3-(2,2-dimethyl-3-hydroxypropyl)toluene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement based on physicochemical and toxicity data.

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement based on physicochemical and toxicity data

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2021

Report date:

2021

Applicant's summary and conclusion

Conclusions:

Based on physicochemical characteristics and based on studies with similar substances from the group of primary aryl alkyl alcohols, absorption by the oral and possibly dermal routes is likely. Especially oral absorption is supported by the results of the acute and repeated dose oral toxicity studies, revealing some clinical signs, effects on body weight, hematological effects, effects on liver weights and effects on the offspring. Bioaccumulation of the substance is rather unlikely, supported by the rapid metabolism and excretion observed in different studies with primary aryl alkyl alcohols after oral and dermal absorption. After being absorbed into the body, 3-(2,2-dimethyl-3-hydroxypropyl)toluene is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow = 3.07) and in turn, the intracellular concentration may be higher than extracellular concentration, particularly in adipose tissues. Due to the effects observed in the subacute oral toxicity studies and studies with other primary aryl alkyl alcohols, 3-(2,2-dimethyl-3-hydroxypropyl)toluene or its metabolites may target the liver. Excretion via urine was observed as the major excretion route in comparative studies and can be anticipated.

Executive summary:

3-(2,2-dimethyl-3-hydroxypropyl)toluene is a mono-constituent substance. It is available in a liquid-solid transition state at ambient conditions. The substance is colourless with a molecular weight of 178.271 g/moL. The substance shows a moderate solubility in water (265.8 mg/L at 25 °C). The log Pow was determined to be 3.07. The test substance has a vapour pressure of 6.43 Pa at 25 °C.

 

Absorption

According to the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c (Endpoint specific guidance), oral absorption is favoured for molecules with molecular weights of less than 500 g/moL. The substance is assumed to partly dissolve in gastrointestinal fluid due to its moderate water solubility of 265.8 mg/L and the log Pow of 3.07 favours absorption by passive diffusion. Moreover, hydrolysis of the test item in the GIT is not expected. Taken together, the physiochemical properties indicate that 3-(2,2-dimethyl-3-hydroxypropyl)toluene becomes bioavailable following the oral route. This assumption is confirmed by the acute and subacute oral toxicity studies with 3-(2,2-dimethyl-3-hydroxypropyl)toluene, where considerable clinical signs, as well as mortalities were observed following administration, indicating a well and rapid absorption of the test item via the oral route (acute study) and where dose-dependent increases in liver weights and deviations in some haematological and clinical chemistry parameters were observed (subacute studies). Furthermore, decreased body weights were observed in adult males and pups in the reproduction/ developmental toxicity screening test, which was accompanied by decreased T4 levels in pups indicating that the test substance was taken up by the pups through the milk. After oral administration of benzyl alcohol, a representative of the group of primary aryl alkyl alcohols, to humans, 80–90% of the dose was taken up within 6 hours, confirming that also 3-(2,2-dimethyl-3-hydroxypropyl)toluene may be readily bioavailable through the oral route (Snapper et al., 1925).

 

Due to the low volatility (vapour pressure of 6.43 Pa at 25 °C and high boiling point of 258.6°C) of 3-(2,2-dimethyl-3-hydroxypropyl)toluene, it is unlikely that the substance will be available as a vapour. As the substance is used in a non solid or granular form, no particle formation is expected. Hydrophilic substances are likely to be retained within the mucus and thus, because of the moderate water solubility of the substance, penetration may be reduced. Although the log Pow of 3.07 would favour uptake through the respiratory tract epithelium by passive diffusion, it is very unlikely that the substance reaches the respiratory tract due to the previously mentioned properties.

 

Dermal uptake is favoured by a liquid state of the substance, a molecular weight of less than 100 g/moL and a water solubility between 100-10,000 mg/L. 3-(2,2-dimethyl-3-hydroxypropyl)toluene is a non-volatile liquid to solid substance with a relatively low molecular weight of 178.271 g/moL, a log Pow of 3.07 and moderate water solubility of 265.8 mg/L, thus dermal absorption may be a potential uptake route. Especially the water solubility enables a partition of the substance from the stratum corneum into the epidermis. However, the substance is not skin and eye irritating or skin sensitising and the acute dermal toxicity study indicate that the test item exhibits less severe toxicity when administered via dermal route than via oral route. Thus, the oral route is considered to be the major uptake route, which was also confirmed in a study with the primary aryl alkyl alcohol phenethyl alcohol, where 70% of the applied dose was recovered in urine as a metabolite after oral administration to rats whereas the same dose applied to the skin resulted in a metabolite recovery of 27% (RIFM, 1990a).

 

In different in vivo dermal absorption studies with primary aryl alkyl alcohols, the absorption pattern differed greatly depending on the application method and species. In humans, between 8.5% and 48% of the applied dose was absorbed after single application of cream containing the respective compound, whereas application in ethanol under occlusion for 6 h/day for 5 days resulted in 90% non-absorbed substance, presumably because of evaporation. In rabbits, absorption rates of 47-57% were found and in rats, percentages of applied doses absorbed through the skin varied between 62–72% (substance in ethanol, occluded conditions), 80-85% (compound applied in skin cream) and 1.7-3% (compound in shampoo). However, it can be concluded that primary aryl alkyl alcohols and thus also 3-(2,2-dimethyl-3-hydroxypropyl)toluene can potentially be absorbed through the dermal route. The peak plasma levels in humans were measured after 1.5 hours. In rats, peak levels were achieved at 0.5/2/4 hours and in rabbits at 4/6 hours depending on the applied concentration, but rapid dermal absorption can be assumed (Belsito et al.).

 

Distribution

As mentioned above, the physicochemical properties of 3-(2,2-dimethyl-3-hydroxypropyl)toluene favour absorption by the oral and dermal route. The systemic absorption and distribution within the body is also demonstrated by the occurrence of clinical signs and mortality in the acute oral toxicity study as well as dose-dependent effects on body weights, liver weights and by effects on some haematological and clinical chemistry parameters in the repeated dose toxicity studies as well as by effects on pups. After being absorbed into the body, 3-(2,2-dimethyl-3-hydroxypropyl)toluene is most likely widely distributed due to its relatively low molecular weight and may enter into the interior part of cells due to its lipophilic properties (log Pow 3.07) and in turn, the intracellular concentration may be higher than extracellular concentration, particularly in adipose tissues. This supported by the fact that effects on the pups occurred during the lactation period and thus, the substance is likely to pass into the milk. However, the test item is unlikely to have a bio-accumulative potential, because it is not highly lipophilic (log Pow is not greater than 4) and there are no other physic-chemical properties indicating a bioaccumulating potential. Due to effects on the liver observed in the subacute repeated-dose toxicity studies, it can be assumed that the liver may be a target organ of the substance.

 

In different in vivo dermal absorption studies with phenethyl alcohol in pregnant and non-pregnant rats, the substance or its metabolites was recovered in the skin, gastrointestinal tract, blood, liver, urinary tract and a number of endocrine and secretory organs. Phenethyl alcohol or its metabolites was also recovered in fetuses (Belsito et al.).

 

Metabolism

There is no direct experimental data to characterize the metabolism of the test substance. Instead, the anticipated metabolism is derived from expert judgement.

 

As some liver effects were observed in the subacute repeated dose oral toxicity studies, the substance is principally able to reach the liver and its metabolic capacities. No toxification or detoxification through cytochrome P450 metabolism is assumed, since no differences in cytotoxicity were observed in the in vitro assays in the absence or presence of the metabolizing system (S9) which is supported by different in vivo studies with primary aryl alkyl alcohols, where no toxic metabolites were produced (Belsito et al.).

 

A general metabolic pathway for the group of primary aryl alkyl alcohols was shown to be either direct conjugation, or oxidation of the primary alcohol to an aldehyde which is typically rapidly oxidized to the corresponding carboxylic acid and conjugated to glycine or glucuronidized. In different in vivo dermal absorption studies with primary aryl alkyl alcohols, plasma levels of the compounds or metabolites peaked at approx. 0.5 to 6 hours in rats, rabbits and humans. In different oral absorption studies with primary aryl alkyl alcohols in rats and humans, maximum plasma levels of the compounds or metabolites were achieved between 0.25 and 10 hours, indicating a fast metabolism (Belsito et al.).

 

Excretion

Due to its low molecular weight and moderate water solubility, it can be assumed that the test item is rather excreted via the kidneys and the urine than via feces. This assumption is supported by an overview of primary aryl alkyl alcohol toxicokinetics described in Belsito et al., where aryl primary alkyl alcohols are considered to be excreted mainly in form of glycine conjugates or (to a lesser extent) glucuronides as supported by the findings of different in vivo studies. Peak urine concentrations were found between 24 and 48 hours in rats, rabbits and humans, suggesting a relatively fast excretion. Also repeated dose application did not change the excretion pattern (Belsito et al.).