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Description of key information

For the acute oral toxicity of ditolyl ether several studies in rats, NMRI-mice, B6C3F1-mice, guinea pigs and hamsters are available. A species and strain difference concerning the LD50 values is observed.
LD50(rat, male) = 3622 mg/kg bw ; LD50 (NMRI-mouse, male) = 142 mg/kg bw; LD50 (NMRI-mouse, female) = 183 mg/kg bw; LD50 (B6C3F1-mouse, male) = 200-2000 mg/kg bw; LD50 (guinea pig, m+f) = 200 - 2000 mg/kg bw; LD50 (hamster, male) > 2000 mg/kg bw.

In a valid acute dermal toxicity study a discriminating dose > 2587 mg/kg bw (rat, m+f) was found. No deaths, no symptoms of poisoning were observed.
For acute inhalation toxicity the LC50 > 521 mg/m³ (rat, female); LC50 > 671 mg/m³ (rat, male), was found. The whole body exposition for 7 hours of the saturated test atmosphere caused no mortality and no signs of toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientific acceptable and well documented
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: 84/449/EWG
Principles of method if other than guideline:
5 male mice, 5 male hamster and 6 male and female guinea received a single oral application per gavage of 200 or 2000 mg/kg bw of the test substance. Post-exposure period was 14 days.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male
Details on test animals and environmental conditions:
according to their weight animals were 10 to 13 weeks old at the start of the study. husbandry: standardised conditions, animals were housed in makrolon cages
Route of administration:
oral: gavage
Vehicle:
other: physiol. saline/Cremophor 2%
Details on oral exposure:
16 hours before and 4 hours after the application of the test substance the animals were fastened
Doses:
200, 2000 mg/kg bw
No. of animals per sex per dose:
5 male mice per dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During the post observation period of 14 days animals were inspected twice daily (daily on weekend) and time of onset, duration, and severity of clinical signs recorded, animals were weighened before, after 1 week and at the end of the post-observation period
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
not applicable - estimation of the mean lethal dose on the basis of the dosage of 200 and 2000 mg/kg bw
Sex:
male
Dose descriptor:
LD50
Effect level:
200 - 2 000 mg/kg bw
Mortality:
dose 200 mg/kg bw, mortality 0/5; dose 2000 mg/kg bw, mortality 5/5
Clinical signs:
a dose of 200 mg/kg bw was tolerated without symptoms. with 2000 mg/kg bw all mice revealed sedation, apathy and tremor on the same day of application of the test substance
Body weight:
body weight gain was not influenced on mice treated with 200 mg/kg bw. mice treated with 2000 mg/kg bw died within one day after application of the test substance
Gross pathology:
some of the animals killed at the end of the experiment revealed sparse collapsed lungs. 2 out of 5 mice administered a dose 2000 mg/kg bw revealed changes of stomach and/or intestines (black and red colored areas of the stomach mucosa and black-brown discoloration of the intestine contents
Other findings:
a dose of 2000 mg/kg bw caused in some animals a storage of fine droplets of fat in the hepatocytes

Mortality 0/5 after administration of 200 mg/kg bw,
Mortality 5/5 after administration of 2000 mg/kg bw

Interpretation of results:
study cannot be used for classification
Executive summary:

Method: 5 male mice received a single oral application per gavage of 200 or 2000 mg/kg bw of the test substance. Post-exposure period was 14 days.

Result: LD50 = 200 - 2000 mg/kg bw (B6C3F1 -mouse); mortality 0/5 after administration of 200 mg/kg bw mortality, Mortality 5/5 after administration of 2000 mg/kg bw; with 2000 mg/kg bw all mice revealed sedation, apathy and tremor on the same day of application of the test substance

Reference: Bomhard/Groening (Bayer AG), 1990

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
All available studies are scientifically acceptable and well documented.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientific acceptable and well documented
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Principles of method if other than guideline:
Ca. 200 l air per hour were conducted through ca. 100 ml of the test substance which was heated to 60°C. The air aerated in this way was applied to 5 male or 5 female rats. the animals were housed in a 10 l glass bottle and were exposed whole body to the test substance for 7 hours. Post-exposure period was 14 days.
GLP compliance:
yes
Test type:
other: inhalation hazard test
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
male Wister rats, weight ca. 160 - 220 g, husbandry: standardised conditions, 5 animals per cage (makrolon type III)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Animals were inspected several times on the same day of the application of the test substance. During the post observation period of 14 days animals were inspected twice daily and time of onset, duration, and severity of clinical signs recorded
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
7 h
Concentrations:
test substance was evaporated at 60°C
No. of animals per sex per dose:
5 male and 5 female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During the post observation period of 14 days animals were inspected twice daily and time of onset, duration, and severity of clinical signs recorded, animals were weighened before, after 1 week and at the end of the post-observation period
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, pathology
Statistics:
not applicable - all animals survived
Sex:
female
Dose descriptor:
discriminating conc.
Effect level:
> 521 mg/m³ air (nominal)
Exp. duration:
7 h
Sex:
male
Dose descriptor:
discriminating conc.
Effect level:
> 671 mg/m³ air (nominal)
Exp. duration:
7 h
Mortality:
all animals survived
Clinical signs:
other: no signs of toxicity were observed
Body weight:
male rats, 671 mg/m³; animal 1: start 193 g ,end 212 g; animal 2: start 186 g ,end 202 g; animal 3: start 203 g ,end 232 g; animal 4: start 200 g ,end 226 g; animal 1: start 188 g ,end 203 g
fwmale rats, 521 mg/m³; animal 1: start 196 g ,end 194 g; animal 2: start 200 g ,end 201 g; animal 3: start 199 g ,end 198 g; animal 4: start 194 g ,end 185 g; animal 1: start 203 g ,end 205 g
Gross pathology:
no findings concerning organ injuries caused by the test substance
Other findings:
no data

No mortality and no signs of toxicity, delayed effects were not observable

Interpretation of results:
study cannot be used for classification
Executive summary:

Method: ca. 200 l air per hour were conducted through ca. 100 ml of the test substance which was heated to 60°C. the air aerated in this way was applied to 5 male or 5 female rats. the animals were housed in a 10 l glass bottle and were exposed hole body to the test substance for 7 hours. Post-exposure period was 14 days

Result: LC50 > 521 mg/m³ (rat, female); LC50 > 671 mg/m³ (rat, male), the whole body exposition for 7 hours of the saturated test atmosphere caused no mortality and no signs of toxicity were observable

Reference: Pauluhn (Bayer AG), 1984

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
521 mg/m³
Quality of whole database:
Scientifically acceptable and well documented

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientific acceptable and well documented
Qualifier:
according to
Guideline:
other: Noakes and Sanderson (1969), Brit J Ind Med 26, 59
Principles of method if other than guideline:
Single cutan application of 2.5 ml of the test substance to 5 male and 5 female rats. post observation period was 14 days.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
male + femaleWistar rats, SPF, ca. 9 - 14 weeks old, average weight of 179 g (males) and 152 g (females), husbandry: conventional in makrolon cages typ III
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
animals were inspected several times on the same day of the application of the test substance. During the post observation period of 14 days animals were inspected twice daily (daily on weekends) and time of onset, duration, and severity of clinical signs recorded
Duration of exposure:
4 or 24 h (according Noakes and Sanderson (1969), Brit J Ind Med 26, 59)
Doses:
2.5 ml per animal
No. of animals per sex per dose:
5 male + 5 female rats
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During the post observation period of 14 days animals were inspected twice daily and time of onset, duration, and severity of clinical signs recorded, animals were weighened before, after 1 week and at the end of the post-observation period
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, pathology
Statistics:
not applicable - all animals survived
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
> 2 587 mg/kg bw
Mortality:
all animals survived
Clinical signs:
no symptoms of poisoning were observed
Body weight:
no data
Gross pathology:
section of some animals killed at the end of the test showed no specific findings
Other findings:
no data

Single dermal exposure of rats to 2587 mg/kg bw: no symptoms of toxicity

Interpretation of results:
GHS criteria not met
Executive summary:

Method: according Noakes and Sanderson (1969), Brit J Ind Med 26, 59; single cutan application of 2.5 ml of the test substance to 5 male an d 5 female rats. post observation period was 14 days

Result: LD50 > 2.5 ml/kg bw (2587 mg/kg bw), (rats, male + female); no deaths, no symptoms of poisoning were observed.

reference: Kroetlinger (Bayer AG), 1984

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 587 mg/kg bw
Quality of whole database:
Scientifically acceptable and well documented

Additional information

Concerning rats, NMRI-mice, B6C3F1 mice, guinea pigs and hamsters the NMRI-mice are the most susceptible species (lowest LD50 = 142 mg/kg bw in male NMRI mice) and the dose- response relation was very steep. With an oral dose of 200 mg/kg bw none of the treated B6C3F1- mice, hamsters or guinea pigs died. For male rats a LD50 = 3622 mg/kg bw was found. Based on the broad LD50 values reported in different species and strains a weight-of-evidence approach was taken to conclude that ditolylether should be classified with Acute Tox.4, H302 and no defined LD50 vaue is selected for the risk assessment.

A discriminating dose (rat) > 2587 mg/kg bw (2.5 ml/kg bw) for the acute dermal toxicity was determined in an experiment in rats.

For acute inhalation toxicity a discriminating dose > 521 mg/m³ (rat, female) and a discriminating dose > 671 mg/m³ (rat, male), was found. The whole body exposure for 7 hours of the saturated test atmosphere caused no mortality and no signs of toxicity. The LC50 value could not be exactly determined, and as a result 521 mg/m³ is the discriminating dose of this study.


Justification for selection of acute toxicity – oral endpoint
For the classification of the acute toxicity the results of the studies in rats, NMRI-mice, B6C3F1-mice, guinea pigs and hamsters are considered based on a weight-of-evidence evaluation.

Justification for selection of acute toxicity – inhalation endpoint
The qualitative best study is used

Justification for selection of acute toxicity – dermal endpoint
Only available study is used

Justification for classification or non-classification

Based on the broad LD50 values reported in different species and strains a weight-of-evidence approach was taken to conclude that ditolyl ether should be classified with Acute Tox.4, H 302 and no defined LD50 value is selected for the risk assessment.

LD50 (rat) for dermal toxicity is > 2500 mg/kg bw. No deaths and no signs of poisoning were observed. In a saturated atmosphere a LC50 of > 521 mg/m³ (rat, female) and > 671 mg/m³ (rat, male), was found for a whole body exposure for 7 hours. No mortality and no signs of toxicity were observed. As a result, the discriminating dose for dermal toxicity is 2587 mg/kg bw and the discriminating dose for inhalation toxicity is 521 mg/m³. Overall, the acute toxicity of ditolylether for rats is low. Therefore a classification for dermal and inhalation is not necessary