Naphthenic acids

Endpoint summary

Description of key information

A basic toxicokinetic assessment was performed based on the REACH Guidance on data requirements. The following absorption factors were established: oral 50%, inhalation 50% and dermal 10%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

Naphthenic acid (CAS 1338-24-5; EC 215-662-8), is a UVCB consisting of an acidic (naphthenic) fraction (70-95%) composed mainly of C8 -C20 and 0 -3 rings and non-acidic (unsaponifiable) hydrocarbon (petroleum) fraction (5 -30%) composed mainly of C12 -C22 and <10% aromatics. The substance is described as a viscous, pale yellow to dark amber liquid. Naphthenic acid was experimentally determined to be only slightly soluble in water (88.1 mg/L at 20°C). Even though the range of the partition coefficient of naphthenic acid is broad (2.05 < log Kow < 13.25), its typical value is considered to be high (mean log Kow 7.65). The substance has a low vapour pressure of 31.4 Pa (at 25°C). The molecular weight ranges from 140 to 311 g/mol with a mean of 227 g/mol. This substance is moderately to severely irritating to skin (skin irritant, category 2).

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 enables a qualitative assessment of the toxicokinetic behaviour of the test substance.

Absorption

Oral/GI absorption

Generally, substances with a molecular weight below 500 g/mol are favourable for absorption. Naphthenic acid is also highly lipophilic and absorption by passive diffusion will be favoured. However, the absorption of highly lipophilic substances (log P of 4 or above) by passive diffusion may be limited by the inability of such substances to dissolve into GI fluids and hence make contact with the mucosal surface. Furthermore, based on its limited water solubility the dissolution into the gastrointestinal fluid is limited as well. Nevertheless, the absorption of lipophilic substances can still be enhanced if they undergo micellular solubilisation by bile salts (Aungst and Shen, 1986).

Various acute oral toxicity studies are evaluated in a weight of evidence approach, with LD50 determined as 1000 mg/kg and adverse effects observed like for instance pericholangitis, brain haemorrhage, and cardiac periarteriolar necrosis and fibrosis.

A study for repeated dose toxicity (HPVIS, 2010) combined with a reproduction /developmental toxicity screening test in Wistar rats was performed by oral gavage with Naphthenic acids in corn oil (according to OECD guideline 422). There were 3 treated groups (100, 300 and 900 mg/kg bw) and a control group (corn oil) each counting 12 animals/sex/group. Male rats were dosed during premating, mating and afterwards for 28 days in total and females were dosed during premating, mating, gestation and up to day 3 post-partum.

At the lowest dose of 100 mg/kg bw, no effects were observed both in male and female rats. At the medium and high doses, two mortalities were observed and body weight gain at the high dose was reduced for less than 10% in males and 4% in females versus control groups, associated with reduced food consumption in both groups. Slightly reduced haemoglobin, increased liver weight, paled kidneys and significant increase in kidney weight was observed in males of the medium and high dose group. In females of the same dose groups (but only statistically significant in high dose), an increased liver weight and reduction in the number of corpora lutea was observed as well.

As a result, the dose levels of 300 and 900 mg/kg bw were considered to be toxic in male and female parents with an overall NOAEL for systemic toxicity of 100 mg/kg bw. No reproductive effects were identified up to 900 mg/kg bw. There were no weight differences in any of the other organs nor any pathological changes in the reproductive organs up to the highest dose tested. The NOAEL for mating and reproductive effects was 900 mg/kg/day.

In a 90 days repeated dose study (Weisz, 2018) performed on Wistar rats (10 males and 10 females per dose groups), naphthenic acid is administered via diet (according to OECD guideline 408). Animal food consumption per cage were measured and the mean daily food intake per rat was calculated. Based on food consumption data, the mean dose level of each group was calculated as 1500, 4200 and 12500 ppm or 107, 302 and 881 mg/kg bw/day. Exposure to Naphthenic acids did not result in test item related mortality or clinical signs. The lower body weight, body weight gain and food consumption values in the Mid and High dose groups observed were considered to be caused by the low palatability of the treated diet, with no evidence of a clear systemic toxic effect of the test item. Test item-related microscopic findings were seen in the liver, adrenal and thyroid glands of the High dose groups but were considered as secondary and not and adverse effect of the test item. The NOAEL was set to 302 mg/kg bw/day.

In a developmental toxicity study (Oroszlány,2018), Naphthenic acid was administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD6 to GD19 (OECD guideline 414). The doses levels were (66.7, 200, 600 mg/kg bw/day) and the daily administration ended in induced maternal toxicity at 600 mg/kg bw/day, with clinical signs of piloerection and hunched back, reduced food intake, reduced body weight and body weight gain, and thickening of the non-glandular mucosal region of the stomach. The mid dose of 200 mg/kg bw/day also showed evidence of a slight maternal toxicity and less clinical signs and no effect on body weight.

The offspring did not demonstrate malformations or developmental effects attributed to test item at any dose level. In the high dose group, the incidence of runts was higher and foetal viability was slightly lower than control; also, one litter had reduced foetal weight and reduced ossification; these observations were attributed to maternal toxicity. There were no such effects in the Mid or Low dose groups.

Based on the physico-chemical parameters and the effects observed, the oral absorption factor is set to 50%.

 

Respiratory absorption

Considering the vapour pressure of Naphthenic acid (estimated values ranged from 1.41E-21 to 37.1 Pa at 25°C) and the high viscosity, inhalation of vapours is improbable and aerosols are not expected to be formed with standard uses.

Generally, liquids readily diffuse/dissolve into the mucus lining of the respiratory tract. If also lipophilic, there is a potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. However, in the case of Naphthenic acid, the limited water solubility will limit the rate at which the substance dissolve into the mucus lining of the respiratory track.

Based on the physicochemical properties, the respiratory absorption factor is set to 50%.

Dermal absorption

Naphthenic acid is a viscous liquid substance and therefore it is more easily taken up by the skin in comparison to solid products. In order to cross the skin, a compound must first penetrate into the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane) and may subsequently reach the viable epidermis, the dermis and the vascular network. It is expected that the penetration of Naphthenic acid into the lipid rich environment of the stratum corneum will be favoured considering the lipophilic character of the substance. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Considering that the substance is only slightly soluble in water, dermal uptake of the substance is expected to be low to moderate.

A skin sensitisation maximization test in 6-week-old female Hartley guinea pigs (5 animals/per dose) was performed with Naphthenic acids (Yamato, 2006). The doses applied were 1%, 25% as induction phases and 0.5% as challenge dose and resulted in 4 out of 5 animals showing clear reactions at 48 hours, therefore it is considered to be sensitizing for skin (category 1A).

In a combined dermal toxicity and irritation/corrosion study (HPVIS, 2003) performed on New Zealand White rabbits, 3.16 g/kg Naphthenic acid was applied under occlusive dressing for 24 hours. No deaths occurred at this dose level. The initial response of the skin showed little difference in response between intact or abraded sites. Erythema and edema were partly reversible after 14 days. The test material was considered moderately to severely irritating to the occluded skin (category 2 based on GHS criteria).

As a result, the default dermal absorption factor is set to10%.

Distribution

Lipophilic substances will have a higher tendency to cross the cell membranes and partition into the tissues, so the rate of distribution is higher. The substance is then likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. The target organs are likely to be the brain, the heart, the liver and kidneys, as was confirmed in repeated dose toxicity studies. Based on the low molecular weight fraction and the high log P, but mainly based on the target organs identified after oral administration, distribution is evident.

Accumulation

As the substance is lipophilic, it is expected to concentrate within the adipose tissue where it may accumulate depending on the exposure conditions. Although a lipophilic substance can penetrate readily the lipid rich stratum corneum, it is not absorbed systemically and will be cleared as the stratum corneum is sloughed off. Therefore, very limited accumulation in adipose tissue can be expected.

In addition, accumulation of the native substance is limited due to phase I and phase II metabolism (as described below), which increases solubility of the substance.

Metabolism

Once absorbed, extensive hydroxylation or reduction may occur to increase the solubility of the substance (phase I biotransformation), followed by rapid sulfation or glucuronidation (phase II biotransformation) is expected. The highly lipophilic character of the various fraction in naphthenic acid, the increased liver weights and adaptive histology in the repeated dose toxicity endpoint to an increased liver metabolism which will render more water-soluble metabolites of naphthenic acid.

Excretion

The water soluble conjugated metabolites from Phase II biotransformation will be excreted from the systemic circulation through the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium.

From the assumptions above, excretion via the urine or other body fluids (e.g. bile) is considered to be most probable. It might be expected that the non-absorbed fraction of naphthenic acid will be eliminated via the faeces together with a small fraction eliminated via the bile excretion. The absorbed naphthenic acid fractions after metabolization will be more water-soluble molecule to be mainly excreted via the kidneys. Therefore it is not considered to accumulate.