3-(4-tert-butylphenyl)propionaldehyde

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

7

Absorption rate - inhalation (%):

100

Additional information

Although REACH does not specifically require generation of toxicokinetic information, it does require that all relevant available information is used to assess the toxicokinetic behaviour of a substance, and that human health hazard assessment considers the toxicokinetic profile of the substance.

 

Acute and subchronic toxicity data indicate that Bourgeonal is absorbed following administration by gavage and metabolised by the liver. No specific studies on the absorption, distribution, metabolism and elimination (ADME) are available.

Bourgeonal is a small organic molecule and the physico-chemical properties suggest it is likely to be absorbed via oral route following exposure, but it is expected to have limited bioavailabilty via inhalation route. Nevertheless, as no experimental data is available to quantify an absorption rate, the default values recommeded in ECHA Guidance R8 are applied

There is, however, several studies on dermal absorption of the very closely related molecule p-t-Butyl-alpha-methylhydrocinnamic aldehyde (CAS 80 -54 -6, EC 201 -289 -8), both in vivo and in vitro, on human and rat epidermis. It is overall concluded that p-t-Butyl-alpha-methylhydrocinnamic aldehyde (CAS 80 -54 -6, EC 201 -289 -8) shows an extremely low dermal absorption potential, and the highest absorption observed in human epidermis when using the absorption enhancer matrix ethanol is 7%.

p-t-Butyl-alpha-methylhydrocinnamic aldehyde (CAS 80 -54 -6, EC 201 -289 -8) and Bourgeonal differing in their chemical structure by only one methyl group, this experimental absorption rate can be extrapolated to Bourgeonal.

 

Bourgeonal: (Target)

Molecular weight: 190.29 Da

Water solubility: 132 mg/L in ultrapure water

Partition coefficient: log Kow = 3.2

 

Experimental toxicokinetic studies were not available.

No specific studies on the absorption, distribution, metabolism and elimination (ADME) of Bourgeonal are available. 

The following remarks on the toxicokinetics of Bourgeonal are based on the available studies.

 

ABSORPTION

The physicochemical characteristics of Bourgeonal (log Pow 3.2) and the molecular mass are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion. This assumption of oral absorption is confirmed by the data from the subchronic oral toxicity.

 

N-octanol/water partition coefficient and molecular weight of Bourgeonal are in ranges which favour dermal absorption. Nevertheless experimental data on a very closely related molecule p-t-Butyl-alpha-methylhydrocinnamic aldehyde (CAS 80 -54 -6, EC 201 -289 -8) indicate that absorption of Bourgeonal by dermal route is expected to be low and not be above 7%.

 

DISTRIBUTION and METABOLISM

As a small molecule a wide distribution is expected. This assumption is confirmed by the changes shown in the repeated dose toxicity studies following oral application.

Bourgeonal is expected to follow the metabolic pathway of the structurally related cinnamyl derivates. This group of substances are known to be metabolised to the respective acid further to benzoic acid and its conjugates. Subsequent glycine conjugation of benzoyl CoA leads to hippuric acid derivatives which have been observed as a major urinary metabolites in rodents (Adams et al, 2004).

The expected un-conjugated metabolite, tert-butyl benzoic acid (TBBA) was detected in the urine of rodents treated for 5 days with Bourgeonal in a dose dependent manner. Analysis of urine of male rats treated for 5 days at 25 and 100 mg/kg/day showed a mean of 35.75 and 274.8 ug/mL of TBBA detected (Givaudan, 2009).

Cytochrome P450 mediated hydroxylation at the tert-butyl substituent and at benzylic carbon is also likely. Hydroxylation of the aromatic ring is possible. The hydroxylated groups would be expected to be rapidly glucoronidated leading to detoxication and/or rapid excretion.

Study

Toxicity Study by Oral Gavage Administration to Sexually Mature Male CD Rats for 5 Days:

At the end of a 5 Day study on Bourgeonal dosed at 25, 100 and 250 mg/kg bw, animals were placed overnight in an individual metabolism cage without food. Urine samples were collected after administration of the fifth dose for a maximum of 22 hours. Samples were subsequently analysed for 4-tert-butylbenzoic acid (TBBA), 4-iso-butylbenzoic acid and 4-iso-propylbenzoic acid. Bioanalysis was subject to the satisfactory validation of the bioanalytical method, which was performed as part of this study prior to analysis of the study samples. Treatment with Bourgeonal at these concentrations was associated with systemic toxicity and testicular/epididymal toxicity, and the urine contained TBBA, a known metabolite biomarker of testicular toxicity in rats.

ELIMINATION

The n-Octanol/water partition coefficient (log Pow 3.2) is suggestive of accumulation of unchanged Bourgeonal in fatty tissues subsequent to absorption from gastrointestinal tract or from lungs.

 

The following information is taken into account for any hazard / risk assessment:

 

Experimental toxicokinetic studies are not available. The log Pow 3.2 is suggestive of accumulation of unchanged Bourgeonal in fatty tissues subsequent to absorption from gastro-intestinal tract or from lungs.