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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The substances displayed below are considered read-across analogues based on similar physico-chemical and toxicological properties of the pigments. The substance of this chemical sub-class (monohydrazone pigments, BONA pigment lakes) include an organic part, bearing an aminosulfonic acid coupled onto hydroxy-naphthoic acid, and an inorganic cation represented by an alkaline earth metal such as manganese, strontium or calcium. Thus, the read across is also based on structural similarities as a result of equal manufacturing processes. All BONA Metal Laked Pigments are of low solubility in water and octanol. Dissociation of these metal salt pigments, which is enhanced under a highly acidic condition (such as in the stomach), leads, at least partially, to the release of the metal cation and the organic acid. Therefore, the impact of the metal component and the organic acid is discussed separately. In addition, toxicological information on moieties is available, which provides supporting information regarding the effect of substituents on the toxicological profile. Moreover, reductive cleavage of the azo bond, catalysed by (microbial) azo-reductase or other reductive liver enzymes, may result in the release of these moieties which therefore represent (common) metabolites. Hazard assessment of the metals is assessed by inclusion of information on inorganic soluble salts of the metals.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Colour index name CAS number EINECS number
Pigment Red 57:1(Ca) 5281-04-9 226-109-5
Pigment Red 57(Sr) 73612-29-0 277-552-6
Pigment Red 57:2 (Ba) 17852-98-1 241-806-4
Pigment Red 48:1(Ba) 7585-41-3 231-494-8
Pigment Red 48:2(Ca) 7023-61-2 230-303-5
Pigment Red 48:3(Sr) 15782-05-5 239-879-2
Pigment Red 48:4(Mn) 5280-66-0 226-102-7
Pigment Red 52(Sr) 67828-72-2 267-291-6
Pigment Red 52:2(Mn) 12238-31-2 241-780-4

Tested products contain at least 80% of the colorant. Purities range from 80% to 90%. Typical impurities are low levels of the starting materials 3-hydroxy-2-naphthoic acid (BONA) and the coupling amine, water of crystallization and free water as depicted in Table 3. Due to the lacking process in synthesis, all substances contain a fraction of the corresponding sodium salt. No impurity was considered to cause any concern regarding human toxicology. Impurities were reported to have no classifications according to information provided by ECHA (https://echa.europa.eu/de/information-on-chemicals/cl-inventory-database).


3. ANALOGUE APPROACH JUSTIFICATION
It is referred to the attached pdf file.

4. DATA MATRIX
It is referred to the attached pdf file.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Route of administration:

oral: gavage

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

no

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

no

Remarks on result:

not measured/tested

Critical effects observed:

no

Remarks on result:

not measured/tested

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Pigment Red 57:1 caused no effects on fertility in a valid screening study performed according to OECD testing guideline 422 at doses of 100, 300, and 1000 mg/kg bw/day (MHLW 1993). Up to the highest dose of 1000 mg/kg bw, no indication on female or male fertility were observed. The 14-day pre-mating period allows only a limited assessment of male fertility, but further information on male fertility can be derived from the fertility element and the histopathology of the long term feeding study with the sodium salt of Pigment Red 57 (CTFA 1981). The fertility element is similar to the one-generation study (OECD 415) with the limitation that 60 instead of 70 days treatment prior to mating are used. No adverse effects on fertility or reproductive organs were observed at dose levels in the diet of up to 2%. This study is adequate in design and reporting for hazard assessment. Discoloration of urine by the test item indicates systemic availability despite the better water solubility compared to Pigment Red 57:1.

The chlorinated analogue Pigment Red 48:2 was also tested in a GLP-compliant screening study performed according to OECD testing guideline 422 at doses of 40, 200 and 1000 mg/kg bw. Pigment Red 48:2 had no effects on the reproductive parameters such as estrous cycle, mating index, fertility index, delivery index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, or parturition or maternal behaviour. On the examination of neonates, there were no significant differences in the number of offspring or live offspring, sex ratio, live birth index, or viability index on day 4. No abnormal findings attributed to the test substance were found in external features, clinical signs, body weights, or necropsy of the offspring.

 

The long-term feeding study in rats with the sodium salt of Pigment Red 57 contained a fertility element which is similar to a one-generation study (OECD 415) with the following deviations: Both males and females were treated 60 days prior to mating. Pup weight was only determined for litters. Histopathology of reproductive organs was performed for the adult F1 animals which had been exposed in utero, via lactiation and via the feed for one year or life-long exposure. Neither fertility nor reproductive organs were affected by feeding of doses of 0.05, 0.3 or 2% in the diet.

The OECD SIDS document of barium bis[2-chloro-5-[(hydroxy-1-naphthyl)azo]toluene-4-sulphonate] (Pigment Red 53:1) describes a study which appears to be identical in design to the study by CTFA (UNEP 1999). No adverse effects were recorded for reproductive toxicity indeces at 10000 ppm in the feed. Parental toxicity consistent with other repeated dose studies of this pigment was observed.

 

Results regarding a three-generation study in rats with Pigment Red 57:1 are mentioned in various secondary sources. The actual study (Weil 1973) was performed following a non-standard design with doses of 0.5, 5, 15 and 50 mg/kg bw. Rats are treated via the feed for three generations and each generation produced one to three sets of offspring which were used for mating or pathology. Historical control data was not available. Analysis in the feed was not performed. Limited details are reported regarding macroscopic and microscopic examinations. The study reports effects on fertility for males of the second generation at 50 mg/kg bw, but not of the first or third generation. Histopathology investigations on reproductive organs were apparently not performed for the F2 generation. Detailed data is only given for the three control groups and the high dose group of the F1b group regarding lung, liver, kidney, heart, adrenal, thyroid, trachea and prostate. The findings of the three-generation study are poorly reported and inconclusive and therefore do not contribute to hazard assessment. No effects on lactation were observed.

Short description of key information:
Experimental data is available for the analogue substances Pigment Red 57:1, Pigment Red 48:2 and the sodium salt of Pigment Red 57. Both Pigment Red 48:2 and Pigment Red 57:1 caused no effects on fertility in a GLP-compliant screening study performed with up to 1000 mg/kg bw according to OECD testing guideline 422 (MHLW 1993 and 2009). No effects were observed in the one-generation fertility element of long-term feeding study with 0.05, 0.3 or 2% of the sodium salt of Pigment Red 57 (CTFA 1981b). Presumably the same study was performed with Pigment Red 53:1 as indicated in the OECD SIDS document and no effects on fertility occurred with a feed concentration of 10000 ppm.

Effects on developmental toxicity

Description of key information

Experimental data is available for the analogue substances Pigment Red 57:1, Pigment Red 48:2 and the sodium salt of Pigment Red 57.  Both Pigment Red 48:2 and Pigment Red 57:1 caused no developmental toxicity in a GLP-compliant screening study performed with up to 1000 mg/kg bw according to OECD testing guideline 422. (MHLW 1993 and 2009). Absence of teratogenicity of Pigment Red 57:1 was found in a study in rats with 50 mg/kg bw (Durloo 1972).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

Study reports for the non-chlorinated analogue Pigment Red 57:1 are available for two teratogenicity studies in rats and in rabbits (Durloo 1972).

The study in rabbits is of limited value as only 10 pregnant females per dose group were used. Pregnant rabbits received 5, 16 or 50 mg/kg bw by gavage during gestation days 6 - 18 and they were sacrificed on gestation day 29. No effects were recorded regarding the number of viable and dead fetuses, resorption sites, mean fetal weight, distribution of sex, mean litter size, frequency of skeletal anomalies and frequency of visceral and structural anomalies.The study in rats was performed with doses of 5, 16 and 50 mg/kg bw, applied by gavage during gestation days 5 to 15. No adverse effects were reported regarding the same endpoints as for rabbits.

The study included limited investigations regarding maternal toxicity, as only body weight gain of dams was reported. No individual data and no statistical evaluation are given in the report. The highest dose is slightly above the subacute NOAEL for adverse effects on kidney.

No indication of developmental toxicity was observed in the OECD 422 screening studies with Pigment Red 57:1 and 48:2 (MHLW 1993 and 2009).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

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 reproductive toxicity under Regulation (EC) No. 1272/2008.