Ditolyl ether

Toxicity to reproduction: other studies

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

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Reference 2

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 3

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 4

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 5

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 6

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

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

Test material information

Constituent 1

Reference substance name:

Ditolyl ether

EC Number:

248-948-6

EC Name:

Ditolyl ether

Cas Number:

28299-41-4

Molecular formula:

C14H14O

IUPAC Name:

Benzene, 1,1'-oxybis[methyl-

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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
550, 1650 resp. 5000 ppm (= ca. 45, 132 or 425 mg/kg bw/d (male rats))
Basis:
nominal in diet

Doses / concentrations 2

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

1

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

2

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.