trans-crotonic acid

Endpoint summary

Description of key information

Based on the available physicochemical and toxicological data, Crotonic acid is considered to be bioavailable after oral exposure. Absorption after dermal exposure is limited and exposure via inhalation is not relevant due to the low vapour pressure and high particle size. Following uptake the compound is likely to be readily distributed throughout the body. The formation of reactive metabolites is considered unlikely. Excretion of Crotonic acid occurs most likely via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

In line with chapter R.7 c (ECHA, 2012) the main toxicokinetic properties of Crotonic acid (CAS-No. 107-93-7) are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance. Specific toxicokinetics or dermal absorption studies are not available for the substance.

1. Relevant physico-chemical properties of Crotonic acid

 

Molecular weight:                    86.09 g/mol

Physical state:                        crystal (white)

logPow:                                 0.85

Water solubility:                       94 g/L

pKa:                                      4.69

Vapour pressure:                     0.25 hPa (20°C)/ 25 Pa (20°C)

Particle size:                           >125 µm

 

2. Absorption

 

Oral Absorption

 

Based on its low molecular weight of 86.09 g/mol Crotonic acid is likely to be absorbed in the GI tract since small molecules with a molecular weight below 500 g/mol do favour absorption. This assumption is supported by the results of the acute oral toxicity study (Hoechst AG (a), 1967) indicating signs of systemic toxicity like imbalance and narcosis prior to death. It is generally thought that ionized substances do not readily diffuse across biological membranes. On this basis, absorption of acids are favoured at pHs below their pKa values. Since the pKa of Crotonic acid is 4.69 an absorption in the stomach (pH stomach < 4.69) seems to be most relevant. The log Pow value of 0.85 leads to the conclusion that absorption of the test substance occurs generally by passive diffusion which requires a moderate log Pow value (between -1 and 4). However, due to the good water solubility absorption by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

 

Absorption after inhalation

 

Substances with a vapour pressure of less than 0.5 KPa (500 Pa) have a low volatility. Since the vapour pressure of Crotonic acid is 25 Pa the availability for inhalation as a vapour is low. In addition, the potential to be inhaled by humans is given if the particles exhibit an aerodynamic diameter below 100 µm. Since Crotonic acid does not contain any particles smaller than 125 µm an exposure to inhalable particles of the compound is not expected. If an inhalable/respirable dust were generated and based on the physico-chemical properties, a precipitation on the mucous membranes of the upper airways followed by mucociliary cleansing and transport into the stomach seems more likely than an absorption in the alveolar region of the respiratory tract. The results obtained in the acute inhalation toxicity study (Hoechst AG (b), 1967) are in agreement with this assumption. Within this study rats were exposed to the vapoured test item in an exposure chamber (whole body exposure). The concentration of the test item is unknown as the evaporated test item recrystallised partly before the vapour reached the inhalation chamber. Nevertheless, no mortality and no systemic toxicity were observed.

 

Dermal absorption

 

With respect to the low molecular weight (< 100 g/mol) and the log Pow between 1 and 4 a dermal uptake of Crotonic acid might be expected. However, a substance must be non-ionised at the skin's pH to partition into the skin and also sufficiently soluble in water to partition from the stratum corneum into the epidermis. Based on the pKa of 4.69 dermal absorption of Crotonic acid is anticipated to be low to moderate. This is further supported by the results of an acute dermal toxicity study (Toxi-Coop Zrt. (b), 2012) performed on rats. During the study no mortality and no systemic toxic effects were observed for the highest dose of 2000 mg/kg bw.

 

3. Distribution/Metabolism 

 

In view of the clinical signs observed in the acute oral toxicity study (Hoechst AG (a), 1967) with Crotonic acid, its low molecular weight, the water solubilty of 94 g/L and the log Pow of 0.85 a wide distribution and no accumulation of Crotonic acid in the body can be expected.

Generally, metabolism will render a xenobiotic molecule more polar and harmless, leading to fast and quantitative excretion. For Crotonic acid, no conversion into a metabolite that was more cytotoxic or more genotoxic than the parent substance was noted when comparing in vitro test results with metabolic activation to in vitro test results without metobolic activation system (genetic toxicity tests). Thus, the formation of reactive metabolites is unlikely.

 

4. Excretion

 

Based on its log Pow (0.86) the test substance has no potential to bioaccumulate in the human body. The low molecular weight (below 300 g/mol), the good water solubility and the ionization of the molecule at pH of urine (pH urine > pKa Crotonic acid) indicated urinary excretion as most relevant route of excretion for Crotonic acid.

5. Generic absorption rates

Based on the above information and due to the fact that there are no specific toxicokinetic data available the generic values of 100 % for oral absorption and inhalation absorption of respirable particles as well as 25 % for dermal absorption were derived.