Manganese, 4-[(5-chloro-4-methyl-2-sulfophenyl)azo]-3-hydroxy-2-naphthalenecarboxylic acid complex

Endpoint summary

Description of key information

The hazard of bioaccumulation is derived from published data on the organic anion and manganese.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

No toxicokinetic investigations are available on the pigment. Toxicokinetic properties of the pigment are derived from acute and subacute toxicity studies and physico-chemical data. In the analogue Ca-pigment, the organic part was found to be deprotonized at the sulfonate and the carboxylate function (Kennedy et al. (2000) Angew. Chem. Int. Ed. 2000, 39, No. 3). This is also expected for the manganese complex. This is consistent with the practical experience that the interaction between Mn2+and the organic anion is affected by extreme pH. “Delaking” of Bona metal laked pigments occurs at pH less than 3 and above 10. The pigment is of low solubility in water (42 mg/L) and octanol (33 mg/L) at neutral pH with a log POW of – 0.1 (Ciba Inc 2008). It has a molecular weight of 473 g/mol.

Oral route

No repeated-dose oral studies are available for the Manganese salts of the Bona metal laked pigments. In the acute oral toxicity study with Pigment Red 48:4(Mn), rats excreted red stained feces after application of a single dose of 5000 or 10000 mg/kg bw and red stained urine at 10 000 mg/kg bw (Ciba 1972). This occurred within an unspecified interval within 8 days after gavage application of the aqueous pigment suspension. No mortality and no clinical signs of toxicity were recorded. In contrast, acute oral LD50values for soluble inorganic Manganese salts such as MnSO4 are in the range of ca 1000 mg/kg bw. This indicates that Mn2+in Bona metal laked pigments is of much lower acute toxicity. Mn2+is most likely not absorbed in the intestine if contained in the intact pigment and pH-dependent disintegration in the stomach is probably not complete and/or the complex is partly re-formed in the intestine. Red coloration of the urine indicates that at 10 000 mg/kg bw, some substance was taken up and eliminated. Poor uptake after ingestion is also indicated from comparison to the acute toxicity upon intraperitoneal injection. The LD50 for ip dosing with Pigment Red 48:4 for rats was 1400 mg/kg bw (BASF AG 1973).

Information on the organic part is derived from repeated-dose toxicity data including a treatment-free recovery element of analogue Ca2+or Sr2+containing pigments: Pigment Red 48:2(Ca), Pigment Red 57:1(Ca) and Pigment Red 57(Sr) salt. The sodium salts of the pigments have an orange colour; therefore, the fate of the intact organic anion can be traced by coloration. For acute and repeated oral application of high doses, both red staining of faeces and orange discoloration of urine are observed starting the first day of dosing and resolving within days after the last dose. From this it is concluded that while a fraction of the pigment passes the intestine without uptake, another fraction is taken up and the organic acid is eliminated via the kidney. Considering the orange discolouration, the azo bond of the chromophore should still be at least partly intact. As the solubility of the sodium salt was measured as 0.3 g/L and 1.5 g/L for the sodium salt of Pigment Red 57 and Pigment Red 48, respectively (unpublished data, Ciba 2009), the organic acid is indeed sufficiently soluble for elimination without further metabolism. Enzymatic cleavage of azo bonds to the respective amines is also possible and this would result in non-colored soluble metabolites. Azo reduction of 1-amino-2-naphthol-based azo dyes was reported to by catalysed by human intestinal microflora [Xu, H., et al.: Anaerobic metabolism of 1-amino-2-naphthol-based azo dyes (dyes) by human intestinal microflora. Appl Environ Microbiol, 2007.73(23): p. 7759 -7762].

Information on Mn2+is summarized from a great number of publications that have investigated the fate of Manganese compounds with various solubility and oxidation states, and an absorption rate of 3 – 5% with biliary clearance is given (reviewed in Santamaria 2010, Dorman 2007). Manganese is an essential trace element that is subject to homeostatic control. Tissues accumulate manganese if serum protein binding and biliary clearance capacities are exceeded. Solutions of Mn (II) are susceptible to oxidation at neutral and basic pH and oxidative processes in the small intestine can be assumed. Mn(III) is bound to transferrin whereas Mn (II) is bound to albumin and b-globulin and other proteins. It is found in the central nervous system and in all other mammalian tissues. After gavage application to rats of 24.3 mg Mn/kg bw as soluble MnCl2, Mn was detected at the earliest time point of 0.5 h in blood, with peak concentration after 1 h (Roels 1997). Blood concentrations returned to normal within 12h. After 9 months and 15 months of feed application of MnSO4at 1500, 5000 and 15000 ppm to rats and mice, increased levels were found in the following organs: liver, kidney, brain and pancreas (US NTP 1993), the highest increase being seven-fold in kidney. Other organs were not investigated in that study. Whole body retention of manganese in six female volunteers as investigated after ingestion of eggs enriched with 54Mn was determined to be in the range of 10% and 3% after 5 and 10 days, respectively (Davidsson 1988).

Inhalation route

Experimental data is available for low molecular weight, highly soluble Manganese salts and this shows that such species are taken up by the body upon inhalation. A threefold increase in manganese concentration in bone was determined after a 14-day inhalation study of 3 mg/m3 Mn using 54MnCl2 as tracer; olfactory bulb concentrations were increased ca 2-fold at 0.3 mg/m3 air and ca 5-fold at 3 mg/m3 air. Relative regional concentrations were olfactory bulb > striatum> cerebellum (Dorman 2001). An overall low increase in Manganese concentrations in lung, liver, pancreas, testes or ovary was also observed in a 13-week inhalation study in rat with MnSO4 at doses of 0.01, 0.1, or 0.5 mg Mn/m3 air (Dorman 2004). For the chelated manganese in the pigment, the situation is expected to be different. Based on the moderate solubility in water and the molecular weight of > 200, respiratory absorption is not favoured (ECHA Guidance Document R.7.c, May 2008). For the same reasons, is also not expected that uptake via the olfactory bulb contributes significantly to the overall body burden. Systemic availability upon inhalation is expected mainly via clearance into the gastrointestinal tract. As the uptake of manganese from the gastrointestinal tract is poor, the overall manganese body burden from inhalation is lower than that of inorganic salts.

Dermal route

No experimental data is available regarding skin permeability. In general, there are few reliable parameters for the prediction of skin permeation. The parameters given in the guidance document by ECHA on toxicokinetics indicates a low potential for skin permeability. Absorption is anticipated to be low to moderate if the water solubility is between 1 and 100 mg/L. The molecular weight is in the range of 500 g/mol where the molecular size may be too high for uptake. The log Pow of < 0 indicates that lipophilicity is too low for skin absorption. The conditions of pH on the skin do not favour disintegration of the complex.

Conclusion

Overall, systemic availability can be assumed for oral and inhalation exposure. Accumulation of Manganese can be assumed for chronic exposure to doses that overload biliary clearance. There is no potential of bioaccumulation for the organic anion.