Ditolyl ether

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study according OECD TG 408

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

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. mortality, clinical signs, food/water intake, body weights were recorded and hematological, clinical biochemistry determinations, and gross necropsy, histopathology were performed

GLP compliance:

yes

Limit test:

no

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

Details on test animals or test system and environmental conditions:

Male + female Wister rats, SPF, at start of the experiment ca. 5-6 weeks old, average weight 77 g males, and 75 g females , husbandry: standardised conditions, single cage (makrolon type II).

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Altromin flour

Details on oral exposure:

Feed and water were available ad-libitum.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Content of test substance and formulation was determined.

Duration of treatment / exposure:

13 weeks.

Frequency of treatment:

Daily.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
550, 1650 resp. 5000 ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
ca. 45, 132 or 425 mg/kg bw/d (male rats)
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
ca. 56, 174 or 604 mg/kg bw/d (female rats)
Basis:
nominal in diet

No. of animals per sex per dose:

10 males + 10 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Animals were inspected twice daily (daily on weekends and holidays) and clinical signs recorded. ophthalmological examinations were done on 10 male and 10 female animals of the control and 5000 ppm group at the beginning and the end of the trial. body weight of the animals was determined before the test and weekly afterwards. food and water intake was determined weekly. laboratory tests on blood samples were accomplished after 1 and 3 months.

Sacrifice and pathology:

Animals were sacrificed after 3 months and organs/tissues dissected. Histopathology was carried out on the preserved organs and tissues.

Other examinations:

no further data

Statistics:

According Mann et al. (Ann. Math. Stat. 18, 50 (1947) and Wilcoxon (Biometrics 1, 80 (1948).

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

132 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Reduced body weight gain/ increased liver weights and influence on the metabolism of proteins

2

Dose descriptor:

NOAEL

Effect level:

174 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Increased liver weights and influence on the metabolism of proteins

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

425 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Any other information on results incl. tables

All dose groups: no changes of the hematological, pathological-anatomic, histopathological or ophthalmologic parameters.
5000 ppm : in the males body weight gain reduced by ca. 10 %;  in both sexes liver weights were 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

Executive summary:

Method: 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. Mortality, clinical signs, food/water intake, body weights were recorded and hematological, clinical biochemistry determinations, and gross necropsy, histogpathylogy were performed.

Result: the NOAEL = 132 mg/kg bw/day (male rats), NOAEL = 174 mg/kg bw/day (female rats)

Reference: Kroetlinger, Schilde (Bayer AG), 1988