Anthraquinone

Endpoint summary

Description of key information

Key study: Read-across from experimental data on the analogue CAS No.518-82-1. Test method equivalent to OECD guideline 408. GLP study. 
90-day oral toxicity study: 
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)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Remarks:

other: read-across from a study with an analogue

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

Dose descriptor:

NOAEL

Effect level:

62 other: mg/kh bw/day

Sex:

male

Basis for effect level:

other: Rats

Dose descriptor:

NOAEL

Effect level:

31 other: mg/kg bw/day

Sex:

female

Basis for effect level:

other: Rats

Dose descriptor:

NOAEL

Effect level:

147 other: mg/kg bw/day

Sex:

male

Basis for effect level:

other: Mice

Dose descriptor:

NOAEL

Effect level:

> 848 other: mg/kg bw/day

Sex:

female

Basis for effect level:

other: Mice

Critical effects observed:

not specified

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:

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)

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.

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)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

31 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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 408. GLP study.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Key study: Read-across from experimental data on the analogue CAS No.518-82-1. Test method equivalent to OECD guideline 408. GLP study.

90-day oral toxicity study:

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)

The occurrence and severity of spontaneous chronic progressive nephropathy (CPN) in control male F344 rats as well as the frequency of treatment-related CPN exacerbation were histopathologically reevaluated. A series of 43 National Toxicology Program (NTP) 90-day toxicity studies comparing the influence of NIH-07 or NTP-2000 diets was examined. Relationships between the histopathologic findings at 90 days and renal tubule proliferative lesions recorded in subsequent 2-year bioassays for 24 chemicals were statistically analyzed. CPN lesions were observed in 100% of the control male rats regardless of diet, but CPN was more severe in control rats fed NIH-07. Approximately one-third of the 90-day studies demonstrated a treatment-related exacerbation of CPN severity, which was independent of diet. For chemicals that proceeded to 2-year bioassays, all studies with a statistically significant increase in renal tubule tumors (RTT)at 2-years had treatment-related exacerbation of CPN in the 90-day and 2-year studies. These findings indicate that CPN occurs ubiquitously in young male F344 rats and that treatment-related exacerbation of CPN in 90-day studies is a relatively common occurrence, having the potential to be predictive of an increased incidence of RTT in subsequent 2-year bioassays (Travlos GS,Hard GC,Betz LJ,Kissling GE,Toxicol Pathol.2011 Feb; 39(2):381-9).

Chronic progressive nephropathy (CPN) is a rodent-specific, age-related renal disease, particularly of male rats, characterized by a spectrum of distinct histological changes which may begin early in the animal's life and progress to end-stage renal disease in certain rat strains. Although CPN-related pathology is well known to most toxicological pathologists other features of CPN such as pathogenesis, modulating factors, proliferative nature, response to chemical exposure and relationship to tumorigenesis are less clearly acknowledged. CPN is generally regarded as a degenerative to atrophic disease with compensatory regenerative hyperplasia. The proliferative nature of CPN often becomes problematic in advanced to end-stage renal disease. At this stage, a number of tubule profiles may be mistaken for atypical tubule hyperplasia, the reported precursor lesion of tubule adenoma. CPN associated proliferative tubule profiles must be carefully separated from atypical tubule hyperplasia particularly in studies where chemical exposure has exacerbated CPN. Over the past several years increasing evidence has supported the hypothesis that CPN may be regarded as a type of "mode of action" during renal carcinogenesis in rodent bioassay studies. Retrospective studies of control and treated animals have consistently shown a relationship between the increased severity of CPN and the presence of atypical tubule hyperplasia and small, incipient renal adenomas. Understanding CPN-related tumorigenesis is important for human risk assessment interpretation. Since CPN is a rodent specific disease with no apparent similar human kidney disease condition, evidence that renal tumors may arise from an interaction with CPN could assist regulatory agencies in interpreting data from studies with exacerbated CPN (John Curtis Seely and Gordon C. Hard, Journal of Toxicologic Pathology, Vol. 21 (2008), No. 4 pp. 199).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest duration (90 days) and lowest NOAEL was chosen as key study.

Justification for classification or non-classification

Based on the available information from 90 -day oral toxicity studies in rats and mice conducted with the analogue emodin, the only effect observed was a decrease on body weights. Based on this information, the substance anthraquinone is not classified for Specific target organ toxicity — repeated exposure since these effects are considered not to support classification.