Bismuth(3+) neodecanoate

Endpoint summary

Description of key information

No adverse effects were observed in acute oral and dermal toxicity studies conducted with a mixture of bismuth neodecanoate and neodecanoic acid. Additionally, based on in vivo oral and dermal LD50 data on the assessment entities bismuth and neodecanoate, acute toxicity estimates for bismuth (3+) neodecanoate have been calculated resulting in LD50 values > 2000 mg/kg bw. Thus, no classification for acute oral or dermal toxicity or STOT SE (oral and dermal) is required.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

No details on test material were included, and details about gavage volume and environmental conditions of the animals were not stated. Study conducted under GLP but no certificate was included. Further, the age of the animals was not stated.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1981-05-12

GLP compliance:

yes

Remarks:

certificate not included

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

Composition statement Cos Cat 83 is attached

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Housing: animals were individually housed in wire mesh bottom cages in environment-controlled rooms and provided food and water ad libitum
- Acclimation period: at least 5 days
- Weight at study initiation: males: 255.0-317.2 g; females: 213.6- 252.4 g

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Remarks:

undiluted

Details on oral exposure:

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: dose levels based on results of dose range findinge study

Doses:

1000, 1368, 1871, 2559, 3500, 4787 mg/kg bw

No. of animals per sex per dose:

5 animals/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: trial test: 8 days, main study: 15 days
- Frequency of observations and weighing: animals were observed frequently on the day of dosing and twice daily thereafter, body weights were recorded initially, on days 8 and 15 or at death
- Necropsy of survivors performed: yes, all animals that dies during the study and those sacrificed at termination were subjected to a gross necropsy and abnormalities were noted

Statistics:

Miller-Tainter Determination of LD50

Preliminary study:

A trial test with 10 animals/dose and a dose range finding study with 2 animals/dose were conducted to determine dose levels for the main study. Male and female Sprague Dawley rats (5 animals/dose) were dosed with 5 g/kg bw of bismuth neodecanoate. All animals died during the first four days of observation. A second study was conducted to define the dose levels for the main study. One male and one female rat were dosed with 500, 889, 1581, 2812 and 5000 mg/kg bw and observed for 8 days. Both animals in the high dose groups (2812 and 5000 mg/kg bw) died after 2 days. All animals in the other treatment groups survived. No details about clinical signs and necropsy are stated.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 030 mg/kg bw

Based on:

test mat.

95% CL:

>= 2 437 - <= 3 624

Mortality:

Main study
Males:
3/5 animals died in the 3500 mg/kg bw group
5/5 animals died in the 4787 mg/kg bw group

Females
2/5 animals died in the 1871 mg/kg bw group
2/5 animals died in the 2559 mg/kg bw group
5/5 animals died in the 3500 mg/kg bw group
3/5 animals died in the 4787 mg/kg bw group

Clinical signs:

Trial Test:
5g/kg bw
Decreased activity observed in 4/5 males and all females
Ataxia observed in all males and females
Salivation observed in 1/5 males
Lacrimation observed in 1/5 females
Death observed in all animals

Main study
1000 mg/kg
Ataxia observed in 4/5 males and all females
Decreased activity observed in 1/5 males and 3/5 females

1368 mg/kg
Decreased activity observed in 2/5 males and 4/5 females
Ataxia observed in 4/5 males and all females
Salivation observed in 1/5 males
Lacrimation observed in 1/5 females
Wet-abdomen observed in 2/5 females

1871 mg/kg
Decreased activity observed in 3/5 males and 3/5 females
Ataxia observed in 4/5 males and 4/5 females
Gaspring observed in 1/5 males
Wet-abdomen observed in 1/5 females
Lacrimation observed in 1/5 males and 3/5 females
Diarrhea observed in 1/5 females
Deaths observed in 2/5 females

2559 mg/kg bw
Decreased activity observed in 4/5 males and 5/5 females
Ataxia observed in 3/5 males and 3/5 females
Wet-abdomen observed in 1/5 females
Lacrimation observed in 1/5 males and 3/5 females
Diarrhea observed in 4/5 males
Deaths observed in 2/5 females

3500 mg/kg bw
Decreased activity observed in 5/5 males and 5/5 females
Ataxia observed in 3/5 males and 2/5 females
Salivation observed in 1/5 females and 1/5 males
Wet-abdomen observed in 2/5 females
Lacrimation observed in 1/5 males and 4/5 females
Diarrhea observed in 1/5 males
Deaths observed in 3/5 males and 5/5 females

4787 mg/kg bw
Decreased activity observed in 5/5 males and 5/5 females
Ataxia observed in 5/5 males and 5/5 females
Salivation observed in 1/5 females and 1/5 males
Wet-abdomen observed in 4/5 females
Lacrimation observed in 4/5 females
Diarrhea observed in 1/5 females
Deaths observed in 5/5 males and 3/5 females

Body weight:

Males
Trial Test
5 g/kg bw
339 ± 16.3 g (day1)

Main study
1000 mg/kg bw
Day 1: 266.8 ± 9.1 g; day 8: 330.8 ± 13.4 g; day 15: 376.0 ± 15.7 g

1368 mg/kg bw
Day 1: 262.0 ± 15.7 g; day 8: 328.4 ± 18.9 g; day 15: 376.8 ± 23.3 g

1871 mg/kg bw
Day 1: 261.4 ± 10.0 g; day 8: 313.4 ± 20.4 g; day 15: 358.8 ± 28.7 g

2559 mg/kg bw
Day 1: 255.4 ± 12.1 g; day 8: 307.2 ± 16.0 g; day 15: 354.8 ± 15.8 g

3500 mg/kg bw
Day 1: 255.0 ± 10.9 g; day 8: 307.5 g; day 15: 363.0 g

4787 mg/kg bw
Day 1: 317.2 ± 14.3 g



Females
Trial Test
5 g/kg bw
236.8 ± 3.6 g (day1)

Main study
1000 mg/kg bw
Day 1: 213.6 ± 15.5 g; day 8: 239.0 ± 16.2 g; day 15: 250.2 ± 20.0 g

1368 mg/kg bw
Day 1: 227.8 ± 8.3 g; day 8: 251.4 ± 16.3 g; day 15: 261.2 ± 15.6 g

1871 mg/kg bw
Day 1: 219.4 ± 16.7 g; day 8: 252.7 ± 32.9 g; day 15: 260.0 ± 38.2 g

2559 mg/kg bw
Day 1: 218.4 ± 8.1 g; day 8: 246.7 ± 12.0 g; day 15: 258.0 ± 11.1 g

3500 mg/kg bw
Day 1: 231.8 ± 8.2 g

4787 mg/kg bw
Day 1: 252.4 ± 19.5 g; day 8: 260.0 g; day 15: 264.0 g

Gross pathology:

Trial Test 5 g/kg bw
No noteworthy findings in males and females, except in one female: bladder contains blood-like liquid

Main study
No noteworthy findings in males and females of the dose groups 1000, 1368, 1871, 2559 and 3500 mg/kg bw
No noteworthy findings in males and females of the 4787 mg/kg group, except in one female: intestine contains blood-like liquid

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 for male rats was calculated to be 3294 mg/kg bw; the LD50 for female rats was calculated to be 2612 mg/kg bw. The combined LD50 was calculated to be 3030 mg/kg bw.

Executive summary:

Sprague Dawley rats were exposed to Bismuth neodecanoate in an acute oral toxicity study. A trial test with 10 animals/dose and a dose range finding study with 2 animals/dose were conducted to determine dose levels for the main study. Male and female Sprague Dawley rats (5 animals/dose) were dosed with 5 g/kg bw of bismuth neodecanoate. All animals died during the first four days of observation. A second study was conducted to define the dose levels for the main study. One male and one female rat were dosed with 500, 889, 1581, 2812 and 5000 mg/kg bw and observed for 8 days. Both animals in the high dose groups (2812 and 5000 mg/kg bw) died after 2 days. All animals in the other treatment groups survived. No details about clinical signs and necropsy are stated.

Based on these results the main study was conducted with 1000, 1368, 1871, 2559, 3500 and 4787 mg/kg bw bismuth neodecanoate and 5 males and 5 females per dose group. All animals were observed for 14 days and clinical signs were recorded twice daily. Body weight was recorded at day 1, 8 and 15. At the end of the observation period a necropsy of all animals was conducted.

Ataxia, decreased activity, salivation, lacrimation as well as a wet abdomen, diarrhea and death were observed with increasing dose. 3/5 males in the 3500 mg/kg bw group and 5/5 males in the 4787 mg/kg died prematurely, 2/5 females in the 1871 mg/kg bw, 2/5 females in the 2559 mg/kg bw, 5/5 females in the 3500 mg/kg bw and 3/5 females in the 4787 mg/kg bw group died prematurely.

Based on these findings the LD50 for male rats was calculated to be 3294 mg/kg bw; the LD50 for female rats was calculated to be 2612 mg/kg bw. The combined LD50 was calculated to be 3030 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The age and individual body weight of the animals were not stated. Additionally, no information about the environmental conditions was available. No details about the administration of doses and applied amount of test material were given and the test material was not sufficiently described. No justification for dose selection was available.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

2017-10-09

GLP compliance:

yes

Remarks:

certificate not included

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: New York State Rabbit Development, Hartwick, NY
- Housing: the animals were individually housed in wire mesh bottom cages in environment-controlled rooms
- Diet (e.g. ad libitum): NIH Animal Feed A (certified)
- Water (e.g. ad libitum): yes
- Acclimation period: a minimum of 5 days

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Type of wrap if used: occlusive binder, that consisted of a layer of plastic wrap and stockinette sleeve, held in place with masking tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the exposure sites were gently wiped with clean gauze to remove as much non-absorbed test article as possible
- Time after start of exposure: 24 hours

Duration of exposure:

24 hours

Doses:

2.0 g/kg bw

No. of animals per sex per dose:

5 animals/sex/dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: all animals were observed frequently on the day of dosing and twice daily thereafter.
- Necropsy of survivors performed: yes, all animals that died during the study and those sacrificed at termination were subjected to a gross necropsy and abnormalities were noted
- Other examinations performed: body weights were recorded initially, on days 8 and 15 or at death

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died prematurely

Clinical signs:

Anorexia observed in 3/5 males and 2/5 females
Diarrhea observed in 2/5 males and 3/5 females
Soft stools observed in 3/5 males and 4/5 females
Decreased activity observed in 3/5 females
Bloody stool observed in 1/5 females
Nasal discharge observed in 1/5 females

Body weight:

No noteworthy findings

Gross pathology:

No noteworthy findings

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 of bismuth neodecanoate (Cos Cat 83) is considered to be greater than 2.0 g/kg body weight. No classification for acute dermal toxicity is required.

Executive summary:

Bismuth neodecanoate (Cos Cat 83) was evaluated for acute dermal toxicity in male and female New Zealand White rabbits. The test article was applied undiluted to each of ten rabbits at a level of 2.0 g/kg body weight. All animals survived the 15 day post-application observation period and no adverse clinical findings or body weight changes were observed. Based on these results, the acute dermal LD50 of the test article in considered to be greater than 2.0 g/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Bismuth

Acute toxicity: oral

In an acute oral toxicity test in rats with bismuth (mean particle diameter was 10 µm), no deaths occurred at a dose of 2000 mg/kg body weight. Therefore the LD50 is >2000 mg/kg bw for both sexes.

Neodecanoate

Neodecanoic acid has a low potential for toxicity via the oral and dermal routes. 

Oral

Male and female rats were gavaged with neodecanoic acid at concentrations of 1, 1.5, 2, 3, or 4 ml/kg to assess acute oral toxicity.  All animals that died during the study did so within 3 days of exposure. Signs of toxicity included lethargy, hypothermia, piloerection, dyspnea, and ataxia. Based on these results, it is concluded that the LD50 is approximately 2.27 ml/kg (2066 mg/kg). 

Dermal

In a study that assessed acute dermal toxicity, male and female rats were exposed to 4 ml/kg (3640 mg/kg) neodecanoic acid via an occluded dermal patch for 24 hours. After 24 hours, the patch was removed and clinical observations were made once daily for 9 days. There were no deaths observed in this study and there were no signs of a toxicity response.  It is concluded that the LD50 is greater than 3640 mg/kg. 

 

Bismuth (3+) neodecanoate

One acute toxicity study in Sprague Dawley rats via the oral route with a mixture of bismuth neodecanoate and neodecanoic acid is available. A trial test with 10 animals/dose and a dose range finding study with 2 animals/dose were conducted to determine dose levels for the main study. Male and female Sprague Dawley rats (5 animals/dose) were dosed with 5 g/kg bw of bismuth neodecanoate. All animals died during the first four days of observation. A second study was conducted to define the dose levels for the main study. One male and one female rat were dosed with 500, 889, 1581, 2812 and 5000 mg/kg bw and observed for 8 days. Both animals in the high dose groups (2812 and 5000 mg/kg bw) died after 2 days. All animals in the other treatment groups survived. No details about clinical signs and necropsy are stated.

Based on these results the main study was conducted with 1000, 1368, 1871, 2559, 3500 and 4787 mg/kg bw bismuth neodecanoate and 5 males and 5 females per dose group. All animals were observed for 14 days and clinical signs were recorded twice daily. Body weight was recorded at day 1, 8 and 15. At the end of the observation period a necropsy of all animals was conducted.

Ataxia, decreased activity, salivation, lacrimation as well as a wet abdomen, diarrhea and death were observed with increasing dose. 3/5 males in the 3500 mg/kg bw group and 5/5 males in the 4787 mg/kg died prematurely, 2/5 females in the 1871 mg/kg bw, 2/5 females in the 2559 mg/kg bw, 5/5 females in the 3500 mg/kg bw and 3/5 females in the 4787 mg/kg bw group died prematurely.

Based on these findings the LD50 for male rats was calculated to be 3294 mg/kg bw; the LD50 for female rats was calculated to be 2612 mg/kg bw. The combined LD50 was calculated to be 3030 mg/kg bw. Thus, no classification as acutely toxic via the oral route is required.

 

Additionally, one acute dermal toxicity study conducted with a mixture of bismuth neodecanoate and neodecanoic acid is available. Bismuth neodecanoate (Cos Cat 83) was evaluated for acute dermal toxicity in male and female New Zealand White rabbits. The test article was applied undiluted to each of ten rabbits at a level of 2.0 g/kg body weight. All animals survived the 15 day post-application observation period and no adverse clinical findings or body weight changes were observed. Based on these results, the acute dermal LD50 of the test article in considered to be greater than 2.0 g/kg body weight.

 

The acute oral and dermal toxicity studies were included as bridging studies for systemic effects displaying the applicability to read-across to the assessment entities bismuth cations and neodecanoic acid anions (for a detailed description of the read-across approach please refer to the separate report attached to section 13).

Therefore, in the assessment of the systemic toxicity of bismuth (3+) neodecanoate, a read-across to data for neodecanoate and soluble bismuth substances is applied since only the ions of bismuth and neodecanoate are systemically available and determine the toxicological potential of bismuth (3+) neodecanoate.

 

 

Beside of these results in the acute oral and dermal toxicity studies conducted with the mixture of bismuth neodecanoate and neodecanoic acid, signs of acute oral or acute dermal toxicity are not expected for bismuth (3+) neodecanoate, since the two moieties bismuth and neodecanoic acid have not shown signs of acute oral or acute dermal toxicity in experimental testing (both LD50 > 2000mg/kg). Under the assumption that the moieties of bismuth (3+) neodecanoate show their toxicological profile individually upon dissolution, the acute oral and dermal (systemic) toxicity of bismuth (3+) neodecanoate can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1.

A study for acute toxicity via inhalation was not conducted with bismuth (3+) neodecanoate, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

The calculated oral and dermal LD50 for bismuth (3+) neodecanoate is > 2000mg/kg. Additionally, in acute oral and dermal toxicity studies conducted with a mixture of bismuth neodecanoate and neodecanoic acid no adverse effects could be observed. Thus,the substance subjected to registration, bismuth (3+) neodecanoate, is not to be classified according to regulation (EC) 1272/2008 for acute oral and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

Justification for classification or non-classification

No adverse effects were observed in acute oral and dermal toxicity studies conducted with a mixture of bismuth neodecanoate and neodecanoic acid. Additionally, based on in vivo oral LD50 data for the moieties bismuth and neodecanoate, acute toxicity estimates for bismuth (3 +) neodecanoate are calculated resulting in LD50 values > 2000 mg/kg bw.

According to the criteria of REGULATION (EC) No 1272/2008, bismuth (3 +) neodecanoate does neither have to be classified and has no obligatory labelling requirement for acute oral or dermal toxicity nor for specific target organ toxicity after single exposure (STOT SE, oral and dermal).