Registration Dossier

Administrative data

Description of key information

An acute oral and dermal toxicity studies with rats are available, both showing LD50 values >2000 mg/kg bw.

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:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed in 1975, no GLP, but considered appropriate for the endpoint.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no information on body weight
GLP compliance:
no
Remarks:
performed before GLP principles were in place.
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institute's colony (Wistar derived)
- Age at study initiation: not indicated
- Weight at study initiation: males 200-310 g, females 105-203 g
- Fasting period before study: 16 hours
- Housing: in groups of five in screen-bottomed stainless steel cages.
- Diet (e.g. ad libitum): stock diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: no information provided

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25
- Humidity (%): no information provided
- Air changes (per hr): well ventilated
- Photoperiod (hrs dark / hrs light): no information provided

IN-LIFE DATES: no information provided
Route of administration:
oral: gavage
Vehicle:
DMSO
Remarks:
50% (w/v)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: not indicated
- Amount of vehicle (if gavage): not indicated
- Justification for choice of vehicle: not indicated
- Lot/batch no. (if required): not indicated
- Purity: not indicated

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw
Doses:
4.6 - 5.5 - 6.6 - 7.9 - 9.5 mL/kg equal to 2.30 - 2.75 - 3.30 - 3.95 - 4.75 g/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: not performed
- Necropsy of survivors performed: yes
Statistics:
The LD50 was calculated according to the method of C. Weil, 1952 (Biometrics 8; 249-263)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2.76 other: g/kg bw
Based on:
test mat.
95% CL:
> 2.32 - < 3.29
Mortality:
Death occurred from 3 hours to 3 days after treatment. See table for mortality figures.
Clinical signs:
Within a few hours after dosing sluggishness and diarrrhoea were observed; several rats lost consciousness and died. Survivors recovered after 3 days.
Body weight:
no data
Gross pathology:
no gross abnormaloties reported of the survivors.

doses

mortality

Solution (mL/kg)

Test substance (g/kg)

Males number

Females number

%

4.6

2.30

1/5

2/5

30

5.5

2.75

1/5

2/5

30

6.6

3.30

5/5

4/5

90

7.9

3.95

5/5

3/5

80

9.5

4.75

5/5

5/5

100

Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral toxicity study with Dianol 33 in rats, the LD50 was calculated to be 2.76 g/kg bw (LD50 between 2.75 g/kg bw (30% mortality) and 3.30 g/kg bw (90% mortality)).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 760 mg/kg bw
Quality of whole database:
Study performed in 1975, no GLP, but considered appropriate for the endpoint.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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
Study period:
18 January - 01 February 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar strain, Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean.
- Housing: Individually housed in labeled Macrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Woody-Clean type 3/4, Tecnilab-BMI BV, Someren, The Netherlands) and paper as cage-enrichment (Enviro-dri, Tecnilab-BMI BV, Someren, The Netherlands).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: The acclimatization period was at least 5 days before the start of treatment under laboratory conditions.
- Health inspection: A health inspection was performed prior to treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from any abnormality.

Results of analysis for diet (nutrients and contaminants), sawdust, paper and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis are retained in the NOTOX archives.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.7 - 22.2ºC
- Humidity (%): 26 - 60%
Temporary deviations from the minimum level of relative humidity occurred. Laboratory historical data do not indicate an effect of the deviations.
- Air changes (per hr): approximately 15 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours artificial
fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 18 January - 01 February 2011
Type of coverage:
occlusive
Vehicle:
polyethylene glycol
Details on dermal exposure:
One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.

The formulation was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The formulation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.
*. Manufacturers: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).

Frequency: Single dosage, on Day 1.

Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.
Duration of exposure:
24 hours.
Doses:
2000 mg/kg

No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
VEHICLE: Polyethylene glycol 400 (Merck, Darmstadt, Germany) (specific gravity 1.125)
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.

Dose volume: 10 mL/kg body weight.

DOSAGE PREPARATION: The formulation (w/w) was prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle.

Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none.
Statistics:
None.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Piloerection and chromodacryorrhoea was shown by one male on Day 1. No clinical signs were shown by the other animals.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007),
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Additional information

Acute oral toxicity:

In an acute oral toxicty study with rats, 5 animals/sex were exposed to different concentrations of the substance, mortality occured from 3 hours till 3 days after treatment. Within a few hours after dosing sluggishness and diarrrhoea were observed; several rats lost consciousness and died. Survivors recovered after 3 days. The LD50 was calculated to be 2.76 g/kg bw (LD50 between 2.75 g/kg bw (30% mortality) and 3.30 g/kg bw (90% mortality)).

Acute dermal toxicity:

In a reliable acute dermal toxicity study in rat, performed according to OECD guidelines, the LD50 is >2000 mg/kg bw. Piloerection and chromodacryorrhoea was shown by one male on Day 1. No clinical signs were shown by the other animals. No other effects were observed and no mortalities occurred at 2000 mg/kg bw.

Justification for classification or non-classification

Based on the results observed in the acute toxicity studies with rats, 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2 –ol does not have to be classified and has no obligatory labelling requirement for acute oral and dermal toxicity according to the:

- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007),

- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.