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Description of key information

Rapid and complete oral absorption and low dermal absorption; predominantly extracellular distribution; rapid excretion of unchanged compound via urine. No bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Toxicological profile

For the evaluation of Ammonium thiocyanate use is made of a category approach on the principle that for salts of thiocyanic acid that are readily dissociable in water, the toxicity is driven by SCN-, whereas the cation (NH4+, Na+, or K+) does not play a role of importance for the hazard evaluation, except possibly for local effects where ammonium ion might not be representative for the K or Na salt.

Therefore, in case data is lacking for Ammonium thiocyanate for a specific endpoint, use is made from cross-reading where possible from sodium or potassium thiocyanate. Dose levels are then converted based on the difference of molecular weight between these salts, to make them equivalent on the basis of the amounts of thiocyanate.

 

Thiocyanates are of low acute toxicity. There are many acute oral LD50 values reported in literature for the ammonium, sodium and potassium thiocyanate salts, that are all within the same range falling in the category of 300-2000 mg/kg bw (GHS Cat IV). There is no large species difference, although possibly dogs are more sensitive. Also information on acute toxicity via other routes of application, including i.p., s.c. and i.v. in various species, indicate a similar level of acute toxicity compared to oral. This indicates that oral absorption is complete, and that following absorption by any route the distribution over the extracellular volume is the same. (Except for i.v. administration, where KSCN is about 5 times more toxic, which is caused by the toxicity of the potassium for the heart.)

Acute dermal toxicity is low, with an LD50 available for KSCN > 2000 mg/kg bw. There is no information on inhalation toxicity.

Local effects to skin and eyes are mediated by the cation, where the ammonium thiocyanate shows more severe effects in the eyes compared to sodium and potassium thiocyanate. Ammonium thiocyanate is not irritating to skin, but showed moderate to severe eye irritation in rabbits. More decisive for classification are the results from a BCOP test which concluded that to severe eye irritant Cat.1.

Thiocyanates are not sensitising as indicated by a LLNA with NaSCN.

 

For repeated dose, there is a standard 90-day oral gavage study in rats with NH4SCN resulted to a NOAEL of 20 mg/kg bw/day, based on changes in haematological and clinical chemistry parameters seen at 100 mg. Mortality was observed at 500 mg/kg bw/day. Dogs seem to be more sensitive as dose levels of potassium and sodium thiocyanate of 100 mg/kg bw per day caused a progressive loss of weight, apathy, head droop, ataxia, and ultimate death. Dogs receiving about 20 mg NaSCN or KSCN/kg bw per day for 12 weeks were in excellent condition throughout.

There are many studies on thiocyanate but generally they only focus on thyroid function. Studies indicate that hypothyroidy from thiocyanate exposures depend on iodide status. Effects are fully reversible after ceasing exposures or with additional iodide supplementation.

 

For reproduction toxicity limited data is available. Again, the available studies focus on the possible goitrogen effects of thiocyanate. A 2-generation study with fixed dose levels in the food leading to exposures of 100-1000 mg/kgbw for the females, resulted to hypothyroidy of these animals, but did not results in overt reproduction toxicity as judged by the normal body weights of the pups.

Although a standard guideline study for the assessment of reproduction toxicity is lacking and thus no firm conclusion regarding the NOAEL for reproduction toxicity can be made (a NOAEL on its own would basically also not be very informative as levels would also depend on iodine and thiocyanate levels in used feed), indications are that at levels not leading to hypothyroidy, reproduction toxicity is unlikely. Classification for reproduction toxicity is therefore not indicated, and further studies are not expected to lead to additional relevant information.

Toxicokinetics, metabolism and distribution

There are no OECD guideline or GLP reports available from studies on dermal and gastro-intestinal absorption, distribution, metabolism and excretion.

However based on the available literature and reviews by WHO (1993), DECOS (2003) and the RMM DAR from the KSCN PPP dossier (2008) a basic toxicokinetic assessment can be performed. For the full assessment please refer to section 13 of this IUCLID5 file and section 5.1 of the attached chemical safety assessment.

 

Based on the available data on animals and humans the following conclusions can be drawn.

Oral absorption:

The compound is rapidly and almost completely absorbed after oral exposure. In humans the distribution of thiocyanate in the body is predominantly extracellular. The majority of the thiocyanate entering the body is rapidly excreted as compound via urine. Small amounts are excreted in the expired air as CO2 or HCN or are taken up in the one-carbon pool via formic acid. Studies in humans have shown that thiocyanate can be transported to the foetus.

Dermal absorption:

Dermal absorption is considered to be low based on the general notion that salts of ionic substances are not easily absorbed via skin. The estimated log Kow value (KOWWIN v1.67) is -2.29 for ammonium thiocyanate, and in general with a logPow <-1 no dermal absorption is taken into account. Comparing the oral LD50 of around 500 mg/kg bw, with the dermal LD50 is > 2000 mg/kg (showing no mortality) confirms lower absorption rates via dermal route.

The rate of absorption will be low, but in case only very small amounts are deposited on the skin, a relative larger fraction of the deposited amount will be absorbed. On the other hand, when a large amount /volume is deposited, the low rate of absorption makes that the actual absorbed amounts as fraction of the exposure is very low.

There is one study from literature on KSCN in human subjects indicating a dermal absorption of 10.15% ± 6.60% of the administered dose.(Feldmann RJ, Maibach HI., 1970, Absorption of some organic compounds through the skin in man, Invest Dermatol. 54(5):399-404.). This involves exposure of very small amount of radiolabelled material, and consequently the reported absorbed fraction is relatively high. (4 µg KSCN/cm2, total surface 13 cm2, skin not washed for 24 hrs; observations for 5 days). The study concluded to a absorption rate of 10.15% ± 6.60% of the administered dose, with a maximum rate of 0.1%/hr seen between day 3 and 4. Considering that this study represents the worst case condition (low amounts very long exposure times) the dermal absorption is set at 10%.

Respiratory absorption:

Physical-chemical properties of thiocyanates indicate a low likelihood for exposure via inhalation, with a high boiling point (based on estimations as decomposition occurs from 190°C, and above 100°C it partially rearranges to the isomeric thiourea) and low vapour pressure (<0.015 Pa from evaporation of ammonia at temperatures > 70°C). Furthermore thiocyanates are very hygroscopic, and inhalable particles are not available and will generally also not be formed during handling and use of the substance.

 

 

Thiocyanate can also be formed in the body by transsulfurization, which entails the transference of sulphur by mercaptopyruvate, thiosulphate and other sulphur sources to cyanide. A key role in detoxicfication of cyanide is played by the enzyme rhodanese, which catalyses the reaction of thiosulphate with cyanide to thiocyanate and sulphite.

Thiocyanate is secreted by the mammary and salivary glands and the gastric mucosa. This secretion is functional as the compound serves in mammals as a substrate for the peroxidase in milk, saliva and gastric juice. Excessive amounts of thiocyanate are excreted in the urine. With a normal renal function the half life for the elimination is 2 to 5 days.

 

For the general population the average daily intake of thiocyanates through food via natural sources is estimated to be between 10-14 mg/day (0.17-0.23 mg/kgbw/day). Natural background serum concentrations of thiocyanate found are 33.5 ± 25.4 µM for non-smokers and 111.2 ± 92.1 µM smokers (Tsuge, 2000), and after diner levels up to 160 µM of serum were seen (Eminedoki, 1994). 160 µM SCN- compares to 12 mg NH4SCN/L.Also evaluations have been performed as to the possible beneficial effects of physiological intake levels of in total of 100 mg NaSCN/day and use as feed additive (Weuffen, 2003). This publication also lists values of various background levels of thiocyanates in surface waters, drink water, air, food and body fluids.

 

 

The most consistent and most critical effect of thiocyanate is the inhibition of the thyroid function through competitive inhibition of the uptake by iodine. Goiter endemics were reported to develop when the critical urinary iodine/ SCN− ratio decreases below 3 µg iodine per mg SCN−. Iodine supplementation completely reverses the goitrogenic influence of SCN−. (Erdoğan MF, 2003, BioFactors 19;107–111)

SCN− is also generated from cigarette smoking as a detoxifying product of cyanide.

 

In the absence of severe iodine deficiency or iodine excess, adverse thyroidal effects occur with chronic serum thiocyanate concentrations ≥200 µmol/L whereas non-adverse effects are observed with concentrations in the range of 65–85 µmol/L. No adverse or non-adverse effects are observed at serum concentrations below 50 µmol/L, even among sensitive subpopulations. (Gibbs JP, 2006, Hum.Ecol.Risk Assess. 12:1;157-173)