repeated dose toxicity is considered to be > 1000 mg/kg/day of both sexes under the test conditions (OECD407 key study; see chapter 7.5.1 repeated dose oral).

 

In general, after oral ingestion, 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco will undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. 4,4'-Isopropylidenediphenol, ethoxylated as well as the fatty acids will be formed.

The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract.

The highly lipophilic fatty acids will be absorbed by micellar solubilisation (Ramirez et al., 2001). 4,4'-Isopropylidenediphenol, ethoxylated, on the basis of its physical-chemical properties (molecular weight 316.39g/mol, log Pow 3.3, water solubility is moderate (111,8 mg/L), Pubchem Open Chemistry Database), is favourable for absorption. It needs to be dissolved into the gastrointestinal fluids before it can be taken up from the gastro-intestinal tract after oral administration. Potential for ionization may result in impaired uptake since compounds need to pass the lipid membranes in the gastrointestinal wall. For risk assessment purposes the oral absorption of 4,4'-Isopropylidenediphenol, ethoxylated is set at 50% as a worst case assumption. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

In summary, the above discussed physical-chemical properties of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco and relevant data from available literature indicate hydrolysis before absorption of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco. For risk assessment purposes the oral absorption of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is set at 50% as a worst-case assumption.

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of more than 90% of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is above 530 g/mol and none of the esters has a molecular weight below 100 g/mol only a very small amount of the UVBC will be absorbed by skin.

 

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). In an acute dermal toxicity study a single dose level of 2000 mg/kg4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco was administered to Sprague-Dawley rats (key study, see chapter 7.2.3 acute dermal toxicity). No signs of systemic toxicity were observed, indicating primarily a low dermal toxicity (the LD50 value of the test item is more than 2000 mg/kg body weight). No skin irritation was observed. Therefore, an enhanced penetration of the substance due to local skin damage can be excluded.

 

Overall, due to the experimental low dermal toxicity, the very low water solubility, the high molecular weight (>500), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco in humans is considered as very low.

 

The criteria for 10% dermal absorption as given in the Reach Guidance on information requirements and chemical safety assessment (MW>500 and -1<log Pow >4) are met, and therefore 10% dermal absorption of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco should be considered as appropriate for risk assessment purposes.

 

Inhalation

4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco have a very low vapour pressure of 0,00065 Pa at 20 °C (key study, see chapter 4.6 vapour pressure) thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant.

 

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012).

Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and acid available for respiratory absorption. Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption.

Therefore, respiratory absorption of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco in humans is considered likely after inhalation but not expected to be higher than following oral exposure.

 

Accumulation

Highly lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. (ECHA, 2012).

However, as absorption of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is considered to be low, the potential of bioaccumulation is low as well.

Nevertheless, as further described in the section metabolism below, esters of 4,4'-Isopropylidene-diphenol, ethoxylated, and fatty acids coco will undergo esterase-catalyzed hydrolysis, leading to the cleavage products respective 4,4'-Isopropylidenediphenol, ethoxylated and the fatty acids.

The log Pow of the first cleavage product 4,4'-Isopropylidenediphenol, ethoxylated is 3.3 and it is moderate soluble in water (111,8 mg/L) (Pubchem Open Chemistry Database). Substances are generally considered to be bioaccumulative when the log K_ow≥ 4.5. Consequently, the test substance is unlikely to be bioaccumulative in adipose tissue.

The other cleavage products, the fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism. Overall, the available information indicates that no significant bioaccumulation in adipose tissue of the parent substance and cleavage products is anticipated.

 

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012).

Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rate of absorption.

As discussed above absorption of 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is considered low based on its physico-chemical characterisation as poor water solubility and high molecular weight.

Nevertheless, esters of 4,4'-Isopropylidenediphenol, ethoxylated with fatty acids, coco will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products 4,4'-Isopropylidenediphenol, ethoxylated and the different fatty acids.

4,4'-Isopropylidenediphenol, ethoxylated indicates with its molecular weight (316), its moderate water solubility (111,8 mg/L) and its log Pow (3.3) to be moderately favourable for absorption. Absorbed 4,4'-Isopropylidenediphenol, ethoxylated might undergo conjugation. The conjugates will either be excreted via the bile (high (> 500) molecular weight compounds) or the urine (low (<500) molecular weight compounds).

The fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro, 1977).

Overall, the available information indicates that the cleavage products, 4,4'-Isopropylidenediphenol, ethoxylated and fatty acids coco can be distributed in the organism.

 

Metabolism:

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: after oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

Thus, 4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is probably hydrolysed to the corresponding alcohol 4,4'-Isopropylidenediphenol, ethoxylated and fatty acids coco by esterases.

The first cleavage products, fatty acids are stepwise degraded by beta -oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively.

The other cleavage product 4,4'-Isopropylidenediphenol, ethoxylated will due to its physico-chemical properties (molecular weight of 316, log Pow of 3.3, and moderate solubility in water) be absorbed and can either remain unchanged or may further be metabolized or conjugated (e.g. glucuronides, sulfates, etc.) to more polar products that are excreted in the urine.

 

In the 28 day oral Repeated Dose Toxicity Study of 4,4’-Isopropylidenediphenol, ethoxylated, Esters with fatty acids, coco using rats showed no signs of toxicity. The NOAEL for repeated dose toxicity are considered to be > 1000 mg/kg/day for both sexes under the test conditions (OECD407 key study; see chapter 7.5.1 repeated dose oral).

A Reproduction/Developmental Toxicity Screening Test in rats with 4,4’-Isopropylidenediphenol, ethoxylated, Esters with fatty acids, coco indicates no reproductive / developmental toxicity up to the highest dose level of 1000 mg/kg bw.

 

In an Ames Test the test item 4, 4'-lsopropylidenediphenol, ethoxylated, esters with fatty acids, coco, is considered non-mutagenic to the used bacteria strains.

The results of an in vitro micronucleus assay using CHO-K1 cells showed ambiguous results.

 

The above described studies reveal a low potential for toxicity after repeated exposure. Based on these data and on the properties of the test substance characteristics a low absorption of4,4’-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is assumed.

 

Excretion:

On the basis of the low absorption data the main route of excretion for 4,4’-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco is expected to be excreted via faeces.

Assuming that hydrolysis for4,4’-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco takes place fatty acids and4,4’-Isopropylidenediphenol, ethoxylated as breakdown products will occur in the body. 

Potential cleavage products, the fatty acid components will be metabolized for energy generation or stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above.

The other cleavage product 4,4’-Isopropylidenediphenol, ethoxylated may either further be metabolized or conjugated to polar products (e.g. glucuronides, sulfates, etc.) or excreted unchanged via urine. The conjugates will either be excreted via the bile (high (>500) molecular weight compounds) or the urine (low (<500) molecular weight compounds).

 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50