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4-(Phenylazo)benzol-1,3-diamin
(CAS-Nr.: 495-54-5)

4-Phenylazophenylen-1,3-diaminmonohydrochlorid
(CAS-NR.: 532-82-1)

Ausgabe: September 2003
Stand: Juli 2003

Zusammenfassung:

Mutagenität:

An Bakterien und Säugerzellen gesammelte in-vitro-Daten und ein UDS-Test in vivo weisen positive Ergebnisse auf.

Folglich ist die Einstufung in Mutagenität Kategorie 3 (M: 3); gerechtfertigt. Kanzerogenität:

Der Verdacht auf eine krebserzeugende Wirkung am Menschen ist unzureichend begründet. Es liegen keine verlässlichen Tierstudien vor: In einer positiven, an Mäusen durchgeführten Studie bestehen Zweifel hinsichtlich der Reinheit und/oder der Identität der geprüften Substanz. Hinzu kommen schwere Mängel in der Durchführung der Prüfung: Dieselben Verfasser waren nicht in der Lage, die Ergebnisse mit analytisch definiertem Chrysoidin zu reproduzieren. Auch eine negative Studie an Ratten wird aufgrund beträchtlicher Mängel in der Dokumentation als nicht ausreichend valide erachtet. Überdies deutet der Vergleich der Gentoxizitätsdaten des möglichen Abspaltproduktes Anilin mit Chrysoidin auf einen unterschiedlichen Metabolismus hin. Ein Analogieschluss kann somit nicht getroffen werden.

In Anbetracht der Nachweislage insgesamt ist eine Einstufung bzgl. der Kanzerogenität nicht möglich.

Reprotoxizität:

Fertilitätstoxizität:

Aufgrund fehlender Daten ist ein Einstufungsvorschlag nicht möglich. Entwicklungstoxizität:

Aufgrund fehlender Daten ist ein Einstufungsvorschlag nicht möglich.

(Eine detaillierte Stellungnahme liegt in englischer Sprache vor.)

4-(Phenylazo)benzol-1,3-diamin
(CAS-N r.: 495-54-5)

4-Phenylazophenylen-1,3-diaminmonohydrochlorid
(CAS-NR.: 532-82-1)

Ausgabe: September 2003
Stand: Juli 2003

A) Genotoxizität:

In vitro investigations:

• Studies in bacteria:
  Several studies evaluating the genotoxicity of chrysoidine in the Ames test have shown positive results with and without S-9 mix. In the strains Ta 100; 1537 and 98 concentrations of 0 - 2,500 µg/plate were used (Herbold, B.A. et al., 1982). In another test with Ta 100 concentrations of 0 - 80 µg/plate were used and have shown positive results only with S9-mix (Sandhu and Chipman, 1990).
  Remark: There are further positive studies which do not give additional evidence.
• Studies in mammalian cells:
  In an UDS test on primary rat hepatocytes with concentrations of 0 - 2.5 µg/ml the result was positive (Sandhu and Chipman, 1990).
• In vivo investigations:
  Studies in Drosophila melanogaster in feed (1 %) and by injection (1 % in H2O or oil) were both negative (Foureman et al., 1994).
  a micronucleus test in mice (NMRI) with a dose regimen of 0; 12; 60 and 300 mg/kg body weight according to OECD No. 474 was negative (BASF, 1988).
  In rats, an UDS test with doses of 800; 1,250 and 2,000 mg/kg orally administered in corn oil gave weak positive response at each dose level with poor dose dependency. The study was independently repeated in a second experiment with the same results (ICI, 1991).

In conclusion, since there are no studies available with evidence that the substance or a relevant metabolite reach the germ cells, a cetagory 3 based on positive results in an assay showing interactions with DNa in somatic cells in vivo (UDS Test) is warranted.

B) Carcinogenicity

1. Human data:
   a report of bladder cancer in three amateur anglers with exposure to chrysoidinedyed maggots (Searle and Teale, 1982) stimulated reports of four further cases (Massey et al., 1984; Sole, 1984) and two casecontrol studies (Cartwright et al, 1983; Sole and Sorahan, 1985). a study in UK used an existing largescale bladder cancer casecontrol study (over 900 pairs) and made further enquiries regarding fishing, maggots and dyes used on or in the maggots. The relative risks were 0.7 (95 % CI, 0.2-2.3) based on five exposed cases for yellow maggots (ready or selfcoloured) (Cartwright et al, 1983). Another study in UK was smaller (202 pairs) but showed a higher percentage of use of dyed maggots (14 % of cases, 8 % of controls). a threefold excess risk was noted for the use of bronze maggots for more than five years (Sole and Sorahan, 1985). This study almost certainly included five cases from the previous case reports that stimulated the casecontrol studies, but this factor is unlikely to remove the statistically excess risk. Evidence for carcinogenicity in humans is inadequate (IARC, 1987).
2. Carcinogenicity studies in rats and mice:
   There are no valid studies available according to nowadays standards, only a negative rat study (I) and a positive mouse study (II) with serious deficiencies:
   1. Rat (oral administration):
      "Maruya (1938) reported that no tumors occurred in a group of 10 rats fed a diet containing 1,000 mg chrysoidine per kg of diet for 51 - 366 days."
      (cited from IARC Monographs (1975))
   2. Mouse (oral administration):
      "a group of 60 male and 60 female C57BL mice was fed a low vitamin diet containing 2,000 mg chrysoidine per kg of diet for 13 months, after which a control diet was given for the remainder of their life span. Two other groups of 100 (50 males and 50 females) and 130 (60 males and 70 females) mice served as controls. In the chrysoidinetreated animals liver tumors (25 adenomas and 50 adenocarcinomas) were observed in 75/104 mice, the first tumor being observed after 10 - 11 months. Metastases to the lungs occurred in 3 animals. In the control groups 1/89 and 2/117 animals developed liver tumors without metastases to the lungs. In addition, 28/104 treated mice developed leukemias and reticulumcell sarcomas, compared with 9/89 and 12/117 in the control groups (Albert, 1956)."
      (cited from IARC Monographs (1975))

   Tumor table (mouse study)

   Group	Sex	No. of animals	Liver adenoma	Liver carcinoma	Combined liver neoplasia	Metastases in the lung	Leukemia and reticulumcell sarconomas	Leukemia and reticulumcell sarconomas simultaneously		Other tumors	Total No. of animals with tumors
   								Liver	Cancer