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Key value for chemical safety assessment

Effects on fertility

Description of key information

There is no fertility study with ditolyl ether available.

The study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment - [exposure considerations].

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No evidence of toxicity to reproductive organs was observed in a 13 weeks oral feed study in rats as no treatment- related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination. On the basis of this study no effects on fertility were expected (NOAEL > 425 mg/kg bw/day (rats, male) and NOAEL > 604 mg/kg bw/day (rats, female).

As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009) histopathological examination of reproductive tissues in repeated dose toxicity rodent studies is of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Based on the considerations above no further testing is required for the fertility assessment of ditolyl ether since ditolyl ether has no effect on any reproductive organ in male and female rats even after subchronic exposure for 13 weeks.


Short description of key information:
There was no fertility study with ditolyl ether available. No effects on reproductive organs were observed in 13 weeks oral feed study in rats. The pathologic evaluation consisted of gross and microscopic examination of reproductive organs, in male rats, prostate, seminal vesicle, testis and epididymis; in the female rats, mammary gland, uterus, and ovary. No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL > 425 mg/kg bw/day (rats, male) and NOAEL > 604 mg/kg bw/day (rats, female)).

Effects on developmental toxicity

Description of key information

1st species:

25 inseminated Wistar rats per group were orally administered daily doses of 0, 300, and 1000 mg kg bw on days 6-15 of pregnancy. Dams were examined regarding body weight, appearance and behaviour. On day 20 of gestation dams were killed and the foetuses delivered by caesarean section were examined for morphological changes. Doses up to 300 mg/kg bw/g were tolerated without any signs of maternal toxicity and without toxic signs for the embryonal and foetal development.

2nd species:

There is no developmental toxicity study with ditolyl ether in a 2nd species available.

The study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment - [exposure considerations].

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Equivalent or similar to a oecd 414 guideline study.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In all dose groups, no indications of teratogenesis were observed.
At 1000 mg/kg bw/d, there were signs of maternal toxicity (body weight gain reduced during the whole gestation; treatment-related deaths (mortality: 4/25)). Signs of embryotoxicity were reduced number and decreased weights of the fetuses at the high dose level.

Doses up to and including 300 mg/kg bw/g were tolerated without any signs of maternal toxicity and without toxic signs on embryonal and foetal development.

Toxicity to reproduction: other studies

Description of key information

There is no fertility study with ditolyl ether available. No effects on reproductive organs were observed in 13 weeks oral feed study in rats. The pathologic evaluation consisted of gross and microscopic examination of reproductive organs, in male rats, prostate, seminal vesicle, testis and epididymis; in the female rats, mammary gland, uterus, and ovary. No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL > 425 mg/kg bw/day (rats, male) and NOAEL > 604 mg/kg bw/day (rats, female)).

As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009) histopathological examination of reproductive tissues in repeated dose toxicity rodent studies is of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Based on the considerations above no further testing is required for the fertility assessment of ditolyl ether since ditolyl ether has no effect on any reproductive organ in male and female rats even after subchronic exposure for 13 weeks.


Link to relevant study records
Reference
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
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
Species:
rat
Strain:
Wistar
Sex:
male/female
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.
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.
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.
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.

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).

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.

Additional information

No evidence of toxicity to reproductive organs was observed in a 13 weeks oral feed study in rats as no treatment- related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination. On the basis of this study no effects on fertility were expected (NOAEL > 425 mg/kg bw/day (rats, male) and NOAEL > 604 mg/kg bw/day (rats, female).

Justification for classification or non-classification

Based on the available studies a non-classification is justified.