Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 231-131-3 | CAS number: 7440-22-4
Reliable experimental studies in animals indicate a low acute toxicity of elemental silver (including nanoforms), following exposure via the oral, dermal or inhalation route. No mortality or any relevant clinical signs of acute toxicity were observed and the following effect levels were established for silver as follows: LD50oral > 5000 mg/kg, LD50dermal > 2000 mg/kg and LC50inhalation > 5.16 mg/L.
Test animal source:
National Laboratory Animal Centre, Mahidol University
Acute oral toxicity:
Four reliable studies are available regarding the acute oral toxicity of metallic silver. In a study according to OECD TG 401, conducted in 1993 by Allen, silver metal powder (particle size described as < 40 µm) was used as the test item. No deaths or other signs of acute toxicity were observed in this limit test in rats. The LD50 was established as >2000 mg/kg.
Kim et al. (2012) published results of a study conducted according to OECD TG 423 using silver nanoparticles (average particle size: 10 nm). Doses of 300 and 2000 mg/kg were applied to three rats each. No deaths or other signs of acute toxicity were observed in this study. The LD50 was established as >2000 mg/kg.
In 2011, Maneewattanapinyo published a study using material characterised as “colloidal silver nanoparticles“, consisting of 99.96% elemental silver and less than 0.04% ionic silver. The study was conducted according to OECD TG 425 as a limit test, administering a dose of 5000 mg/kg to male and female mice. No deaths or other signs of acute toxicity were observed in this study. The LD50 was established as >5000 mg/kg.
Yun et al. (2015) published results of a study conducted according to OECD TG 420 using citrate-capped silver nanoparticles. A dose of 2061 mg/kg was applied to five male and female rats. No deaths or other signs of acute toxicity were observed in this study. The LD50 was established as >2061 mg/kg.
Similar acute toxicity studies with other silver substances are included in this dossier for metallic silver for comparative reasons.
Acute inhalation toxicity:
Two reliable acute inhalation toxicity studies with elemental silver are available. In a study according to OECD TG 436 by Haferkorn (2012), silver metal powder was used and inhaled by rats for 4 hours at an exposure concentration of 5.16 mg/L. The mass median aerodynamic diameter of inhaled silver particles as determined in the inhalation chamber during the study was MMAD = 2.3 µm. No deaths were observed. Clinical signs, such as slight ataxia and reduced breathing frequency were restricted to the first few hours post exposure and are considered to be general signs in response to inert dust exposure, but not necessarily test item-related. The LC50 (4h) was established at > 5.16 mg/L (>5.16 g/m³). The study included a satellite group of animals for the assessment of respiratory irritation potential (see respective section in this dossier).
Sung et al. (2011) reported a 4-hour acute inhalation toxicity study in rats with silver nanoparticles (acc. to OECD TG 403). Groups of ten rats (5m+5f) were exposed to three different exposure concentrations of ca. 76, ca. 135 and ca. 750 µg/m³ (highest attainable concentration). The median particle size of particles in the inhalation chamber was 18 -20 nm. No mortalities were observed and no other signs of acute toxicity were observed. Some influence of the exposure on lung function parameters, such as tidal volume and minute volume were reported, but these were not dose-dependent. As in the study by Haferkorn, these effects can be considered as generic responses to the inhalation of inert dusts, but are not considered to be related to the test substance silver as such. The LC50 is established in this study as > 750 µg/m³ (highest concentration tested).
A large number of mechanistic studies were identified, in which silver nanoparticles were intratracheally instilled in rats and mice. The major endpoints investigated in such studies are primarily (1) time course and dose-response intensity of pulmonary inflammation via cytokine measurements, differential cell count in BALF, (2) airway and lung parenchymal cell proliferation and (3) histopathological evaluation of lung tissue. Whereas such information might be appropriate to assess the direct effects of a substance on the pulmonary region, it is not considered relevant for hazard and risk assessment purposes. The introduction of the toxicant via instillation techniques is nonphysiologic, involving invasive delivery, usually at a dose and/or dose rate substantially greater than that which would have occurred during inhalation. In addition, the distribution of an instilled material within the respiratory tract will likely differ from the distribution of an inhaled material.The influence of the instilled vehicle in which the test material is suspended or dissolved may have an impact on the distribution of the test substance within the lung, produce effects itself or, if it alters the physicochemical nature of the test material, may alter the effects of the material on the lungs (Driscoll, K.E. et al. 2000; Osier, M. and Oberdörster, G., 1997). The references usingintratrachealinstillation are given below in a tabulated summaryfor information only.
Information on study design
Silva et al. (2015)
Male Sprague Dawley rats
# of animals:
6 rats/dose/time point
0, 0.1, 0.5, or 1.0 mg/kg bw
Route of administration:
1, 7, and 21 days after administration
BAL cell analysis, Lung histopatholgy, Airway cytotoxicity,
ICP-MS analysis (lung, heart, spleen, kidney, liver)
Arai et al. (2015)
Male ICR mice
3 mice (experiment 1) or 8 mice (experiment 2)
10 µg Ag/mouse (target dose); 7.5 µg Ag/mouse (actual dose)
4 and 24 hours after administration
BALF (interleukin conc., silver conc., # of cells), Silver conc. in lung, liver, kidneys, spleen and urine
Gosens et al. (2015)
Female C57BL/6NTac inbred mice
0, 1, 4, 8, 16, 32, 64 and 128 µg/mouse
24 hours after administration
BALF, (cytokines, LDH, ALP, albumin, total protein, cell count, cell differential count), Haematology (total number of cells, cell differential count, haemoglobin content), Liver analysis (glutathione content, silver content)
Seiffert et al. (2015)
Sprague Dawley rats
5 – 6 rats
0.1 mg/kg bw
Lung mechanics (resistance, dynamic compliance, airway responsiveness), Bronchoalveolar lavagage (differential cell count,, total protein, KC, eosinophilic cationic protein, IL-13, IgE, IL-5, CCL11, and bronchoalveolar lavage malondialdehyde), Lung histology.
Kaewamatawong et al. (2013)
3 mice/dose/time point
0, 10, 100, 1000 and 10000 ppm
1, 3, 7 and 15 days after administration
Histopathology, Immunohistochemistry, Distribution/accumulation AgNPs
Osier, M and Oberdörster, G. 1997. Intratracheal Inhalation vs Intratracheal Instillation: Differences in Particle Effects. Fundamental and applied Toxicology 40, 220-227
Driscoll KE, Costa DL, Hatch G, Henderson R, Oberdörster G, Salem H, Schlesinger RB. 2000. Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations. Toxicol Sci., 55(1):24-35
Acute dermal toxicity:
Two acute dermal toxicity studies with elemental silver are available, both using nanoforms of silver as the test items. Kim et al. (2012) published results of an acute dermal toxicity study in accordance with OECD TG 402, using „nano-sized colloidal silver“ (average particle size = 10 nm). The limit dose of 2000 mg/kgbw applied to the skin of rats (5m+5f) did not produce deaths or any signs of acute toxicity. The LD50 (dermal) is established as >2000 mg/kg.
Maneewattanapinyo (2011) reported on a study conducted similarly to OECD TG 434. The test item was characterised as „colloidal silver nanoparticles“, consisting of 99.96% elemental silver and less than 0.04% ionic silver. Doses of ca. 0.17 and 348 mg Ag/kgbwwere applied to the skin of guinea pigs. No mortality and no clinical signs indicating toxicity were observed. Gross pathology also revealed no signs of toxiciy. In this study, the LD50 (dermal) for elemental silver was established as > 348 mg/kg. Because of some reporting deficiencies and because the highest dose in this study is below the limit dose for such tests, this study is considered merely as supporting data.
Acute toxicity other routes:
The references contained in the summary entry for the acute toxicity via non-physiological routes of application are of limited value for risk assessment purposes. The references do not fulfil the criteria for quality, reliability and adequacy of experimental data for the fulfilment of data requirements under REACH and hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X). The information contained therein were included for information purposes only and the deficiencies of the studies are listed below. Generally, the intravenous and intraperitoneal administration is not relevant for the hazard assessment of industrial chemicals.These routes are not considered physiologically relevant because, although it is occasionally used for dosing of chemotherapeutic drugs, humans are not exposed to environmental chemicals via the peritoneum or intravenously.After oral administration a chemical is absorbed by the digestive system and then carried through the portal vein into the liver before it reaches the rest of the body. After i.p. or i.v. administration a portion of the administered chemical will be carried through the hepatic portal system to the liver. Thus, both activation and detoxification of chemicals is less effective when using these non-physiological routes. As a result, only a small amount of active chemical emerges from the liver to the rest of the circulatory system, and many chemicals are significantly less toxic by the oral route than by i.p. or i.v. injection (Wang et al, 2015). Secondly, the i.p. or i.v. administration of a chemical may cause serious bolus effects, due to an escalated increase of the internal dose, whereas the oral route shows a delayed and slow increase of the internal dose, leading to milder and more physiological responses. In summary, there are many reasons to conclude that the i.p. or i.v. route is inappropriate because it limits first-pass metabolism and normal liver detoxification processes, does not necessarily enhance systemic exposures or detection of adverse effects, and can lead to abnormal localised effects.
In the studies by Sarhan et al., 2014 and Ansari et al., 2015, rats were given doses of 2 and 5 g/kg bw respectively by intraperitoneal injection. Despite the identical study design in both references, a discrepancy was observed in the overall findings. The animals exposed to 5 g/kg bw showed no signs of toxicity, whereas less than half of the dose showed signs of liver and kidney toxicity. Due to the irrelevant route of exposure and overall poor reporting and experimental quality, the references were not considered further for hazard and risk assessment purposes.
In a study by Xue et al., 2012 mice were intravenously exposed to doses of 7.5, 30 and 120 mg/kg silver nanoparticles.
Reliable experimental studies in animals indicate a low acute toxicity of elemental silver (including nanoforms), following exposure via the oral, dermal or inhalation route. No mortality or any relevant clinical signs of acute toxicity were observed and the following effect levels were established for silver as follows: LD50oral > 5000 mg/kg, LD50dermal > 2000 mg/kg and LC50inhalation > 5.16 mg/L. In consequence, classification for acute toxicity is not required.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Close Do not show this message again