Naphthenic acids, bismuth salts

Endpoint summary

Description of key information

The source substance bismuth hydroxy nitrate oxide was found being uncritical in a sub-chronic oral toxicity test (OECD 408, NOAEL = 1000 mg/kg bw/d), equivalent to ~3.4 mmol Bi/kg bw/d (based on Bi5H9N4O22).

In s sub-acute oral toxicity study with naphthenic acids grades, a NOAEL of 100 mg/kg bw/d was determined (equivalent to 0.44 mmol naphthenic acids/kg bw/d, calculated based on an average of C14, 1-ring naphthenic acid as average value).

Considering a bismuth content in the target substance of 26.4% as determined and the naphthenic acids, making up the remaining 73.6% as bound and residual free naphthenic acids, the calculated theoretical NOAEL is derived as 100 mg/kg bw/d * 100% / 73.6% ≈ 136 mg/kg bw/d (and the LOAEL at ~ 400 mg/kg bw/d). This conservative approach assumes that all naphthenic acids, those bound to bismuth as well as the excess free naphthenic acids, were bioavailable, contributing to systemic toxicity. This value will be taken forward for hazard and risk assessment.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The substance naphthenic acids, bismuth salts is manufactured from bismuth oxide/hydroxide and 3 equivalents of naphthenic acids, resulting in the bismuth tri-naphthenate. Thus, to assess acute toxicity by oral route, results for bismuth 3+ cations were assessed as well as data for naphthenic acids, the two potential hydrolysis products of the substance. The undissociated substance is considered uncritical, as its molecular mass of ~850 Dalton makes it unlikely that such compounds efficiently pass biological membranes. Thus, the acute oral toxicity on naphthenic acids, bismuth salts will be dominated by its ions, derived from hydrolysis.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source compound naphthenic acids is the starting material for the manufacturing of naphthenic acids, bismuth salts. Naphthenic acids do contain mainly hydrocarbon acids with a carbon range from 10 - 15 (other naphthenic acids may have wider ranges), with a variable number of cyclics contained (n = 0, 1, 2 and rarely 3). To a minor extent also aliphatics may be present as minor "impurities".
The naphthenic acids are reacted in a slight excess of >3 equivalents of naphthenic acids with bismuth oxide to derive naphthenic acids, bismuth salts containing bismuth tri-naphthenate and a slight excess of naphthenic acids, the target substance. Thus, the starting compound for the synthesis of the target compound is actually the source substance. Whereas the bismuth oxide used has a purity of 99% by weight typically, the naphthenic acids, being a UVCB-type substance, are of 100% purity, by definition.
The second source substance used here is bismuth hydroxy nitrate oxide, a soluble form of bismuth(III) compounds, suitable to achieve high Bi3+ concentrations in aqueous biotic systems; this substance was chosen for subacute toxicity testing as surrogate for bismuth compounds, as it allowed achieving high Bi3+ concentrations and thus a maximum bioavailability, compared to bismuth oxide, being hardly absorbed.
Thus, the two source compounds naphthenic acids (as surrogate for naphthenate anions and bismuth hydroxy nitrate oxide (as surrogate for bismuth cations) are appropriate surrogates for assessing the subacute oral toxicity of the target substance.

3. ANALOGUE APPROACH JUSTIFICATION
Although the two source substances are different in respect of properties compared to the target substance, the read-across is justified, as the source substance bismuth hydroxy nitrate oxide allows to achieve a higher bismuth concentration in aqueous systems and thus better absorption, compared to the target substance (water solubility of < 0.036 mg/L). In a sub-chronic oral toxicity study according to OECD 408 no adverse effects were seen up to the highest dose tested (NOAEL = 1000 mg/kg bw/d). The second source substance naphthenic acids has been investigated in a combined 28-day repeated dose oral toxicity study with the reproduction/developmental toxicity screening test with a mammalian erythrocyte micronucleus test in rats, essentially an OECD 422 study, amended by a mutagenicity in vivo module (OPPTS 870.3650) as requested by the US EPA. Doses tested were 0 (control), 100, 300 and 900 mg/kg bw/d. No neurotoxic effects were seen in any dose group and the NOAEL for Neurotoxicity was set to 900 mg/kg bw/d (highest dose group). The NOAEL for systemic toxicity was set to 100 mg/kg bw/d, due to 2 mortalities in the high dose group females and statistically significant effects on liver and kidney weight increase in the high dose and to a lesser extent also in the mid dose group.
Thus, it can be concluded, that the bismuth(III) cations are of low systemic toxicity, whereas the findings on naphthenic acids are more decisive for the repeated dose systemic toxicity of the target substance naphthenic acids, bismuth salts, especially when considering the very low water solubility of the target substance that was determined being < 0.036 mg/L and the expected low absorption rate of the undissociated target substance. However, as the target substance does contain free naphthenic acids (~10%) due to a slight excess used during production, the naphthenic acids findings have to be considered for assessing the systemic toxicity of the target substance

4. DATA MATRIX
The source substance bismuth hydroxy nitrate oxide was found being uncritical in a sub-chronic oral toxicity test (OECD 408, NOAEL = 1000 mg/kg bw/d), equivalent to ~3.4 mmol Bi/kg bw/d (based on Bi5H9N4O22).
In s sub-acute oral toxicity study with naphthenic acids grades, a NOAEL of 100 mg/kg bw/d was determined (equivalent to 0.44 mmol/kg bw/d, calculated based on an average of C14, 1-ring naphthenic acid as average value).
Considering a bismuth content in the target substance of 26.4% as determined and the naphthenic acids, making up the remaining 73.6% as bound and residual free naphthenic acids, the calculated theoretical NOAEL is derived as 100 mg/kg bw/d * 100% / 73.6% ≈ 136 mg/kg bw/d (and the LOAEL at ~ 400 mg/kg bw/d). This conservative approach assumes that all naphthenic acids, those bound to bismuth as well as the excess free naphthenic acids, were bioavailable, contributing to systemic toxicity. This value will be taken forward for hazard and risk assessment.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

ca. 136 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

naphthenic acids, bismuth salts

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

LOAEL

Remarks:

systemic toxicity

Effect level:

ca. 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Effect level:

> 900 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

yes

Lowest effective dose / conc.:

400 mg/kg bw/day (nominal)

System:

gastrointestinal tract

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

Whereas bismuth cations have been shown to be of low systemic toxicity (sub-chronic NOAEL of 1000 mg/kg bw/d ≈ 3.4 mmol Bi/kg bw/d), naphthenic acids in an OECD 422 study have shown organ weigth effects on liver and kidneys and the NOAEL was set to 100 mg/kg bw/d (equivalent to 0.44 mmol naphthenic acids/kg bw/d). Considering the bismuth content of 26.4% w/w in the target compound and therfore assuming naphthenic acids are present bound to bismuth but also free in slight excess from manuafcturing, the NOAEL can be converted to 100 mg/kg bw/d * 100% / 73.6% ≈ 136 mg/kg bw/d for the target substance naphthenic acids bismuth salts.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

136 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

Justification for classification or non-classification

Naphthenic acids, bismuth salts are not subject to classification for systemic toxicity according to CLP as bismuth cations were shown to be of low systemic toxicity, whereas naphthenic acids showed rather unspecific systemic toxicity to liver and kidneys. The NOAEL(derived) was 136 mg/kg bw/d and the LOAEL was ~ 400 mg/kg bw/d, above the threshold for classification as recommended in CLP (Regulation EC No. 1272/2008). Thus, the substance is not subject to classification for systemic target organ toxicity, repeated exposure (STOT RE).