Silver cyanide

Endpoint summary

Description of key information

Acute oral toxicity study in rats by the "up-and-down" procedure according to OECD425 guideline.
Acute dermal toxicity study in rats, limit dose procedure according to OECD402 guideline.

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

Study period:

21 March 2014 to 25 April 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as an unpublished report.

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

other: CD/Crl: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, DE
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 175 - 192 g
- Fasting period before study: 16 hours before administration of the test item.
- Housing: the animals were kept individually in MAKROLON cages (type III plus) at a room tepmerature of 22 ± 3 °C and a relative humidity of 55 ± 15 %. The rooms were lit (150 lux at appoximately 1.5 m room height) and darkened for periods of 12 hours each.
- Diet: Commercial ssniff (R) R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, DE)
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 h of darkness / 12 h of light

IN-LIFE DATES: From: 21 March 2013 To: 25 April 2014

Route of administration:

oral: gavage

Vehicle:

other: 1 % aqueous hydroxypropylmethylcellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test item was suspended in 1 % aqueous hydroxypropylmethylcellulose. The doses were 55, 175 and 550 mg silver cyanide/kg bodyweight.
- Amount of vehicle (if gavage): 20 mL/kg bodyweight
- Justification for choice of vehicle: Not reported
- Lot/batch no. (if required): Not reported.
- Purity: Not reported.

MAXIMUM DOSE VOLUME APPLIED: 20 mL/ kg bodyweight, maximum administration volume was 3.8 mL/rat

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Available data indicated an LD50 of 123 mg/kg in rats.

Doses:

Dosing was initiated at 55 mg/kg bw and continued using a progrssion factor of approximately 3.2. The resulting sequence was 55, 175, 55, 175, 550, 175, 550 and 175 mg/kg bw. Each dose level was conducted with one female rat.

No. of animals per sex per dose:

2 female rats at 55 mg/kg bw
4 female rats at 175 mg.kg bw
2 female rats at 550 mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Observations were performed before dosing, during dosing, at 5, 15, 30 and 60 minutes and 3, 4, 6 and 24 hours after administration. all surviving animals were observed for a period of 14 days. Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study and at death. Changes in weight were calculated if survival exceeds one day.
- Necropsy of survivors performed: yes
- Other examinations performed: changes of skin and fur, eyes and mucous membranes, respiratory and circulatory function, autonomic and central nervous
system and somatomotor activity, as well as behaviour pattern, were observed at least once a day until all symptoms subsided, thereafter each working day. Attention was also paid to possible tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. Observations on mortality were made at least once daily to minimize loss of animals during the study.

Statistics:

The LD50 was calculated using the method of maximum likelihood.

Preliminary study:

Available information indicated an LD50 of 123 mg/kg in rats. Thus, the Limit Test could be omitted and the study started with the Main Test.

Sex:

female

Dose descriptor:

LD50

Effect level:

175 mg/kg bw

Based on:

test mat.

95% CL:

62.5 - 487

Remarks on result:

other: by oral administration

Mortality:

A single oral administration of 55 mg/kg bw resulted in no premature deaths. Two of four animals died after dosing with 175 mg/kg bw and two of two animals died after dosing with 550 mg/kg bw.

Clinical signs:

other: At 55 mg/kg bw clinical observations included reduced motility, ataxia, tremor, reduced muscle tone, dyspnoea and pilo-erection in 2 of 2 female animals, tonic convulsions and ptosis in 1 animal. All clinical signs had resolved within 24 hours of dosing.

Gross pathology:

No signs or abnormalities observed.

Other findings:

Not reported.

Table 1. Summarised results

Symptoms/criteria	55 mg/kg (n=2) females	175 mg/kg (n=4) females	550 mg/kg bw (n=2) females
Mortality 6 h 24 h 7 d 14 d	0 0 0 0	1 2 2 2	2 2 2 2
Mean body weight (g) Start	178.5	185.0	190.0
After 7 d	217.5 (+21.8)	204.5 (+10.5)	ƚ
After 14 d	230.5 (+29.1)	221.5 (+19.7)
Inhibition of body weight gain	none	none	ƚ
Necropsy findings	none	none	none

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute lethat dose (LD50) of silver cyanide in the female rat was estimated to be 175 mg/kg bodyweight.

Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of silver cyanide in rats. The study was conducted according to GLP and OECD 425 guideline.

Methods

Female rats were dosed with silver cyanide by oral gavage. Dosing was initiated at 55 mg/kg bw and continued using a progression factor of approximately 3.2 according to up-and-down procedure. The resulting sequence was 55, 175, 55, 175, 550, 175, 550 and 175 mg/kg bw. Each dose level wass conducted with one female rat. Following administration, observations were made and recorded systematically with individual records being maintained for each animal. Observations were performed before dosing, during dosing and 5, 15, 30 and 60 minutes and 3, 4, 6 and 24 hours after administration. All surviving animals were observed for a period of 14 days.

Results

Mortality

A single oral administration of 55 mg/kg bw resulted in no premature deaths. Two of four animals died after dosing with 175 mg/kg bw and two of two animals died after dosing with 550 mg/kg bw.

Clinical signs

Clinical observations at 55 mg/kg bw included reduced motility, ataxia, tremor, reduced muscle tone, dyspnoea and pilo-erection in 2 of 2 female animals, tonic convulsions and ptosis in 1 animal. All clinical signs had resolved within 24 hours of dosing. Reduced motility, ataxia, tremor, reduced muscle tone, dyspnoea and pilo-erection in 4 of 4 female animals, and tonic convulsions, STRAUB tail, ptosis and mydriasis in 2 animals were observed at 175 mg/kg bw. Abnormal abdominal position and abnormal dorsal position were noted in one animal which died prematurely. In the surviving two animals all clinical signs had resolved within 24 hours of dosing. At 550 mg/kg bw clinical observations were reduced motility, ataxia and dyspnoea in 2 of 2 female animals, tremor, reduced muscle tone, tonic convulsions, pilo-erection, ptosis and abnormal dorsal position in 1 animal.

Bodyweight

All animals gained the expected body weight.

Necropsy

No sings or abnormalities were observed at necropsy.

Conclusion

The acute lethal dose (LD50) of silver cyanide in the female rat was estimated to be 175 mg/kg bodyweight with 95 % confidence intervals of 62.5 to 487 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

175 mg/kg bw

Quality of whole database:

One GLP-compliant study is available, performed by up-and-down procedure according to OECD guideline and produced quality and reliable data.

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

Study period:

16 July 2014 to 24 July 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as an unpublished report.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: CD : Crl CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles river Laboratories, Research Models and Services, Sulzfeld, Germany
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 230 - 281 g (males), 222 - 250 g (females)
- Fasting period before study: Yes, approximetely 16 hours before test item administration.
- Housing: Rats kept individually in MAKROLON cages (type III plus), with granulated textured wood (Granulat A2, J. Brandenburg, Germany) used as bedding material.
- Diet (e.g. ad libitum): Commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, German)
- Water (e.g. ad libitum): tap water offered ad libitum
- Acclimation period:At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Photoperiod (hrs dark / hrs light):12 h light / 12 h dark (about 150 lux at approx. 1.50 m room height)

IN-LIFE DATES: From: 17 July 2014 To: 24 July 2014

Vehicle:

water

Remarks:

Aqua ad iniectabilia

Details on dermal exposure:

TEST SITE
- Area of exposure: 5 x 6 cm
- % coverage: approx. 10 % of body surface
- Type of wrap if used: The test item was applied to 8 layers of gauze. The gauze was covered with a plastic sheet and secured with adhesive plaster on the application site.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3000 mg/kg b.w. of the paste (test item-vehicle preparation) (based on the weight)
- Concentration (if solution): 2000 mg/kg b.w.
- Constant volume or concentration used: No
- For solids, paste formed: yes, 10 g test item was mixed with 5 g water in a mortar to obtain a paste.

Duration of exposure:

24 hours

Doses:

2000 mg/kg b.w. (limit test)

No. of animals per sex per dose:

5 rats per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were performed before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration.
- Necropsy of survivors performed: yes
- Other examinations performed: changes of skin and fur, eyes and mucous membranes, respiratory and circulatory function, autonomic and central nervous system and somatomotor activity as well as behaviour pattern, were observed at least once a day until all symptoms subsided, thereafter each working day.Observations on mortality were made at least once daily to minimize loss of animals during the study. Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study. Changes in weight were calculated and recorded.

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Sex:

male/female

Dose descriptor:

LDLo

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortalities observed.

Clinical signs:

other: None.

Gross pathology:

None.

Other findings:

None.

Table 1. Summary of the results

Symptoms/criteria	Silver cyanide 2000 mg/kg b.w. (n=5)
	males	females
Clinical signs	None	None
Skin reaction	None	None
Mortality within 6 h	0	0
24 h	0	0
7 d	0	0
14 d	0	0
Mean bodyweight (g) start	257.8	230.6
After 7 d	303.8 (+17.8)	236.4 (+2.5)
After 14 d	364.0 (+41.2)	255.8 (+10.9)
Inhibition of bodyweight gain	None	None
Necropsy findings	None	None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Silver cyanide requires no labelling according to the EC directive 67/548/EEC. According to the EC Regulation 1272/2008 and Globally Harmonized Classification System (GHS), the test material is not classified for acute dermal toxicity.

Executive summary:

Introduction

Silver cyanide was examined for acute toxicity after a single dermal application to rats. The study was conducted according to OECD 402 and EC method B.3.

Materials and methods

Silver cyanide was applied once for 24 hours on the shaved intact dorsal skin of rats. One dose level of 2000 mg/kg b.w. was used.

The treatment was followed by an observation period of 2 weeks.

Results

Under the present test conditions, a single dermal administration of 2000 mg silver cyanide/kg b.w. did not reveal any signs of toxicity. No animal died prematurely. All animals gained the expected weight throughout the whole experimental period. No macroscopic findings were observed at necropsy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

One GLP-compliant study is available, performed according to OECD and EU guidelines and produced quality and reliable data.

Additional information

In the acute oral toxicity of silver cyanide in rats, female rats were orally gavaged at a rate of 20 mL/kg bw with a single dose of silver cyanide solution in 1% aqueous hydroxypropylmethylcellulose. Nominal concentrations of 55, 175 and 550 mg/kg bw were tested. The LD50 was estimated to be 175 mg/kg bw (95 % confidence interval 62.5 to 487 mg/kg bw). Signs of clinical toxicity were observed and were reversible within 24 hours at the lowest dose.

In a limit test for acute dermal toxicity in rats, a single application of 2000 mg/kg bw silver cyanide solution was applied on the shaved intact dorsal skin of 5 rats for 24 hours. No premature deaths or signs of toxicity were observed. Silver cyanide is not classified for acute dermal toxicity according to GHS and EC regulation 1272/2008.

Justification for selection of acute toxicity – oral endpoint
Only one study covering the endpoint but it is a Guideline study (OECD425) conducted to GLP standards

Justification for selection of acute toxicity – dermal endpoint
Only one study covering the endpoint but it is a Guideline study (OECD402) conducted to GLP standards. No acute dermal toxicity or signs of clinical toxicity were observed at the limit dose of 2000 mg/kg bw silver cyanide.

Justification for classification or non-classification

According to GHS and EC regulation 1272/2008, silver cyanide is classified as category 3 for acute oral toxicity based on an oral LD50 of 175 mg/kg bw. No classification for acute dermal toxicity is required as no toxicity effects were observed in a limit test at 2000 mg/kg bw.