Naphthenic acids, bismuth salts

Endpoint summary

Description of key information

Based on data from bismuth compounds and naphthenic acids, all showing low oral and dermal toxicity, in a read-across approach to the cationic and anionic moieties of the target substance naphthenic acids, bismuth salts are considered not acutely toxic by oral and dermal route. Given the low vapour pressure of the substance (< 1 Pa) and the high molecular mass (~ 850 Dalton) exposure by inhalation is very unlikely.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute 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 with 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 salicylate, a soluble form of bismuth(III) compounds, suitable to achieve high Bi3+ concentrations in aqueous biotic systems.
Thus, the two source compounds naphthenic acids (as surrogate for naphthenate anions and bismuth salicylate (as surrogate for bismuth cations) are appropriate surrogates for assessing the acute 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 salicylate 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) and no effects were seen (no mortality or clinical signs at a dose level of 2000 mg/kg bw). The second source substance naphthenic acids has been investigated in three different acute toxicity assessments with different naphthenic acid specification, consistently showing a low oral toxicity (LD50 values of >= 3000 mg/k bw for crude kerosene acids and >= 5200 mg/kg bw for mixed crude oil fractions, reported by W.T. Rockhold, 1955; LD50 value of >= 5880 mg/kg bw, reported by Exxon, 1979; and an LD50 value of 3550 mg/kg bw, reported by S. Pennesi, S. and V.D. Lynch, 1977).
Thus, it can be concluded, that both, the bismuth(III) cation as well as the naphthenic acids are of low acute oral toxicity and a LD50 of > 2000 mg/kg bw can be assumed for bismuth naphthenate, 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.

4. DATA MATRIX
The source substance bismuth salicylate was found being uncritical in an acute oral toxicity test (OECD 423 acute toxic class method, LD50 > 2000 mg/kg bw, no mortality or clinical signs observed, equivalent to > 5.5 mmol Bi/kg bw).
In three weight of evidence acute oral toxicity studies with naphthenic acids grades, acute oral toxicity in the range of 3000 – 5880 mg/kg bw were observed (equivalent to 13.3 – 26.0 mmol/L (calculated based on an average of C14, 1-ring naphthenic acid as average value).
Considering the 3:1 molar ratio of naphthenic acid and bismuth in the target substance (on average estimated as Bi(O2C13H24)3) as well as the molecular average mass of 850 Dalton, the calculated theoretical LD50 is derived as > 3768 mg/kg bw as worst case. In consequence, it is expected that naphthenic acids, bismuth salts are not acutely toxic upon oral exposure.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 768 mg/kg bw

Based on:

test mat.

Remarks on result:

other: result is based on the lowest LD50 of naphthenic acids grades tested

Interpretation of results:

GHS criteria not met

Conclusions:

Based on available acute toxicity data on naphthenic acids and bismuth (3+) compounds, the acute oral toxicity of bismuth naphthenate towards rats is conservatively assessed being > 3768 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 768 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 dermal toxicity, 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 or skin. Thus, the acute dermal 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 with 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, not capable of passing the human skin, the naphthenic acids, being a UVCB-type substance, are of 100% purity, by definition.
As neither bismuth naphthenate, due to its size (molecular weight of ~850 Dalton) nor bismuth cations are capable of passing the human skin, no dermal toxicity data for bismuth compounds are available. However, the in vitro data on skin irritation, showing no effects, as well as the in vivo LLNA data on bismuth hydroxy naphthenate, showing neither skin sensitisation nor irritation (even when tested up to 50%), do support the thesis that bismuth compounds are not absorbed through human skin.
Thus, the source compound naphthenic acids (as surrogate for naphthenate anions from bismuth naphthenate is an appropriate surrogate for assessing the acute dermal toxicity of the target substance.

3. ANALOGUE APPROACH JUSTIFICATION
The target substance naphthenic acids, bismuth salts, containing mainly bismuth tris-naphthenate, has a huge molecular weight (~ 850 Dalton) and it is known that such substance can hardly pass human skin. However, the slight excess of naphthenic acids, used to shift the reaction towards tri-substitution, will mainly determine the dermal toxicity of the UVCB substance, and naphthenic acids, due to a much smaller molecular size will be potentially capable of passing human skin. Thus, the focus for assessing acute dermal toxicity will be on naphthenic acids.
The source substance naphthenic acids has been investigated for dermal toxicity in an OECD 402 like study (Exxon 1979) with dermal application to rabbit skin. A dose of 3.16 g/kg bw was applied and no mortality was observed. Symptoms note at this dose were lethargy, diarrhea, ptosis, adipsia, anorexia, and few feces, but no mortality was seen. Mean values (24, 48 & 72 hours) for erythema and edema at the intact sites were 1.69 and 1.3, respectively. All symptoms were reversible during 14 days observation period.
No dermal toxicity data for bismuth compounds are available, but results from in vitro skin irritation tests (reconstructed human epidermis test method) with bismuth hydroxide showed no signs of irritation and also results from an in vivo LLNA study with rats, dosing up to 50% bismuth hydroxy nitrate, were well tolerated by the animals and no signs of sensitisation were seen. Thus, it can be assumed that bismuth compounds do not significantly pass biological membranes to cause systemic toxicity.
Thus, it can be concluded, that both, the bismuth(III) cation as well as the naphthenic acids are of low acute dermal toxicity and a LD50 of > 2000 mg/kg bw can be assumed for bismuth naphthenate, 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.

4. DATA MATRIX
The source substance naphthenic acids was assessed in an acute dermal toxicity study (combined with a skin irritation study) and found being neither acutely toxic by dermal route nor classified as skin irritant or corrosive. Bismuth compounds are known not to significantly pass human skin, which is supported by an in vitro dermal skin irritation study (reconstructed human epidermis test method) as well as by findings form a LLNA study in rats, dosed up to 50% due to absence of skin irritation effects.
Considering the high molecular weight of the target compound (~ 850 Dalton) which makes passing the skin barrier extremely unlikely, supported by the in vitro and in vivo findings, showing low dermal absorption and absence of significant local or systemic toxicity, the target substance naphthenic acids, bismuth salts is considered not relevant for acute dermal toxicity and an LD50 value of > 2000 mg/kg bw is conservatively assumed.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: based on read-across estimates, supported by absence of skin irritation and sensitisation effects

Interpretation of results:

GHS criteria not met

Conclusions:

Results from naphthenic acids acute dermal toxicity study (LD0 of 3.16 mg/kg bw in combination with absence of irritating effects of bsimuth compounds in an in vitro skin irritation study and an in vivo skin sensitisation study, indicate low dermal toxicity of naphthenic acids, bismuth salts, and an LD50 > 2000 mg/kg bw is conservatively assumed. The results are considered adequate for hazard and risk assessment and further studies are not required.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

Based on data for acute dermal and acute oral toxicity the substance naphthenic acids, bismuth salts does not require classification and labelling according to CLP (Regulation EC No 1272/2008). Although no data for inhalation toxicity are available, the low vapour pressure makes inhalation exposure very unlikely and thus classification for acute inhalation toxicity is also not required.