1,4-dihydroxyanthraquinone

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

Examination of fertility parameters, rats

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Peer reviewed research document
Testing on methylhydroxyanthroquinone and considered good surrogate for read-across

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Principles of method if other than guideline:

Research included work on rats and mice.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

Performed in accordance with recognised methods as part of repeat-dose toxicity evaluation

Test material

Test material information

Constituent 1

Reference substance name:

1,3,8-trihydroxy-6-methylanthraquinone

EC Number:

208-258-8

EC Name:

1,3,8-trihydroxy-6-methylanthraquinone

Cas Number:

518-82-1

Molecular formula:

C15H10O5

IUPAC Name:

6-methyl1,3,8-trihydroxyanthraquinone

Specific details on test material used for the study:

Based on the herbal medicine Emodin

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were quarantined for 11 days and were 6 weeks old on the first day of the studies.

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

Groups of 10 male and 10 female rats and mice were fed diets containing 0, 312.5, 625, 1,250, 2,500, or 5,000 ppm emodin for 14 weeks.
Dietary concentrations in resulted in average daily doses of approximately 20, 40, 80, 170, and 340 mg/kg to males and females once weights were taken into account

Details on mating procedure:

Not part of study - the test was aimed to look at effects on reproductive organs and sperm development

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 weeks

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

312.5 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

1 250 ppm (nominal)

Doses / concentrations 4

Dose / conc.:

5 000 ppm (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Details on study design:

Note that the top dose was estimated to be approximately

Examinations

Parental animals: Observations and examinations:

Observed twice daily; animals were weighed initially, weekly, and at the end of the studies.
Clinical findings were recorded weekly.
Feed consumption was recorded weekly by cage.
Necropsy performed on all core study animals.
Organs weighed were heart, right kidney, liver, lungs, right testis, and thymus.
Blood was collected from the retroorbital sinus of special study male rats on days 5 and 22 and female rats on days 8 and 24 and from all core study rats surviving to the end of the studies for hematology and clinical chemistry analyses.

Oestrous cyclicity (parental animals):

Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies from females in all fgroups and evaluated for the relative frequency of estrous stages and for estrous cycle length.

Sperm parameters (parental animals):

At the end of the test, sperm samples were collected from males in all groups and evaluated for sperm count and motility.
The left testis, left epididymis and left cauda epididymis were weighed

Litter observations:

Not applicable

Postmortem examinations (parental animals):

Full histopathology, including sexual organs

Postmortem examinations (offspring):

Not applicable

Reproductive indices:

Not applicable

Offspring viability indices:

Not applicable

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

All exposed groups of rats had an exposure concentration related body color change pattern from yellow to red.
This also coincided with discoloured bedding and was considered to be of no toxicological significance other than extretion of the test material or coloured metabolites were contaminating the animals

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Final mean body weights and body weight gains of males exposed to 2,500 ppm or greater and females exposed to 1,250 ppm or higher were significantly less than those of the controls

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

During the first week of the study, consumption of feed by males exposed to 2,500 or 5,000 ppm and females exposed to 5,000 ppm was less than that by the controls

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

At the first blood extraction time point (day 5, males; day 8, females), there was evidence of a minimal treatment-related erythrocytosis in males exposed to 1,250 ppm or greater and in females exposed to 5,000 ppm but this was not observed at later time points.

Clinical biochemistry findings:

not specified

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histologic lesions associated with emodin exposure were observed only in the kidney of males and females
These findings increased with increasing exposure concentration in the affected groups.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Description (incidence and severity):

The oestrous cycle length was significantly increased in females exposed to 1,250 or 5,000 ppm

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

No significant differences in sperm motility between the exposed and control groups were observed.

Reproductive performance:

not examined

Effect levels (P0)

1

Dose descriptor:

LOAEC

Effect level:

312.5 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

2

Dose descriptor:

LOAEC

Effect level:

ca. 20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity (P0)

1

Critical effects observed:

yes

Lowest effective dose / conc.:

312.5 ppm

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

2

Critical effects observed:

yes

Lowest effective dose / conc.:

20 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Results: P1 (second parental generation)

Effect levels (P1)

Remarks on result:

not measured/tested

Remarks:

Study aimed only to examine reproductive organs

Results: F1 generation

Effect levels (F1)

Remarks on result:

not measured/tested

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Any other information on results incl. tables

Although the substance was well tolerated, effects were seen on female oestrus cycle at concentrations that led to material toxicity in other organs.

Effects to kidneys were seen at low concentrations.

No effect on male reproductive organs was see and the higher relative testes weight in the top group animals may have reflected a lower whole body weight in these animals.

Applicant's summary and conclusion

Conclusions:

Although the substance was well tolerated, effects were seen on female oestrus cycle at concentrations that led to material toxicity in other organs.
Effects to kidneys were seen at low concentrations.
No effect on male reproductive organs was see and the higher relative testes weight in the top group animals may have reflected a lower whole body weight in these animals.

Executive summary:

From this study, there appears to be no direct effect on the reproductive organs.

The substance is used in traditional medicines.