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Toxicological information

Toxicity to reproduction

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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

Constituent 1
Chemical structure
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 / concentrationsopen allclose all
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
312.5 ppm (nominal)
Dose / conc.:
1 250 ppm (nominal)
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)

open allclose all
Dose descriptor:
LOAEC
Effect level:
312.5 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
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)

open allclose all
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
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.