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Description of key information

Short description of key information on bioaccumulation potential result: 
There are no oral toxicokinetic studies or skin absorption studies with EDTA-Mn(NH4)2 available. Data of EDTA-CaNa2 and data of mostly inorganic manganese compounds were used instead. See the Discussion below (see also the read across document in section 13).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Based on data on EDTA and manganese (see also at section 7.1.1), for organic, soluble EDTA-MnNa2, EDTA-MnK2 and EDTA-Mn(NH4)2 intestinal absorption was estimated to be 5%, and dermal absorption 0.001%. Based on the particle size distribution of EDTA-Mn(NH4)2 (when aerosolized), it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045 (4.5%). The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145 (14.5%). It is expected that neither the manganese nor the EDTA moiety of EDTA-Mn(NH4)2 undergoes biotransformation. Evidence for this conclusion comes fromstudies with EDTA-FeNa which indicated that both EDTA and iron are excreted unchanged following ingestion of EDTA-FeNa.

With regard to other chelates (see also section 13): several studies have been performed using EDTA-CaNa2 or EDTA-Na2H2. According to the dissociation equilibrium, administration of different sodium salts will result in the formation of various anionic species of EDTA depending on the intestinal pH value. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. It can be assumed that the systemic absorption from the intestinal tract is low. The obtained data can be used to predict that dermal absorption should be even lower. Additionally absorbed EDTA does not undergo any biotransformation and is excreted unchanged.

In toxicokinetic studies on humans as well as rats EDTA-CaNa2 and Na salts of EDTA are poorly absorbed from the gastrointestinal tract (2 -18% in rats; less than 5% in humans). EDTA-CaNa2 does not penetrate the skin, only 0.001% was absorbed within 24 h of administration. Intravenously applied EDTA is rapidly excreted in urine (humans 50% within the first hour, 98% within 24 h; rats: 95%- 98% within 6 h).These data were also confirmed by the independent evaluation of the MAK Commission for the Investigation of Health Hazards of Chemical Compounds in the work area (MAK, 46. Lieferung, 2009).

Discussion on bioaccumulation potential result:

In a study conducted by Foreman et al. (1953) 50 mg/kg bw of 14C-labeled EDTA-CaNa2 was administered to rats orally (gavage), intraperitoneally, intravenously or intramuscularly. After oral application calcium EDTA was poorly absorbed from the gastrointestinal tract (2 - 18% within 24 h). Most of the administered dose was excreted via the feces (80 - 95%) and much less in urine (2 -18%). After parenteral application 95 - 98% (iv: 96.09%; ip: 98.67%; im: 95.35%) of the radioactivity was excreted in the urine within 6 h after application, while less than 0.1% was exhaled as CO2. None of the tissues contained more than 0.5% of the radioactivity administered at this time point.

Two additional studies on the toxicokinetics of EDTA-CaNa2 after ip application are available. In one study rats got 10 injections of 300 - 436 mg/kg bw/day 14C-labeled EDTA-CaNa2. 66 - 92% of the administered dose was recovered in urine while generally less than 5% was excreted via the feces. 24 h after the last injection kidneys showed less than 0.1% of the radioactivity (Doolan et al., 1967). In the other study, 18 rats received a single ip application of 400 mg/kg bw 14C-labeled EDTA-CaNa2. Within 22 h 80% of the radioactivity was excreted in urine, while the concentration in kidney homogenate was approximately 0.1 - 0.2% during this time period (Miller et al., 1986).

The effects of sc application of EDTA-CaNa2 on Zn, Cu and Mn metabolism were investigated in female dogs. EDTA-CaNa2 was applied at a dose of 280 mg/kg bw every 6 hours for 54 h. Urine was collected every 6 h and the Zn, Cu and Mn content analysed. EDTA-CaNa2 application increased the urinary excretion of Zn, Cu and Mn significantly (Ibim et al., 1992).

In addition, in limited documented studies by Yang and Chan (1964), the toxicokinetics of EDTA-Na2H2 were analysed in rats. After gavage application of 47.5, 95 and 142.5 mg/kg bw the amount of EDTA ingested was proportional to the amount of urinary excretion with a peak excretion 4 h after application. After gavage administration of 400 mg/kg bw to weanling and adult rats roughly 90% of the dose was recovered in feces, while only 5.3 % (adults) - 8.6 % (weanlings) were recovered in urine within 48 h. It was therefore assumed that most of the orally applied EDTA is not absorbed. After a single gavage application of ca. 475 mg/kg bw to rats, the gastrointestinal tract was removed in intervals up to 32 h and the EDTA content analysed. All EDTA passed through the stomach within 12 h and 93% of the dose was recovered in the colon after 32 h, which demonstrated a poor absorption from GI tract. The EDTA contents of the small intestine and urine reached a maximum about 4 h after dosing. Urinary excretion over the period of 32 h cumulated to 6% of the dose. Yang and Chan (1964) also stated that of a dietary dose of 300, 600 and 3000 mg/kg bw 82%, 44% and 45% could be recovered in urine and feces. However, it is unclear where the residual percentage of EDTA-Na2H2 remained.

Foreman and Trujillo (1954; see section 7.10.5) studied the toxicokinetics of 14C-labeled EDTA-CaNa2 in young, healthy male volunteers. 4.2 mg per person was applied iv or im. 50% of the dose was excreted in the urine within 1 h (iv) or 2.5 h (im), respectively. Additionally, 14C-labeled EDTA-CaNa2 was administered orally at a dose of 1.5 mg per person. EDTA-CaNa2 was poorly absorbed from the gastrointestinal tract. Within 72 h, 91% of the dose was excreted in feces and 4.2%in the urine. No test substance was detected in blood.

Discussion on absorption rate:

In a study with young healthy male volunteers, Foreman and Trujillo (1954; see section 7.10.5) investigated the dermal absorption of EDTA-CaNa2; 3 mg of a mixture of 14C-labeled and unlabled test substance was prepared in water soluble base. The paste was applied over an area of 100 cm2 for 24 h under occlusive conditions. In one study Na salt was used instead of Ca salt. The maximum activity in the urine was 0.001% of the administered dose.

Discussion on bioaccumulation potential result with regard to EDTA-Mn(NH4)2:

With regard to EDTA:

According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in dependence on the intestinal pH-value to the formation of various anionic species of EDTA. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. It can be assumed that the oral and dermal absorption of sodium salts of EDTA and of the ree acid is comparable to the low absorption of EDTA-CaNa2. Calcium salts of EDTA are poorly absorbed from the gastrointestinal tract (2 to 18% within 24 h), a maxium of 5% was detected in the urine. Only 0.001% is absorbed after dermal application. Intravenously injected EDTA is excreted within 24 h in the urine, 50% of the substance in the first h and 90% within 7 h.

With regard to manganese (based on mostly inorganic manganese compounds):

Occupational exposure to manganese from welding, ore handling, production of manganese alloys and other uses are mainly through inhalation. While respirable manganese is readily taken up, larger particles are both directly taken up and some transported upward in the lung by mucociliary movement and finally swallowed and taken up in the intestine. Intestinal uptake is low, 3 to 5%. The absorption of manganese from the gut is dependent on several factors, including the amount ingested, iron status and other dietary components. There is very tight biological regulation of the gastro-intestinal absorption of manganese which is not the case for inhalation exposure. Adult humans not exposed to manganese by inhalation normally maintain stable tissue levels of manganese regardless of intake; this homeostatis is maintained by regulation and absorption and excretion. There is experimental evidence of olfactory uptake of manganese to the brain. The toxicological significance of this olfactory uptake to humans remains uncertain. Absorbed manganese is eliminated with a half-life of 10 to 30 days. Manganese that is delivered to the brain is eliminated over time with reported half-life of 50 to 220 days. It is important to recognise that accumulation and clearance of manganese from the brain might have important implications for neurofunctional effects which are reported in a range of occupational studies.

Based on these data, for organic, soluble EDTA-Mn(NH4)2, intestinal absorption was estimated to be 5%, and dermal absorption 0.001%. Based on the expected particle size distribution of EDTA-Mn(NH4) in case of aerosolization,it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045 (4.5%). The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145 (14.5%). It is expected that neither the manganese nor the EDTA moiety of EDTA-Mn(NH4)2 undergoes biotransformation.