Barium 4-[(5-chloro-4-methyl-2-sulphonatophenyl)azo]-3-hydroxy-2-naphthoate

Endpoint summary

Description of key information

The NOAEL for chronic oral toxicity is established at 25 mg/kg bw based on repeated dose toxicity studies with analogue substances. Higher doses result in kidney damage. This is derived from subacute gavage studies with Pigment Red 57:1(Ca) (OECD 422, GLP, MHLW 1993), Pigment Red 48:2(Ca) (OECD 422, GLP, MHLW 2009) and Pigment Red 57(Sr) (OECD 407, GLP, DIC 2006).

No histopathology findings on kidneys were reported after a two-year skin painting study with mice with Pigment Red 57:1(Ca) (Carson 1984).

Regarding the cation, available data indicate that the data available for the Pigments covers the hazard of both the related anion and cation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

Please see the category read-across justification in the category object.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

>= 25 - < 100 mg/kg bw/day (nominal)

Based on:

other: read-across

Sex:

male/female

Basis for effect level:

other: no adverse effects expected

Dose descriptor:

LOEL

Effect level:

40 mg/kg bw/day (nominal)

Based on:

other: read-across

Sex:

female

Basis for effect level:

other: no adverse effects expected

Critical effects observed:

yes

Lowest effective dose / conc.:

40 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

urinary

Organ:

kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Justification for type of information:

Please see the category read-across justification in the category object.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

> 50 other: mg/kg bw twice weekly

Based on:

other: read-across

Sex:

male/female

Basis for effect level:

other: no adverse effects expected

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Justification for type of information:

Please see the category read-across justification in the category object.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

> 50 other: mg/kg bw twice weekly

Based on:

other: read-across

Sex:

male/female

Basis for effect level:

other: no adverse effects expected

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Oral exposure

Pigment Red 57:1(Ca) 5281-04-9

The study with Pigment Red 57:1(Ca) for repeated dose oral gavage toxicity was performed in Crj: CD(SD) rats with a product of 98% purity following OECD testing guideline 422 (MHLW, 1993) and the principles of GLP. Applied doses were 100, 300 and 1000 mg/kg/day using 5% Gum Arabic solution as vehicle. All animals survived to the end of the study. No clinical findings indicative of chemical toxicity were observed; red-stained faeces of dosed animals were due to the colour of the pigment. The mean body weight gain and food consumption in both sexes of dosed groups were comparable to those in the control groups throughout the study. No biologically significant changes in hematological parameters were noted in any dosed male groups. Males that received 300 mg/kg or more showed significantly decreased serum calcium and phosphorus levels. Further, significant decreases in serum potassium and total cholesterol levels, and significant increases in chloride and GOT levels were shown in the males that received 1000 mg/kg. Males that received 1000 mg/kg showed significant increases in relative kidney weights. Females that received 100 or 1000 mg/kg showed decreases in thymus weights in comparison with the controls. No other significant differences in organ weights were observed in either the males or the females. On the histopathology examination, predominant alterations suggesting effects in dosed rats were observed in the kidney. The lesions included an increased incidence of renal tubular epithelium regeneration in males receiving 300 mg/kg or more, and this and necrotic or foamy tubular epithelial cells in females that received 100 mg/kg or more. These lesions increased in severity and incidence in a dose-dependent manner.NOELsfor repeat dose toxicity are considered to be100 mg/kg bw/day for males and less than 100 mg/kg bw/day for females.

In another study rats were exposed 5 days a week to 1000 mg/kg bw/day for 30 days (22 doses in total). Half of the animals were not exposed during a recovery period, the other animals were sacrificed after the last exposure. No clinical signs except coloration of the feces was observed. No mortality, changes in food and water consumption, and effects on hematology, clinical biochemistry and urinalysis findings was observed. Slight inhibition of bodyweight gain which recovered during the recovery period was observed. Kidney weights were increased, although recovered after the recovery period. Morphological changes to the tubules of the kidney were observed, although no longer visible after the recovery period. TheNOAELwas determined to beless than 1000 mg/kg bw/day.

Pigment Red 57(Sr) 73612-29-0

Reversible kidney toxicity with a NOEL of 25 mg/kg bw and a LOAEL of 75 mg/kg bw was observed in the subacute oral toxicity study (OECD 407) with Pigment Red 57(Sr) using olive oil as vehicle (DIC 2006). Absolute and relative kidney weights were increased after four weeks, but not at the end of the treatment-free recovery period. No macroscopic findings were observed, but histopathology examinations showed that kidneys had a dose-dependent increase in atypical and typical basophilic tubules, degeneration and necrosis of tubular epithelium and dilation of distal and collecting tubules with a NOEL of 25 mg/kg bw. All males of the highest dose group of 200 mg/kg bw had orange coloured pigments in the cell debris. The pigment were still visible in two of five animals at the recovery sacrifice, all other histopathology findings were absent. Kidney findings occurred in females at a lower extent - slight degeneration and necrosis of tubular epithelium was observed only for the high dose group (200 mg/kg bw). Histopathology findings were not observed in animals of the recovery group. Body weight and food intake were not affected during the treatment period. During the recovery period, males of treatment group showed an increased food intake compared to control rats. Clinical signs consisted of salivation at the highest dose group during treatment.

Pigment Red 48:2(Ca) 7023-61-2

In the subacute oral toxicity study with Pigment Red 48:2(Ca) (OECD 422, MHLW 2009) using 1% Tween 80 in water as vehicle, the NOEL was determined to be 40 and less than 40 mg/kg bw for males and females, respectively. The test dosages were 40, 200, and 1000 mg/kg bw/day. In the histological examination of animals sacrificed after the dosing period, degeneration/necrosis of the proximal tubular epithelium in the kidney was noted in males of the 1000 mg/kg group and females of the 40 mg/kg group and higher. Moreover, degeneration/necrosis of the papillary ductal epithelium in females of the 1000 mg/kg group and mild basophilic tubule in males of the 1000 mg/kg group and females of the 200 and 1000 mg/kg groups were noted. Increased kidney weight was noted in males of the 1000 mg/kg group. These changes disappeared after a 2-week recovery period. Test substance-colored stool (red) was observed in all animals of the 40 mg/kg group and higher. Abnormal contents (test substance-colored reddish contents) the digestive organs such as cecum and colon and reddish urine in males were also noted. However, there were no abnormal changes in the digestive system or other organs/tissues in the histological examination. In other parameters, there were no changes attributed to the test substance on behavior test, body weight, food consumption, hematology, or blood chemistry.

Barium

Toxicity of Barium chloride dihydrate was investigated in GLP compliant drinking water studies with rats and mice in the US National Toxicology Program (US NTP 1994). Detailed investigations were performed during the 13-week study and at the 15 months interim sacrifice of the 2-year carcinogenicity studies (US NTP 1994). Additional investigations on Barium plasma levels and incorporation in bone were performed.

In rats, 1000 ppm or 65 mg/kg bw of Ba2+in drinking water was the NOEL for 13 weeks (US NTP 1994). At 2000 ppm treatment resulted in increased levels of phosphorous in serum. At 4000 ppm, reduced body weight and mortality were observed in addition to renal tubule dilatation in the outer stripe of the outer medulla and cortex occurred. 4000 ppm corresponded to 200 mg/kg bw for males and 180 mg/kg bw for females. No treatment-related findings were found in investigations on cardiotoxicity (electrocardiogram and blood pressure).In the subsequent 2-year study in rats (dose levels of 500, 1250, and 2500 ppm), effects did not significantly increase with time and no adverse findings were noted at 1250 ppm. At the highest dose of 2500 ppm, reduction in drinking water consumption and body weight were recorded.

At the interim sacrifice at 15 months, there were no differences in haematology and clinical chemistry parameters as well as in histopathology findings. The plasma barium concentrations (mg/ml) were significantly increased in males receiving 1250 and 2500 ppm and in all exposed groups of females.

Barium levels in bone in rats from the 2500 ppm groups were about 400 times greater than those in the controls. At terminal sacrifice, no treatment-related histopathology findings were noted. As animals reduced their drinking water uptake with age, the mean daily consumption for a concentration in drinking water 1250 ppm was calculated as 30 mg/kg bw for males and 45 mg/kg bw for females.

Findings in mice were consistent with the findings in rat, taking into account that mice were exposed to higher concentrations and that these resulted in more pronounced effects at the highest dose group. After two-year exposure, the incidence of nephropathy was significantly increased in male and female mice receiving 2500ppm (160 mg/kg bw for males and 200 mg/kg bw for females). The nephrophathy was morphologically distinct from spontaneous degenerative lesions that are commonly observed in aging B6C3F mice. The nephropathy is probably caused by crystals of insoluble Barium salts and was considered to be the cause of the higher morbidity. The NOEL was found to be 500 ppm (ca 30 - 35 mg/kg bw of Barium). In contrast to rats, mice do not reduce drinking water consumption.

Incorporation of Barium into the bone was not accompanied by adverse effects in rats and mice. The target organ for repeated dose toxicity was identified as kidney and this is considered to be linked to precipitates of insoluble barium salts.

Conclusion

Results for all analogue pigments are largely comparable. Kidney effects are clearly the most sensitive endpoint for the BONA metal laked pigments. Bolus dosing results in high peak exposures and high local concentrations and may overload the local detoxification capacities. The colourant is quickly taken up and eliminated via the kidney as indicated by dose-dependent urine coloration occurring within the first day of dosing. The regeneration of the renal epithelium indicates a cytotoxic effect, probably by the azo moiety or a metabolite.

In reproductive toxicity screening studies with Pigment Red 48:2(Ca) and 57:1(Ca) , pregnant females seemed somewhat more susceptible than males or non-pregnant females. However, the reported LOAELs of 40 and 100 mg/kg/day (lowest tested doses in each study, respectively) and the limited severity of the kidney effects at the LOAELs are considered compatible with the derived NOAEL of 25 mg/kg bw/day and no further adjustment is considered necessary. The cytotoxic effect of the Pigments Red lead to a constant regeneration of tubular epithelial cells as long as exposure continues. No pronounced increase in toxicity with dose was observed in any of the studies, i.e. higher doses did not induce qualitatively different kidney effects. Also, prolonged exposure up to 2 years did not increase kidney toxicity or induced qualitatively different effects. It appears that continuous application is better tolerated than bolus application. All kidney effects were completely reversible within tested recovery periods of 14 days. Effects at 40, 100, 200 or 300 mg/kg bolus dosing did not induce severe or serious damage, i.e., clear functional disturbance or morphological changes.

An uncertainty is the possible synergy of kidney effects from Barium and the organic anion. Synergy is however not expected as the mode of action appears to be different. Whereas it is linked to precipitates in the case of barium, the anion causes regeneration of the tubular epithelium. Furthermore, the organic anion can undergo azo reduction unless metabolism is overloaded while barium is principally eliminated in the faeces. In addition, a 90-day and a two-year feeding study on Pigment Red 53:1 (5-Chloro-2-[(2-hydroxy-1-naphthalenyl)azo]-4-methyl benzenesulfonic acid, barium salt (2:1), CAS no 5160-02-1) is available (OECD SIDS document of Pigment Red 53:1, 1999). Pigment Red 53:1(Ba) lacks the carbonic acid function on the naphthyl ring. In this study no effect on the kidneys has been observed. It can therefore be concluded that the renal effects observed in the Pigment studies will not be increased by barium. Therefore, taking 25 mg/kg bw for chronic exposure of rats as a starting point for DNEL calculation covers hazards both related anion and cation.

Taking all repeated-dose studies into account both the most relevant NOAELs are the one from a guideline 28-day study with Pigment Red 57(Sr) (25 mg/kg bw) and from the chronic feeding study with sodium salt of Pigment Red 57(Na) (26 mg/kg/bw). Twenty-five mg/kg bw is used as starting point for DNEL derivation because the value stems from the newest study with the most extensive analysis of parameters (including urinalysis) and is the lowest value.

Dermal exposure

Absence of histopathology findings in kidney upon 18 month skin painting study with mice was published (1984). The study was designed between the US FDA and an industry association to assess the safety of the use of Pigment Red 57:1(Ca) in lipstick and therefore, a limit dose of 50 mg/kg bw was chosen. Limited details are given in the literature. The main focus of the study was local effects, but a set of organs for each five males and females was investigated by histopathology. As kidney histopathology was the most sensitive endpoint, this investigation contributes to hazard assessment.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity according to Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008.