Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
Remarks:
reproductive organs in a 13 weeks study were examined.
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented and scientifically acceptable

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988
Reference Type:
publication
Title:
Some aspects relating to the evaluation of the effects of chemicals on male fertility
Author:
Mangelsdorf et al.
Year:
2003
Bibliographic source:
Regulatory Toxicology and Pharmacology 36, 69-98
Reference Type:
publication
Title:
Detection of effects on male reproduction - a literature survey
Author:
Ulbrich & Palmer
Year:
1995
Bibliographic source:
J Am College of Toxicology 14, 293-327
Reference Type:
publication
Title:
A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study
Author:
Janer et al.
Year:
2007
Bibliographic source:
Reproductive Toxicology 24, 103-113
Reference Type:
publication
Title:
Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility
Author:
Dent
Year:
2007
Bibliographic source:
Regulatory Toxicology and Pharmacology 48, 241-258
Reference Type:
publication
Title:
Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats
Author:
Sanbuissho et al.
Year:
2009
Bibliographic source:
J Tox Sci 34: Special Issue SP1-SP22

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD TG 408
Principles of method if other than guideline:
10 male and female rats each were administered orally daily doses of the test substance of 0 (control), 550, 1650 or 5000 ppm (ca. 0, 45, 132 or 425 mg/kg bw/d - male rats; ca. 0, 56, 174 or 604 mg/kg bw/d - female rats) via diet for 13 weeks.
At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate, seminal vesicle, testis and epididymis; in female rats mammary gland, uterus, and ovary.
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
mixture of isomers of ditolyl ether

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Altromin flour
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 wks.
Frequency of treatment:
Daily
Duration of test:
13 wks.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
550, 1650 resp. 5000 ppm (= ca. 45, 132 or 425 mg/kg bw/d (male rats))
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
550, 1650 resp. 5000 ppm (= ca.56, 174 or 604 mg/kg bw/d (female rats))
Basis:
nominal in diet
No. of animals per sex per dose:
10 male + 10 female rats/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Reproduction organs were examined.

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 425 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: 5000 ppm had no changes towards the hematological, pathologic-anatomic, or histopathological  parameters including reproductive organs in males and females
Dose descriptor:
NOAEL
Effect level:
> 604 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: 5000 ppm had no changes towards the hematological, pathologic-anatomic, or histopathological parameters including reproductive organs in males and females.

Observed effects

5000 ppm (highest applied dose) ditolyl ether in the diet for 13 weeks had no adverse effects on the reproduction organs on male and female rats.

Any other information on results incl. tables

All dose groups: no changes of the hematological, pathologic-anatomic, histopathological or ophthalmologic parameters.
5000 ppm : in the males body weight gain reduced by ca. 10 %;  in both sexes liver weights increased, but Cytochrome P-450 and N- or O-Demethylases not induced; clinical-chemical investigations: indications of a treatment-related influence on the metabolism of proteins (increased content of albumin and decreased content of globulin in the serum) and indications of a slight cholestasis (increased activities of the alkaline phosphatase in the plasma).

Applicant's summary and conclusion

Conclusions:
Gross and microscopic examination of all major organs, including reproductive organs (in male rats prostate, seminal vesicle, testis and epididymis; in female rats mammary gland, uterus, and ovary) revealed no adverse effects.
Executive summary:

Ten male and female rats each were administered orally daily doses of the test substance of 0 (control), 550, 1650 or 5000 ppm (ca. 0, 45, 132 or 425 mg/kg bw/d - male rats; ca. 0, 56, 174 or 604 mg/kg bw/d - female rats) via diet for 13 weeks.

At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate, seminal vesicle, testis and epididymis; in female rats mammary gland, uterus, and ovary.

NOAEL = 425 mg/kg bw/day (rats, male) and NOAEL = 604 mg/kg bw/day (rats, female); the pathological examination revealed no difference between the dosed and control groups.