Naphthenic acids, reaction products with diethylenetriamine

Endpoint summary

Description of key information

The repeated dose toxicity of NA-DETA can be reasonably derived by available data on NA-DETA and read-across to naphthenic acids. Liver toxicity together with related systemic effect is expected upon prolonged exposure to NA-DETA.  The NOAEL of 6 mg/kg bw for subchronic toxicity of NA-DETA is considered to be valid. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

6 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available data comprise one 14-day repeated dose toxicity study on NA-DETA and one combined repeated dose toxicity with reproduction/developmental toxicity sceening study on naphthenic acid and one subchronic toxicity study on naphthenic acid. All three studies are considered to be of equal value for the chronic toxicity assessment of NA-DETA.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The repeated dose toxicity of NA-DETA is derived based on the available data on NA-DETA and the read-across using naphthenic acid as source chemical.

Analog Approach Justification (target chemical: NA-DETA, source chemical: naphthenic acid):

Based on the general biotransformation principles three pathways can be reasonably predicted: a) NA-DETA undergoes enzymatic hydrolysis at amide/imide bond; b) NA-DETA undergoes oxidative N-dealkylation at amide/imide bond, followed by deamination; c) NA-DETA undergoes oxidative N-dealkylation at secondary amine, followed by deamination/oxidation. The result of these introduced pathways is release of naphthenic acid, so that the systemic exposure to naphthenic acid can be derived as toxicity mode of action.

Mode of action of NA-DETA upon prolonged exposure

Two types of mode of action of NA-DETA can be derived:

- local irritation effect on tissues nearby to the portal of entry

- systemic exposure to naphthenic acids.

The local effects is expected to predominate at rather higher exposure dose levels while effect due to the systemic exposure to naphthenic acids is expected to become more distinctive as the exposure period increases. 

According to the preliminary cytotoxicity data in genotoxicity studies (chromosome aberration test and gene mutation test in mammalian cells) NA-DETA is cytotoxic to mammalian cells. Further supporting evidences are that NA-DETA is irritating to skin and eyes. In the 14 -day repeated dose toxicity study in rats mortality occurred at dose levels of 500 mg/kg bw and higher and distinctive changes in the gastro intestinal tract was found in dead animals.

Upon exposure to NA-DETA the tissues nearby to the portal of entry are expected to be the target organ, which means the gastro-intestinal tract, respiratory tract or contact site of skin depending on the exposure routes. The local effect may comprise tissue damage, inflammatory response and poor general health conditions. The reproduction performance may also be affected, but as of secondary nature.

In the 14-day repeated dose toxicity study in rats using NA-DETA as test material no evident toxic effect was observed at dose levels of 100 mg/kg bw and below. The NOAEL of 100 mg/kg bw for irritation effect can be considered to be valid for long-term exposure, since the local irritation effect is a matter of concentration but not of the total systemic exposure level.

At dose levels not associated to local irritation effect the systemic exposure to naphthenic acid may become more important.

The commercial naphthenic acid was investigated according to OECD Guideline 422. The treatment related effects were found in liver, kidney, thyroid and adrenals. Further the red blood cell count for males and the white blood cell count for females were altered, indicating systemic inflammation status.

The naphthenic acid from Canadian oil sands tailings was investigated for its subchronic toxicity using female rats. At dose level of 60 mg/kg bw the liver was found as target organ and the author postulated the induction of hepatic detoxification enzymes as underlying mechanism.

Both studies are indicating the liver as target organ and metabolic overload as underlying mechanism, which should be applicable for the prediction of repeated dose toxicity of NA-DETA. Upon repeated exposure to NA-DETA at dose levels not associated to local irritation effect, liver toxicity is expected to occur together with systemic effect related to metabolic overload.

Comments on the use of the NOAEL of 6 mg/kg bw to derive the DNEL for NA-DETA.

The liver effect found in the OECD 422 study at 300 mg/kg bw is of adaptive nature, whereas the liver effect found in the subchronic toxicity study at 60 mg/kg bw is to be assessed as adverse. The enhanced liver effect found in the subchronic toxicity study can be explained as the synergic combination of increased amount of multiple fused ring components with prolonged exposure duration.

Because the target chemical NA-DETA is the reaction mass of the commercial naphthenic acid, the use of 6 mg/kg bw to derive the DNEL is a very conservative approach, resulting into the overestimation of toxicity of NA-DETA. No further assessment factor related to the read-across uncertainly is justified.

 

Justification for not taking account the observed seizure for hazard assessment of NA-DETA

In the subchronic toxicity study using naphthenic acid from the Canadian oil sands tailings as test material the seizure was observed for animals treated at dose levels of 6 and 60 mg/kg bw. Such effect was not observed in other repeated dose studies using commercial naphthenic acid as test material and seems to be specific to naphthenic acids originating from Canadian oil sands tailings. Also the acute toxicity profile for naphthenic acids originating from oil sands tailings comprised lethargy and ataxia and differed to those of other commercial ones (The American Petroleum Institute, Consortium Registration #1100997, 2012).

Therefore, the observed neurotoxicity indication is considered of limited relevance for the hazard assessment of NA-DETA, because NA-DETA is the reaction mass of the commercial naphthenic acids.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Weight of evidence approach is used for the endpoint repeated dose toxicity.

Justification for classification or non-classification

The availabld data on NA-DETA as well as on read-across surrogated napthenic acid support non-classification for the endpoint repeated dose toxicity.

No classification is warranted.