Registration Dossier

Administrative data

Description of key information

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 a period of 13 weeks. Mortality, clinical signs, food/water intake, body weights were recorded and hematological, clinical biochemistry determinations, and gross necropsy, histopathology were performed.
Until the end of the study no difference in the appearance and the behaviour of the treated and control animals was evident. Food and water intake was not affected in any dose group. The body weight gain was slightly decreased in male animals in the highest dose group (5000 ppm; ca. 10%). The mortality was not affected in any dose group. No adverse effects were evident from the hematological examinations at any dose group. In the highest dose group the liver weights were increased, but no histopathological findings of the liver or induction of cytochrom P-450 or the N- and O-demethylases were observed. The pathological and histopathological examinations revealed no damage on other organs or tissues. Therefore no adverse effects up to and including 1650 ppm were found.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity 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
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals 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).
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.
Remarks:
Doses / Concentrations:
550, 1650 resp. 5000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
ca. 45, 132 or 425 mg/kg bw/d (male rats)
Basis:
nominal in diet
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
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).
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
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
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
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

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).

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

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
132 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Ditolyl ether was tolerated up to and including 1650 ppm when given via the feed without adverse symptoms.

Therefore is the NOAEL = 132 mg/kg bw/day (male rats) and the NOAEL = 174 mg/kg bw/day (female rats).

No studies for dermal or inhalative repeated dose are available - by oral application ditolyl ether is of low systemic toxicity. Furthermore, in the toxicokinetic studies with diphenylether - as a surrogate for ditolylether - was demonstrated to be quantitatively absorbed and eye irritation studies showed no potential for irritation of mucous membranes. Therefore, a repeated dose dermal or inhalative study is not required and cannot be justified either scientifically or in terms of animal welfare.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
13 w key study is used

Justification for classification or non-classification

A classification is not required as no serious or irreversible effects in an oral subchronic study were seen up to and including 1650 ppm (132 mg/kg bw/day).