α,α'-propylenedinitrilodi-o-cresol

Endpoint summary

Description of key information

Based on its physical-chemical properties particularly water solubility, log Pow and molecular weight, the substance and its hydrolysis products which quickly form under physiological conditions, will most likely be absorbed via the GI tract and become systemically available.

Uptake into the systemic circulation following dermal exposure is limited due to the solid nature of the substance at room temperature. Also, based on the appearance as a solid/highly viscous molten mass and the very low vapour pressure at ambient temperature it is unlikely that relevant amounts of the substance will become systemically bioavailable via inhalation.

After becoming bioavailable, it is assumed that the substance will circulate within the blood stream. Based on the chemical structure, metabolism by Phase I and Phase II and respective diamine oxidase enzymes may occur and finally the metabolism products will be excreted via the kidney in the urine.

Neither the parent molecule nor its hydrolysis products are considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physico-Chemical Data

 

The substance appears as a solid / highly viscous molten mass with bright crystalline fractions at standard ambient temperature and pressure. The molecular weight of the substance is 282.337 g/mol and the molecular formula is C₁₇H₁₈N₂O₂. At standard ambient pressure, the melting point is 53°C while the boiling point could not be determined due to limited stability of the substance when further heated.

The substance is moderately water soluble as indicated by the measured water solubility value of 190 mg/L at 20°C. The empirically measured log Pow is pH dependent and was found to be in the range of 1.5 to 3.6 (HPLC method).

A BCF value of 21.27 L/kg wet-weight was calculated using EPIWIN. The substance has a very low vapour pressure which was determined to be1 x10^-4Pa at 20°C. When placed in an aqueous solution, hydrolysis reactions will readily cleave the double bonds at the nitrogen atoms causing the formation of a propylenediamine molecule and two salicylaldehyde (2-hydroxybenzaldehyde) residues. The diamine product has a molecular weight of 74.13 g/mol, is miscible with water and has a calculated (EPIWIN) log Pow of -1.20 and a BCF value of 3.162 L/kg wet-weight (EPIWIN). Salicylaldehyde has a molecular weight of 122.12 g/mol, is slightly soluble in water and has a calculated (EPIWIN) log Pow and BCF value of 2.01 and 7.265 L/kg wet-weight, respectively.

2 Toxicokinetic analysis

 

Absorption

 

Oral route:

Based on the substance's molecular weight and log Pow, absorption through the walls of the gastrointestinal (Gl) tract is likely to occur via passive diffusion. Generally the smaller a molecule, the more easily it may be taken up and substances with a log Pow between -1 and 4 are prone to be sufficiently lipophilic to cross plasma membranes. Also, based on the moderate water solubility the chemical may partly dissolve into the Gl fluids, which enhances its overall availability for absorption. Moreover, once the chemical comes in contact with the digestive fluids of the stomach, hydrolysis reactions will occur. Due to the reduced molecular weight (< 200 g/mol) of the two hydrolysis products, it is possible that they directly cross the gut epithelial by passing through aqueous pores or through membranes by bulk transport of water.

 

With regards with to toxicological data, several acute oral systemic toxicity studies in rats determined the LD50 values to be in the range of 1350 and 2250 mg/kg. However, only local effects on the GI tract with no systemic effects were observed which indicates that the substance and its respective hydrolysis products have a limited potential to cause acute systemic toxicity following a single oral administration. Similarly no definite signs of systemic toxicity were observed in a 14 day dose range finder and a subacute combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test. Although it cannot be excluded that the substance or its hydrolysis products were absorbed through the wall of the GI tract, it appears that no toxicological relevant amounts will reach the systemic circulation following oral intake.

Overall, following oral administration, systemic availability of the parent substance is not likely but bioavailability of the respective hydrolysis products can be assumed.

 

Inhalation route:

Considering the very low vapour pressure, the resulting low volatility and the fact that the chemical exists as a sold/highly viscous molten mass with bright crystalline fractions at room temperature it is unlikely that the substance will be inhaled either in vapour form or as dust particles under use conditions.

 

Dermal route:

The physicochemical properties of the parent substance and its hydrolysis products, such as log Pow, molecular weight and water solubility, do favour dermal absorption. However, as the chemical consists a sa solid/viscous molten mass at room temperature, it has to dissolve into the surface moisture of the skin before uptake can begin. This prerequisite will drastically limit the amount of chemical absorbable when placed in contact to the skin.

The immunological response observed in several skin sensitisation tests using guinea pigs provides evidence that at least small amounts of the substance or its respective hydrolysis product become systemically available following epicutaneous administration. Besides these sensitising effects, acute systemic dermal toxicity testing performed on rats did not reveal that toxicological relevant amounts were absorbed into the systemic circulation. Here, no systemic effects were observed and the LD50 was determined to be greater than 2000 mg/kg bw (limit dose).

 

Distribution

 

Once absorbed into the systemic circulation the parent substance will readily hydrolyse to form the two aforementioned hydrolysis products. In general, due to the water solubility, systemic distribution can be assumed. More specifically, within the systemic circulation it is expected that the hydrolysis products are distributed within the blood stream. Here the transport efficiency to the body tissues is limited by the rate at which the substances cross cell membranes. More specifically, access of the water soluble products to the central nervous system or the testes is likely to be restricted by the blood-brain and blood-testes barriers (Rozman and Klaassen, 1996).

Due to the lacking systemic toxicity of the substance and the emerging hydrolysis products as observed in repeated dose oral toxicity studies, no relevant target organ was identified which could provide further hints towards the distribution profile. Based on the low BCF value, the parent compound and the hydrolysis products have a negligible potential to bioaccumulate in the human body.

 

Metabolism

Based on the chemical structure, the hydrolysis product salicylaldehyde may be metabolized to salicylic acid by Phase I enzymes (e.g. oxidation or reduction of the carbonyl group) aiming to further increase the compound’s hydrophilicity. Here, metabolism to more toxic metabolites cannot completely be excluded. Furthermore, Phase II conjugation reactions are likely to occur which covalently link an endogenous substrate (such as glycine, glucuronic acid etc) to the salicylaldehyde product or the Phase I metabolites in order to ultimately facilitate excretion.

In addition the propylenediamine may be enzymatically degraded by diamine oxidase and will be excreted following Phase II modifications.

 

Excretion

 

Based on the expected biotransformation reactions and the molecular size of the parent molecule and its respective hydrolysis products, it is most likely that the final metabolites are excreted via the urine.

 

3 Summary

Based on its physical-chemical properties particularly water solubility, log Pow and molecular weight, the substance and its hydrolysis products which quickly form under physiological conditions, will most likely be absorbed via the GI tract and become systemically available. Uptake into the systemic circulation following dermal exposure is limited due to the solid nature of the substance at room temperature. Also, based on the appearance as solid/highly viscous molten mass and the very low vapour pressure at ambient temperature it is unlikely that relevant amounts of the substance will become systemically bioavailable via inhalation.

After becoming bioavailable, it is assumed that the substance will circulate within the blood stream. Based on the chemical structure, metabolism by Phase I and Phase II and respective diamine oxidase enzymes may occur and finally the metabolism products will be excreted via the kidney in the urine.

Based on its BCF values neither the parent molecule nor its hydrolysis products are considered to be bioaccumulative.

4 References

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press,,, 2nd Edition 688-689.

 

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

 

Rozman K.K., Klaassen C.D. (1996) Absorption, Distribution, and Excretion of Toxicants. In Klaassen C.D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York.

 

Bonse G., Metzler M. (1978) Biotransformation organischer Fremdsubstanzen. Thieme Verlag, Stuttgart.