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EC number: 212-977-2 | CAS number: 897-06-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
Description of key information
A carcinogenic potential is assumed for androstadiendion based on two carcinogenicity studies in rats and mice with the read-across substance androstendion (NTP, 2010). These studies reveald an equivocal evidence of carcinogenic activity in rats and a clear evidence of carcinogenic activity in mice after administration of androstendion over 2 years in oral doses up to 50 mg/kg bw. Steroid hormones in general can promote the growth of specific hormone dependent tissues and tumors.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study (supervised by NTP)
- Qualifier:
- according to guideline
- Guideline:
- other: NTP laboratory health and safety guidelines
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Principles of method if other than guideline:
- Cited from report: "The NTP conducts its studies in compliance with its laboratory health and safety guidelines and FDA Good Laboratory Practice Regulations and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use are in accordance with the Public Health Service Policy on Humane Care and Use of Animals. Studies are subjected to retrospective quality assurance audits before being presented for public review."
- GLP compliance:
- yes (incl. QA statement)
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Strain: B6C3F1
- Source: Taconic Farms, Inc. (Germantown, NY, USA)
- Age at study initiation: 5 to 6 weeks old
- Weight at study initiation (mean): males 23.3 g, females 19.1 g
- Housing: singly (males) or in groups of five (females) per cage (solid bottom polycarbonate cages)
- Diet and Water: ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 22 +/- 1.6 (72 +/- 3 °F)
- Humidity (%): 50 +/- 15
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- Administration volume: 10 mL/kg
VEHICLE: 0.5 % aqueous methylcellulose - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulations were analysed every 2 to 3 months during the 2-year studies; animal room samples were also analysed. The analytical method used was HPLC.
- Duration of treatment / exposure:
- 104 to 106 weeks
- Frequency of treatment:
- once daily, 5 days/week
- Post exposure period:
- no, animals were sacrificed on the day after the last dosing
- Remarks:
- Doses / Concentrations:
10, 20, and 50 mg/kg bw
Basis:
other: males; actual ingested - Remarks:
- Doses / Concentrations:
2, 10, 50 mg/kg bw
Basis:
other: females; actual ingested - No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: For dose selection results from previously conducted 2-week and 3-month studies were used. The lower dose group of 2 mg/kg in females was selected due to suspected ovarian atrophy observed in the 3-month study; however, this finding was not confirmed upon reexamination.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: observed twice daily; clinical findings were recorded every 4 weeks
BODY WEIGHT: Yes, all animals
- Time schedule for examinations: animals were weighed on day 1, day 4 (males), day 5 (females), weekly for 13 weeks, monthly thereafter, and at the end of the studies.
CLINICAL PATHOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, complete necropsies were performed on all rats
HISTOPATHOLOGY: Yes, complete histopathology was performed on all animals
In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone, brain, clitoral gland, esophagus, eye, gallbladder, harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, seminal vesicle, skin, spleen, stomach (forestomach and glandular), testis with epididymis, thymus, thyroid gland, trachea, urinary bladder, and uterus. - Statistics:
- Survival Analysis: The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for possible dose-related effects on survival used Cox¿s (1972) method for testing two groups for equality and Tarone¿s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.
Calculation of Incidences were performed: Incidences of neoplasms or nonneoplastic lesions as the numbers of animals bearing such lesions at a specific anatomic site and the numbers of animals with that site examined microscopically.
Analysis of Neoplasm and Nonneoplastic Lesion Incidences: Poly-k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) to assess neoplasm and nonneoplastic lesion prevalence. Tests of significance included pairwise comparisons of each dosed group with controls and a test for an overall dose-related trend. Continuity-corrected Poly-3 tests were used in the analysis of lesion incidence, and reported P values are one sided.
Analysis of Continuous Variables: Two approaches were employed to assess the significance of pairwise comparisons between dosed and control groups in the analysis of continuous variables. 1) Parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972). 2) Nonparametric multiple comparison methods of Shirley (1977) (as modified by Williams, 1986) and Dunn (1964). - Details on results:
- CLINICAL SIGNS AND MORTALITY
Survival of dosed groups was similar to that of the vehicle control groups.
BODY WEIGHT AND WEIGHT GAIN
Mean body weights of 10 and 50 mg/kg females were generally less than those of the vehicle controls after weeks 81 and 17, respectively.
HISTOPATHOLOGY:
The incidences of hepatocellular adenoma in males and females were significantly increased in the 50 mg/kg groups. In females, the incidences of hepatocellular carcinoma were significantly increased in all dosed groups. Incidences of hepatocellular adenoma or carcinoma (combined) in males and females were significantly increased in the 50 mg/kg groups. Incidences of hepatoblastoma were marginally increased in dosed males. Incidences of multiple hepatocellular adenomas and carcinomas were significantly increased in 10 and 50 mg/kg males, and there was an increased incidence of multiple hepatocellular adenomas in 50 mg/kg females. The incidence of eosinophilic focus was significantly increased in 50 mg/kg males, and the incidences of mixed cell focus and cytoplasmic vacuolization were significantly increased in 50 mg/kg females.
There was a marginally increased incidence of pancreatic islet adenoma in 50 mg/kg males and in 10 and 50 mg/kg females, with an earlier day of first incidence in males. The incidences of clitoral gland hyperplasia and clitoral gland duct dilatation were significantly increased in 10 and 50 mg/kg females. The incidence of glomerular metaplasia of the kidney was significantly increased in 50 mg/kg females, and the incidences of cytoplasmic alteration of the submandibular salivary gland were significantly increased in all dosed female groups. The increased incidences of cytoplasmic alteration of the submandibular salivary gland and glomerular metaplasia of the kidney in female mice indicated a masculinizing effect from androstenedione treatment.
In 50 mg/kg females, the incidence of malignant lymphoma was significantly decreased. - Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Executive summary:
Cited from NTP report:
"Groups of 50 male and 50 female mice were administered 0, 2 (females only), 10, 20 (males only), or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of dosed groups was
similar to that of the vehicle control groups. Mean body weights of 10 and 50 mg/kg females were generally less than those of the vehicle controls after weeks 81 and 17, respectively."
"There was clear evidence of carcinogenic activity of androstenedione in male B6C3F1 mice based on increased incidences of multiple hepatocellular adenoma and hepatocellular carcinoma and increased incidence of hepatoblastoma. There was clear evidence of carcinogenic activity of androstenedione in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma. Increased incidences of pancreatic islet adenoma in male and female mice were also considered chemical related."
Androstenedione administration caused increased incidences in nonneoplastic lesions of clitoral gland, kidney, and submandibular salivary gland of female mice. Decreases in the incidences of malignant lymphoma in female mice were considered related to androstenedione administration.
Reference
Cited from NTP report:
"There was clear evidence of carcinogenic activity of androstenedione in male B6C3F1 mice based on increased incidences of multiple hepatocellular adenoma and hepatocellular carcinoma and increased incidence of hepatoblastoma. There was clear evidence of carcinogenic activity of androstenedione in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma. Increased
incidences of pancreatic islet adenoma in male and female mice were also considered chemical related."
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Study duration:
- chronic
- Species:
- mouse
- Quality of whole database:
- The study is GLP compliant and is of high quality (Klimisch score=1)
- Organ:
- liver
- pancreas
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
In analogy to the read-across substance androstendion the following self classification for androstadiendion is recommended according to Regulation (EC) No.1272/2008 (CLP) :
Carc. 2 ( H351: Suspected of causing cancer)
Published carcinogenicity studies with androstendion, conducted within the scope of NTP (NIH, US) assessment, revealed equivocal evidence of carcinogenic activity in rats and clear evidence of carcinogenic activity in mice based on increased incidences of multiple hepatocellular adenoma and carcinoma and increased incidence of hepatoblastoma as well as increased incidence of pancreatic islet adenoma. However, for classification of androstendion it has to be taken into account that steroids hormones in general can promote the growth of specific hormone dependent tissues and tumors.
The classification is in accordance with German legislation for classification of androgenic steroids. The German Committee on Hazardous Substances (AGS) recommended for androgenic steroids classification as Carc. Cat. 3 for carcinogenic effects according to criteria of Directive 67/458/EEC (see argumentation for the assessment of steroid hormones, Technical Rule for Hazardous Substances 905; elaborated by the German Committee on Hazardous Substances (AGS) and published by the German Federal Ministry of Labour and Social Affairs, version of 2008/2005/1999, only available in German, http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen- 905-906.html).
Additional information
For androstadiendion (CAS No. 897-06-3) no carcinogenicity data are available. Therefore, carcinogenicity data of androstendion (CAS No. 63-05 -8) were used. A search for structure-analogue substances using the QSAR Toolbox 3.3.5 recommended androstendion as one out of 11 category substances for a read-across approach (for details see QSAR OECD Toolbox Report on Androstadiendion attached in chapter 7, Endpoint Summary: Toxicological information).
Results of 2-year carcinogenicity studies with androstendion on rats and mice were published within the scope of National Toxicology Program (NIH, US) assessment (NTP, 2010). In these studies androstendion was administered by gavage to male and female rats and male mice at dosages of 0, 10, 20, or 50 mg/kg body weight each day and to female mice at dosages of 0, 2,10, or 50 mg/kg body weight for two years. At the end of the study tissues from more than 40 sites were examined for every animal.
Cited from
NTP report: "Under the conditions of these 2-year gavage studies, there
was equivocal evidence of carcinogenic activity of androstenedione in
male F344/N rats based on increased incidences of alveolar/bronchiolar
adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There
was equivocal evidence of carcinogenic activity of androstenedione in
female F344/N rats based on increased incidences of mononuclear cell
leukemia. There was clear evidence of carcinogenic activity of
androstenedione in male B6C3F1 mice based on increased incidences of
multiple hepatocellular adenoma and hepatocellular carcinoma and
increased incidence of hepatoblastoma. There was clear evidence of
carcinogenic activity of androstenedione in female B6C3F1 mice based on
increased incidences of hepatocellular adenoma and hepatocellular
carcinoma. Increased incidences of pancreatic islet adenoma in male and
female mice were also considered chemical related.
Androstenedione administration caused increased incidences in
nonneoplastic lesions of the liver in male and female rats and mice;
pancreatic islets and exocrine pancreas of female rats; and clitoral
gland, kidney, and submandibular salivary gland of female mice.
Decreases in the incidences of testicular interstitial cell adenoma in
male rats, mammary gland fibroadenoma, cysts, and hyperplasia in female
rats, and malignant lymphoma in female mic were considered related to
androstenedione administration."
However, for the assessment of carcinogenicity it has to be taken into account that steroid hormones in general can promote the growth of specific hormone dependent tissues and tumors. Overall, androstendion caused liver cancer (variety of liver tumors, including adenomas, carcinomas and hepatoblastomas) and pancreatic islet cancer (adenomas) in male and female mice. The occurrence of lung tumors (a few adenomas and one carcinoma) in male rats and mononuclear cell leukemia in female rats may have been related to androstendion exposure. Increases in non-neoplastic lesions of the pancreas in female rats and of the clitoral gland, kidney, and salivary gland in female mice were attributed to androstendion exposure. Androstendion treatment reduced the incidence of neoplasms in several tissues that are well known endocrine targets (decreases in the incidences of testicular interstitial cell adenoma in male rats, mammary gland fibroadenoma, cysts, and hyperplasia in female rats, and malignant lymphoma in female mice).
For an assessment of steroid hormones see also the argumentation for steroid hormones related to the Technical Rule for Hazardous Substances 905, which was elaborated by the German Committee on Hazardous Substances (AGS) and published by the German Federal Ministry of Labour and Social Affairs (version of 2008/2005/1999, only available in German, http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/ Begruendungen-905-906.html). In this argumentation 73 steroid hormones or precursors of steroid hormones were each allocated to one of seven hormone classes based on their predominant pharmacological activity (i.e. androgenic, mild androgenic, anabolic, estrogenic, gestagenic, mild gestagenic or glucocorticoide), and recommendations for their classification were elaborated. Androstendion was allocated to group 1 (androgenic steroids) resulting in a classification with Carc. Cat. 3 according to criteria of Directive 67/458/EEC.
Justification for selection of carcinogenicity via oral route endpoint:
The carcinogenicity study in mice is selected since it revealed clear evidence of carcinogenic activity compared to the study in rats, which revealed equivocal evidence of carcinogenic activity.
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