Anthraquinone

Carcinogenicity

Description of key information

Key study: Read-across from experimental data on the analogue CAS No. 518-82-1 (emodin). Test method equivalent to OECD guideline 451. GLP study. 
There was no evidence of carcinogenic activity of emodin in male rats. There was equivocal evidence of carcinogenic activity in female rats. 
There was equivocal evidence of carcinogenic activity in male mice. There was no evidence of carcinogenic activity in female mice. 
The substance is not classified as carcinogenic.  

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The analogue CAS nº 518-82-1 emodin shares the same functional group with the substance CAS nº 84-65-1 anthraquinone and the results can be extrapolated to anthraquinone.

Principles of method if other than guideline:

Read-across approach from a study on the analogue CAS nº 518-82-1 emodin.

GLP compliance:

yes

Relevance of carcinogenic effects / potential:

There was no evidence of carcinogenic activity in male rats. There was equivocal evidence of carcinogenic activity in female rats.

There was equivocal evidence of carcinogenic activity in male mice. There was no evidence of carcinogenic activity in female mice.

Based on the experimental results obtained with the analogue emodin, the read-across approach is applied and the results can be extrapolated to substance anthraquinone under test conditions.

The analogue emodin shares the same functional group with anthraquinone and also has comparable values for the relevant molecular properties. These properties are:

- a high log Pow value which is 3.39 for anthraquinone and 4.01 for emodin,

- a low water solubility (both substances are insoluble in water) and

- similar molecular weights which are 208.22 for anthraquinone and 270.23 for emodin.

 

As indicated in the European Chemical Agency Practical Guide 6 “How to report read –across and categories”, the structural grouping was realized using “OECD QSAR APPLICATION TOOL BOX” version 1.1.0 (see attachement).

Table 1: Data Matrix, Analogue Approach

CAS Number		518-82-1	84-65-1
CHEMICAL NAME		Analogue 1 Emodin	Anthraquinone
PHYSICO-CHEMICAL DATA
Melting Point		Experimental results: 256-257 °C	Experimental results: 286 ºC
Boiling Point		Estimated data: The calculated boiling point is 479.69 ºC (EPI Suite, MPBPVP v1.43)	Experimental results: 377 ºC
Density		No data	Experimental results: 1.42-1.44
Vapour Pressure		Estimated data: The calculated vapour pressure is 8.91E-010 Pa at 25 ºC (EPI Suite, MPBPWIN v1.43).	Weight of evidence: The calculated vapour pressure is 5.1E-006 Pa at 25 ºC (EPI Suite, MPBPWIN v1.43). The experimental vapour pressure of the substance is 1.16X10-7 mm Hg at 25 ºC (peer reviewed publication).
Partition Coefficient (log Kow)		Estimated data: The calculated partition coefficient is(EPI Suite, KOWWIN v1.68 estimate).	Weight of evidence: The calculated partition coefficient is(EPI Suite, KOWWIN v1.68 estimate). The experimental partition coefficient octanol-water of the substance is 3.39 (peer reviewed publication).
Water solubility		Practically insoluble in water.	Experimental results: 0.17 mg/L at 20 ºC
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation		Estimated data: No readily biodegradable (BIOWIN v4.10)	Weight of evidence: Based on available experimental data from bibliography the substance is considered as readily biodegradable.
Anaerobic Biodegradation		No data	No data
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish		No data (insoluble in water)	No data (insoluble in water)
Acute Toxicity to Aquatic Invertebrates		No data (insoluble in water)	No data (insoluble in water)
Toxicity to Aquatic Plants		No data (insoluble in water)	No data (insoluble in water)
Toxicity to soil macroorganisms		Experimental results:Eisenia fetida 56-d LC50 > 512 mg/kg soil dw (mortality) 56-d EC50 = 182 mg/kg soil dw (the test substance significantly inhibited reproduction).	Read-across from emodin: 56-d LC50 > 394 mg/kg soil dw (based on mortality) 56-d EC50 = 140 mg/kg soil dw (based on effects on reproduction)
Toxicity to birds		No data.	Experimental results: LC50 > 5000 ppm
MAMMALIAN TOXICITY
Acute Oral		No data	Experimental results: LD50 > 2000 mg/kg bw
Acute Inhalation		No data	No data
Acute Dermal		No data	Experimental results: LD50 ≥ 3000 mg/kg bw
Skin irritation / Eye irritation		No data	Experimental results: Not irritating
Skin sensitisation		No data	Experimental results: Sensitising
Repeated Dose		Repeated dose toxicity: oral: Key study: 14 weeks in rats: NOAEL 80 mg/kg bw/day male (based on decreased body weights) NOAEL 40 mg/kg bw/day female (based on decreased body weights)   Repeated dose toxicity: oral: Key study: 14 weeks in mice: NOAEL 190 mg/kg bw/day male (based on decreased body weights)   NOAEL > 1100 mg/kg bw/day female (based on decreased body weights)	Read-across from emodin: Rats: NOAEL 62 mg/kg bw/day male (based on decreased body weights) NOAEL 31 mg/kg bw/day female (based on decreased body weights)   Mice: NOAEL 147 mg/kg bw/day male (based on decreased body weights)   NOAEL > 848 mg/kg bw/day female (based on decreased body weights)
Genetic Toxicity in vitro	Gene mutation in bacteria	Key study: Positive for TA100 in the presence of S9 activation; negative for TA98, with or without S9.	1.- Key study:  The substance AQ-FC did not show any mutagenic activity either with or without metabolic activation in thetester strains (S. typhimurium TA1535, TA1537, TA98 and TA100 or in E. coli WP2uvrA).   2.- Key study: The substance anthraquinone (100% pure) did not show any mutagenic activity either with or without metabolic activation in theAmestester strains used (S. typhimurium TA98, TA100 and TA102).   3.- Key study:  The substance anthraquinone (Friedel-Crafts process) did not show any mutagenic activity either with or without metabolic activation in thetester strains used (TA98 and TA100).
	Chromosomal aberration	1.- Key study:  Chromosome aberrations were induced in cultured CHO cells in the absence of S9 activation and in the presence of S9; the response observed without S9 was stronger than with S9.   2.- Key study: Mammalian cell micronucleus test: The test substance did not reveal any micronuclei inducing activity in either human lymphocytes or in Hep-G2.	Read-across from emodin:Contradictory results from different sources. Data available from in vivo studies.
	Mammalian gene mutation	1.- Key study:  The substance induced a moderate increase in mutant fraction (only tested without metabolic activation).   2.- Key study:  The test substance did not result in an increase in the number of colonies resistant to 6 -TG. Exposure in suspension in the presence of liver homogenate was also negative.   3.- Key study:  The test substance emodin was highly mutagenic without metabolic activation. However, the increase in the induction of mutation was observed at highly toxic concentrations.	Read-across from emodin:Negative.
Genetic Toxicity in vivo		Mammalian erythrocyte Micronucleus test: 1.- Key study: There was no statistically significant enhancement in the frequency of micronucleated PCEs in comparison to the negative controls at both preparation intervals.   2.- Key study:  In peripheral blood samples from mice in the 14-week feed study, an increase in the frequency of micronucleated NCEs was seen in females, but not in males. The result in female mice was concluded to be weakly positive.   Mammalian bone marrow chromosome aberration test: 1.- Key study: No increases in the frequencies of micronucleated erythrocytes were observed in any of the treatment groups (only males were used).   2.- Key study: No increases in the frequencies of micronucleated erythrocytes were observed in any of the treatment groups (males and females were used).	Read-across from emodin: Negative
Carcinogenicity		Key study: No carcinogenic activity.   There was no evidence of carcinogenic activity of emodin in male rats. There was equivocal evidence of carcinogenic activity in female rats.   There was equivocal evidence of carcinogenic activity in male mice. There was no evidence of carcinogenic activity in female mice.	Read-across from emodin: No carcinogenic activity.
Reproductive Toxicity: developmental toxicity		Key study:   NOAEL rats maternal: 57 mg/kg/day (based on maternal body weight and weight gain) NOAEL rats foetal: 80-144 mg/kg/day (highest dose)   NOAEL mice (maternal and foetal): 391 mg/kg/day LOAEL 1005 mg/kg/day (decreased maternal body weight and weight gain decreased foetal body weight).	Read-across from emodin: NOAEL rats maternal: 44 mg/kg/day (based on maternal body weight and weight gain) NOAEL rats foetal: 62-111 mg/kg/day (highest dose)   NOAEL mice (maternal and foetal): 301 mg/kg/day LOAEL 774 mg/kg/day (decreased maternal body weight and weight gain decreased foetal body weight).

Conclusions:

The substance is not classified as carcinogenic.

Executive summary:

Based on the experimental results obtained with the analogue emodin, the read-across approach is applied and the results can be extrapolated to substance anthraquinone under test conditions.

There was no evidence of carcinogenic activity in male rats. There was equivocal evidence of carcinogenic activity in female rats.

There was equivocal evidence of carcinogenic activity in male mice. There was no evidence of carcinogenic activity in female mice.

The substance is not classified as carcinogenic.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Klimisch 2: Read-across approach. The study was performed according to NTP (National Toxicology Program, within the U.S. Department of Health and Human Services) standard protocol. Equivalent to OECD 451. GLP study.

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

The substance to be supported by this registration dossier is anthraquinone obtained by Friedel-Crafts technology (AQ-FC).

Based on the results obtained from the carcinogenicity studies conducted with the analogue emodin, the substance anthraquinone is not classified as carcinogenic.

Additional information

Commercial anthraquinone (AQ) is produced by at least three different production methods:

- Oxidation of anthracene (AQ-OX)

 - Friedel-Crafts technology (AQ-FC)

- Diels-Alder chemistry (AQ-DA)

with the final product varying in color and purity.

AQ-OX begins with anthracene produced from coal tar and different lots can contain various contaminants, particularly the mutagenic isomers of nitroanthracene. AQ has been reported to be negative in a variety of genotoxicity tests including numerous Ames mutagenicity assays. In addition, it is reported that AQ-DA is negative in the Salmonella-Escherichia coli reverse mutation assays, the L5178Y mouse lymphoma forward mutation assay, for inducing chromosomal aberrations, polyploidy or endoreduplication in Chinese hamster ovary cells, and in the in vivo mouse micronucleus assay (Butterworth et al., 2001). Further, a previous 18 month bioassay conducted with AQ administered to male and female B6C3F1 and (C57BL/6 x AKR)F1 mice reported no induction of cancer. Thus, it was somewhat unexpected that in a long-term study conducted by the National Toxicology Program (NTP) AQ-OX induced a weak to modest increase in tumors in the kidney and bladder of male and female F344/N rats and a strong increase in the livers of male and female B6C3F1 mice. In the studies reported in Butterworth et al. (2001) a sample of the AQ-OX used in the NTP bioassay was shown to be mutagenic in the Ames tester strains TA98, TA100 and TA1537. Addition of an S9 metabolic activation system decreased or eliminated the mutagenic activity. In contrast, the purified NTP AQ-OX as well as the technical grade samples AQ-FC and AQ-DA were not mutagenic in the Ames test. The chemical structure of AQ does not suggest that the parent compound would be DNA reactive. Therefore, a mutagenic contaminant was present in the NTP bioassay sample that is either directly mutagenic or can be activated by bacterial metabolism. Analytical studies showed that the primary contaminant 9-nitroanthracene (9-NA) was present in the NTP AQ-OX at a concentration of 1200 ppm but not in the purified material. The 9-NA and any other contaminants that might have been present in the NTP AQ-OX induced measurable mutagenicity at 9-NA concentrations as low as 0.15 µg/plate in tester strain TA98, indicating potent mutagenic activity (Butterworth et al., 2001).

Therefore, many of the reported genotoxicity and carcinogenicity results in the literature for AQ and AQ derivative compounds must be viewed with caution.

 

Results:

Key study: Read-across from experimental data on the analogue CAS No. 518-82-1 (emodin). Test method equivalent to OECD guideline 451. GLP study.

 

There was no evidence of carcinogenic activity of emodin in male rats. There was equivocal evidence of carcinogenic activity in female rats.

There was equivocal evidence of carcinogenic activity in male mice. There was no evidence of carcinogenic activity in female mice.

 

The substance is not classified as carcinogenic.