Fatty acids, tall-oil, reaction products with formaldehyde and (Z)-N-9-octadecenyl-1,3-propanediamine

Endpoint summary

Description of key information

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of ‘Fatty acids, tall-oil, reaction products’.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Fatty acids, tall-oil, reaction products with formaldehyde and (Z)-N-9-octadecenyl-1,3-propanediamine (hereafter called ‘Fatty acids, tall-oil, reaction products’) is a dark brown liquid. This substance of unknown or variable composition, complex reaction products or biological material (UVCB substance) is insoluble in water (< 1mg/L; Brekelmans, 2013). The log P is in the range of 3 to >6.5 (pH 2) and 1.4 to >6.5 (pH 10) at 20 °C, with a vast majority (89% at pH 2 and 76% at pH 10) showing a log Pow >6.5, following the HPLC method (Brekelmans, 2013). The vapour pressure is low (2.9´10^-3Pa at 20°C; 4.5´10^-3Pa at 25°C; Brekelmans, 2013). No pKa value for use in this assessment is available aspKa determination of this UVCB substance was technically not feasible.

The substance is found to be skin sensitiser (Stitzinger, 2013). The substance is not an eye or skin irritant.

The physico-chemical properties used are in general applicable for pure substances only. Hence the physico-chemical properties used in the current assessment are best estimates aiming to describe the intrinsic properties of the UVCB substance as a whole. As a consequence, compounds with a (significantly) different behaviour might be present in the mixture. The results of this toxicokinetic assessment should therefore be treated with care.

 

Absorption

Oral/Gastro-intestinal absorption

As per its low water solubility, ‘Fatty acids, tall-oil, reaction products’ will not readily dissolve into the gastrointestinal (GI) fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Based on the log P range, absorption by passive diffusion can be enhanced for those constituents with moderate log P values (between -1 and 4) but only if they are more water soluble than the ‘Fatty acids, tall-oil, reaction products’. As the substance is quite insoluble in water, oral absorption by passive diffusion of these constituents is not expected. Any other non-water soluble but lipophilic constituent with log P > 4 (highly lipophilic) may be taken up by micellular solubilisation.

It is generally thought that ionised substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration is normally produced, influenced by the ionised status of the substance at the intestine pH. pKa value/range for ‘Fatty acids, tall-oil, reaction products’ could not be technically determined. Therefore, no estimation on the ionised proportion of the substance at biologically relevant pH is possible.

In an acute oral toxicity study in rats (Gabriel, 1995), the substance was tested at 2000 mg/kg bw. No vehicle was used and the substance was dosed unchanged. The substance appears to have an acute oral LD50 greater than 2000 mg/kg bw. No gross abnormalities were observed in any of the animals necropsied at the conclusion of the 14 day observation period. Based on the absence of toxic effects, it is concluded that the substance is poorly absorbed and / or essentially acutely non-toxic when dosed via the oral route.

In a combined 28 day repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (Peter 2013) by oral gavage, the substance was tested at 100, 300 and 1000 mg/kg bw/d. The dosing vehicle was corn-oil. This vehicle was selected as the most suitable to dose the substance even though it can reduce the absorption when compared to water as dosing vehicle. Two females at 1000 mg/kg bw/day were killed in extremis (one on Day 8 of the mating period and one on Day 14 of the post-coitum period). Under these experimental conditions, parental adverse effects at 300 and 1000 mg/kg bw were observed, primarily consisting of granulomatous inflammation in the mesenteric lymph nodes at 300 and 1000 mg/kg bw. Other treatment-related morphologic findings were recorded in the lung (alveolar macrophages) of males and females at 300 and 1000 mg/kg bw, in the forestomach (diffuse hyperplasia of the squamous epithelium) and liver (hepatocellular centrilobular hypertrophy) of males and females at 1000 mg/kg bw, in the spleen (decrease in hematopoietic foci) of males at 1000 mg/kg bw and the adrenals (hypertrophy of the zona fasciculate with corresponding increased adrenal weights) of females at 1000 mg/kg bw. No reproductive or developmental toxicity was observed for treatment up to 1000 mg/kg bw. Based on these results, the NOAEL for systemic parental toxicity was derived to be 100 mg/kg . Although the vehicle used in the above-mentioned study can affect rate uptake, the effects observed demonstrate that the substance was absorbed.

Based on the toxicological information available, the low solubility of the compound and high lipophilicity of most of the components, an oral absorption factor of 50% is proposed.

Respiratory absorption

Given the low vapour pressure of ‘Fatty acids, tall-oil, reaction products’, a very limited availability for inhalation as a vapour is expected.

Once in the respiratory tract, this water insoluble substance is not expected to be retained within the mucus and hence no subsequent absorption is expected. Based on the log P range, absorption by passive diffusion can be enhanced for those constituents with moderate log P values (between -1 and 4) but only if they are more water soluble. As the substance is quite insoluble in water, absorption by passive diffusion of these constituents is not expected. Any other non-water soluble but lipophilic constituent with log P > 4 (highly lipophilic) may be taken up by micellular solubilisation.

In an acute inhalation study (Gabriel, 1974a) with rats, the whole body of the animals was exposed to aerosol of (estimated concentration= 3.1 mg/L; 1-hour exposure). Mortality was observed during the first 24h after exposure and thereafter. The rats showed slow, laboured breathing and were inactive during the exposure period. No other findings (e.g. macroscopic findings) were reported. From the results obtained in this study, it appears that the substance would be considered to be toxic but not highly toxic by the inhalation route of administration since the LC50 is approximately 3.1 mg/L. The study results do not give any (qualitative) indication on the actual absorption rate as these effects can be interpreted as difficulty to breath due to the nature of the aerosol (insoluble). It can be concluded that the toxic effects observed in the study were due to local irritation effects rather than systemic effects. Therefore the results of this study can poorly support the evaluation of absorption and systemic bioavailability after inhalation.

No long-term inhalation toxicity study is available for ‘Fatty acids, tall-oil, reaction products’.

Based on all the above considerations and in the absence of toxicokinetic experimental data via inhalation or other relevant toxicity data, the inhalatory absorption factor is set to 100%, as a worst case assumption.

Dermal absorption

In view of the log P range ‘Fatty acids, tall-oil, reaction products’ is expected to be sufficiently lipophilic to favour dermal absorption although at the meantime lipophilicity could negatively affect in some extent the rate of dermal absorption by decreasing the transfer between the stratum corneum and the epidermis. Based on these parameters, penetration into the lipid-rich stratum corneum and hence dermal absorption is favoured.

In an acute dermal toxicity study (Gabriel, 1974b) ‘Fatty acids, tall-oil, reaction products’ was tested unchanged at 1000, 2000, 4000 and 8000 mg/kg bw. Four animals were tested per sex and per dose. Mortality was observed at 4000 (1 animal died at day 2) and 8000 mg/kg bw (1 animal died at day 2 and 1 animal died at day 3). No clinical signs or other relevant information (e.g. systemic effects) were reported. The study therefore gives a rough indication on the absorption of the substances by the dermal route at very high concentrations.

‘Fatty acids, tall-oil, reaction products’ is not skin irritant .

‘Fatty acids, tall-oil, reaction products’ is considered to be a skin sensitiser (Stitzinger 2013) when applied to intact skin of mice. It is therefore expected that some uptake has occurred through the skin.

No long-term dermal toxicity study is available for ‘Fatty acids, tall-oil, reaction products’.

Generally default values of 10% and 100% are used for dermal absorption, based on molecular weight and log P value (ECHA guidance on IR&CSA, R.7c).

The dermal absorption factor might therefore be set to 50%, based on a log P and low water solubility. The results of the available dermal toxicity studies do not provide any reasons to deviate from this proposed value.

Distribution

In general, the smaller the molecule, the wider the distribution. Furthermore poor soluble substances are expected not to diffuse through aqueous channels and pores. The poor water solubility and molecular weight of ‘Fatty acids, tall-oil, reaction products’ predict that the substance will not easily distribute through the body.

Based on the log P , the bioavailable substance is expected to distribute into cells and the intracellular concentration may be higher than the extracellular concentration particularly in fatty tissues.

In a combined 28 d repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (Peter, 2013) by oral gavage, macroscopic findings primarily consisted of granulomatous inflammation in the mesenteric lymph nodes at 300 and 1000 mg/kg bw. Other treatment-related microscopic findings were recorded in the lung, forestomach, liver, spleen and the adrenals. These observations indicate that these are potentially the target organs.

In conclusion, and based on the above considerations, it is expected that ‘Fatty acids, tall-oil, reaction products’ distributes through the body in some extent but the process will be significantly hampered by its physico-chemical properties

 

Accumulation

Although the substance is expected not to easily distribute into the body (due to the very low water solubility), a small amount could reach the cells (as showed in the 28-day study here above) and therefore also the adipose tissues where it could potentially accumulate based on the log P.

 

Metabolism

Once absorbed, ‘Fatty acids, tall-oil, reaction products’ might undergo phase I biotransformation followed by conjugation reactions (phase II).

 

Excretion

Given the poor water solubility and relatively mainly highly lipophilic character of the components, bioavailable ‘Fatty acids, tall-oil, reaction products’ and its insoluble conjugates will be mainly excreted via the feces.

No absorbed ‘Fatty acids, tall-oil, reaction products’ after oral exposure will be eliminated via the feces.

 

References

Brekelmans (2013). Determination of physico-chemical properties of reaction product of oleic acid, n1-(9Z)-9-octadecen-1-yl-1,3-propanediamine and paraformaldehyde. WIL Research Europe B.V. Technical report.

Gabriel (1974a). Acute inhalation toxicity – rats. Biosearch Incorporated. Technical report.

Gabriel (1974b). Acute dermal toxicity – rats. Biosearch Incorporated. Technical report.

Gabriel (1995). Acute oral toxicity, single level – rats. Biosearch Incorporated. Technical report.

Peter (2013). Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of reaction product of oleic acid, N1-(9Z)-9-octadecen-1-yl-1,3-propanediamine and paraformaldehyde in rats by oral gavage. WIL Research Europe B.V. Technical report.

Stitzinger (2013). Assessment of contact hypersensitivity to reaction product of Oleic acid, N1-(9Z)-9-octadecen-yl-1,3-propanediamine and paraformaldehyde in the mouse (local lymph node assay). WIL Research Europe B.V. Technical report.