Registration Dossier
Registration Dossier
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EC number: 248-948-6 | CAS number: 28299-41-4
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There is no fertility study with ditolyl ether available.
A screening for reproductive / developmental toxicity does not need to be conducted because a pre-natal developmental toxicity study is available.
A testing proposal of an extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension) is included in the IUCLID dataset (section 7.8.1). The study will be initiated after approval by ECHA.
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.
A testing proposal for a developmental toxicity study 2nd species (rabbit) is included in the IUCLID dataset (section 7.8.2). The study will be initiated after approval by ECHA.
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
- 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
- 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.
- 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.
Reference
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).
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.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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