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Description of key information

Absorption, distribution, metabolism and excretion of silver are assessed based on published data and earlier reviews (see discussion).

Key value for chemical safety assessment

Absorption rate - oral (%):
10
Absorption rate - dermal (%):
1

Additional information

Toxicokinetic information on “silver” is required for the assessment of the relative contribution of the possible routes of entry into the human body (inhalation, skin, ingestion), and for a comparison of relative bioavailability of different silver substances. The majority of this information was directly extracted from a scientific review (ATSDR, 1990).

 

Absorption

Oral absorption

ATSDR, 1990:Based on medical case studies and experimental evidence in humans, many silver compounds, including silver salts and silver-protein colloids, are known to be absorbed by humans across mucous membranes in the mouth and nasal passages, and following ingestion. The absorption of silver acetate following ingestion of a 0.08 mg/kg/day dose of silver acetate containing radiolabelled silver (110mAg) was studied in a single female by in vivo neutron activation analysis and whole body counting: approximately 21% of the dose was retained in the body at 1 week (East et al. 1980; MacIntyre et al. 1978)

However, the reliability of this method is not documented and several assumptions in the publication by East et al. leading to this estimate render this a likely overestimate. In a well-documented comparative investigation assessing the bioavailability of110msilver nitrate in mice, rats, monkeys and dogs via oral, intravenous and intraperitoneal administration, only about 1% or less of an oral dose was absorbed with the exception of dogs (<10%). The authors argue that the extent of absorption was likely to be associated with transit time through the gastrointestinal tract, which is longer for dogs and humans than in mice and rats. For this reason, a value of 10% for oral absorption in humans is taken forward for risk characterisation purposes.

 

Dermal absorption

Several published sources report incidental data on dermal absorption of silver:

(i) One well-documented case report study (Nguyen, 1999) of 11 human volunteers on absorption of silver from the nasal septum after cauterisation for nose bleed suggests a significant increase of silver blood concentrations 3 hours after administration. However, this is not considered relevant for human health risk assessment of healthy individuals.

(ii) In a well-documented study with guinea pigs (Wahlberg, 1965), less than 1% of the applied dose of silver nitrate was absorbed through the skin. However, this study has major methodical deficiencies, and is therefore considered only as supporting data.

(iii) One review article (Hostynek, 1993) exists which contains only references to published silver-related investigations (Wahlberg, 1965; Skog & Wahlberg, 1964), in which a percutaneous absorption experiment with110mAg as tracer in guinea pigs in vivo is described. Whereas the authors conclude on a dermal absorption rate of < 1%, this study also has considerable methodological shortcomings compared to current standards.

(iv) All other available data relate to either non-standard test systems, or absorption through wounded or burnt skin, and therefore are not relevant to the assessment of percutaneous absorption through intact skin, as required for risk assessment purposes.

In the absence of measured data on dermal absorption of silver, current guidance suggests the assignment of either 10% or 100% default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yields substantially lower figures, which can be summarised briefly as follows:

- measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

 

- however, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than its mass.

 

The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours):

From exposure to liquid/wet media: 1.0 %

From dry (dust) exposure:  0.1 %

 

This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007).

 

 

Inhalation absorption

Silver iodide does not occur in the form of inhalable particles during the production and uses, as addressed in this dossier (see also statements in sections on granulometry/particle size and inhalation toxicity). Thus, inhalation absorption is not addressed further here.

  

Distribution

ATSDR, 1990:The distribution of silver to various body tissues depends upon the route and quantity of silver administered and its chemical form. An oral dose of silver, following absorption, undergoes a first pass effect through the liver resulting in excretion into the bile, thereby reducing systemic distribution to body tissues (Furchner et al. 1968). The subsequent distribution of the remaining silver is similar to the distribution of silver absorbed following exposure by the inhalation and dermal routes and following intramuscular or intravenous injection. Silver distributes widely in the rat following ingestion of silver chloride (in the presence of sodium thiosulfate) and silver nitrate in drinking water (at 88.9 mg silver/kg/day for silver nitrate) (Olcott 1948); The amount of silver in the various tissues was not measured, although qualitative descriptions of the degree of pigmentation were made. High concentrations were observed in the tissues of the reticuloendothelial system in the liver, spleen, bone marrow, lymph nodes, skin, and kidney. Silver was also distributed to other tissues including the tongue, teeth, salivary glands, thyroid, parathyroid, heart, pancreas, gastrointestinal tract, adrenal glands, and brain. Within these tissues advanced accumulation of silver particles was found in the basement membrane of the glomeruli, the walls of blood vessels between the kidney tubules, the portal vein and other parts of the liver, the choroid plexus of the brain, the choroid layer of the eye, and in the thyroid gland (Olcott 1948; Moffat and Creasey 1972; Walker 1971)

 

Metabolism

Silver is not subject to any metabolism in its true sense regardless of its original chemical speciation.

 

 

Excretion

ATSDR, 1990:Following oral exposure to silver acetate in humans, silver is eliminated primarily in the faeces, with only minor amounts eliminated in the urine (East et al. 1980). The rate of excretion is most rapid within the first week after a single oral exposure (East et al. 1980). Whole-body retention studies in mice and monkeys following oral dosing with radiolabelled silver nitrate indicate that silver excretion in these species follows a biexponential profile with biological half-lives of 0.1 and 1.6 days in mice and 0.3 and 3 days in monkeys. In similarly exposed rats and dogs, silver excretion followed a triexponential profile with biological half-lives of 0.1, 0.7, and 5.9 days in rats and 0.1, 7.6, and 33.8 days in dogs (Furchner et al. 1968). Data for whole body clearance of silver at two days after exposure for these four species are presented in Table 2-5 (Furchner et al. 1968). Transit time through the gut may explain some of these interspecies differences in silver excretion. Transit time is approximately 8 hours in mice and rats, and approximately 24 hours in dogs and monkeys (Furchner et al. 1968). Animals excrete from 90% to 99% of an administered oral dose of silver in the feces within 2 to 4 days of dosing (Furchner et al. 1968; Jones and Bailey 1974; Scott and Hamilton 1950). Excretion in the faeces is decreased and deposition in tissues, such as the pancreas, gastrointestinal tract, and thyroid, is increased when saturation of the elimination pathway in the liver occurs as a result of chronic or high level acute exposure to silver (see Table 2-4) (Constable et al. 1967; Olcott 1948; Scott and Hamilton 1950).