Registration Dossier

Administrative data

Description of key information

In an acute oral and dermal toxicity study with rats an LD50 >2000 mg/kg bw for Ethylene glycol dibenzoate was determined.

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:
09 January 2017 - 14 February 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
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.
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
Stability at higher temperatures: stable, maximum temperature: 60°C, maximum duration: 1 hour
Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
female
Details on test animals and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 9-11 weeks old)
- Weight at study initiation: 140-196 grams
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days before the start of the treatment, under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 – 21.1
- Humidity (%): 35 - 50
- Air changes (per hr): approx 10
- Photoperiod (hrs dark / hrs light): 12/12

Deviations from the minimum level of daily mean relative humidity occurred. Hoever, laboratory historical data do not indicate an effect of the deviations and therefore it is not considered to affect the study adversely.

IN-LIFE DATES: From: 09 January 2017 to 14 February 2017
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
Specific gravity: 1.125
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes, the test item preparations were stirred on a magnetic stirrer during dosing.

Frequency: single dosage, on Day 1.

VEHICLE:
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. There was no information available regarding thesolubility or stability in vehicle.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The preparations (w/w) were kept at room temperature protected from light and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item. In order to obtain homogeneity, the test item (preparations) were heated in a water bath with a maximum temperature of 61.5ºC for a maximum of 33 minutes. The test item (formulations) were allowed to cool to a temperature of maximally 40ºC prior to dosing.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
6 (2 groups of three females in a stepwise manner)
Control animals:
no
Details on study design:
- Method: The test was performed in a stepwise treatment, starting with one group of 3 females and a dose level of 2000 mg/kg bw. Based on the results, one additional group was dosed at 2000 mg/kg bw.
- 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.
- 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:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture and piloerection were noted for all animals on Day 1 and/or Day 2.
Body weight:
The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral toxicity study with rats, performed according to OECD/EC test guidelines, an LD50 >2000 mg/kg bw for Ethylene glycol dibenzoate was determined. Based on these results, Ethylene glycol dibenzoate does not meet GHS criteria for classification.
Executive summary:

In an acute oral toxicity study with rats, performed according to OECD/EC test guidelines, an LD50 >2000 mg/kg bw for Ethylene glycol dibenzoate was determined. Based on these results, Ethylene glycol dibenzoate does not meet GHS criteria for classification.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
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:
26 September 2017 - 10 October 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
other: Appendix to Director General Notification, No. 12-Nousan-8147. Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries of Japan (JMAFF)
Version / remarks:
November 2000, including the most recent revisions
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
dd. 03 November 2015
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
Stability in vehicle: Stability for at least 5 hours at room temperature under normal laboratory conditions and 8 days in the refrigerator is confirmed over the concentration range 1 to 200 mg/mL
Species:
rat
Strain:
other: Crl: WI(Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant:yes
- Age at study initiation: approx. 10 weeks old
- Weight at study initiation: males: 270-296 g; females: 182-189 g.
- Fasting period before study: no
- Housing: Group housing (up to 5 animals of the same sex together) on arrival and individual housing during the study. Polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust were used.
- Diet: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum throughout the study, except during designated procedures.
- Water: Municipal tap-water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 45-67
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 26 September 2017 To: 10 October 2017
Type of coverage:
occlusive
Vehicle:
polyethylene glycol
Remarks:
(PEG400; specific gravity: 1.125)
Details on dermal exposure:
TEST SITE
- Area of exposure: 25 cm^2 for males, 18 cm^2 for females
- % coverage: 10% of the total body surface
- Type of wrap if used: The test item 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.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): using the vehicle
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 2000 mg/kg bodyweight
- Constant volume or concentration used: yes
Duration of exposure:
24 hours
Doses:
2000 mg/kg bodyweight (10 mL/kg bodyweight)
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Mortality: twice daily; Clinical observations: at periodic intervals on the day of dosing (at least three times) and once daily thereafter; Body weights: on day 1 (pre-administration), day 8 and day 15.
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Chromodacrorrhoea (snout) was noted for one male on Day 2.
Scabs (right flank or left flank) or general erythema (back and left flank) were noted for four females during the observation period. These local effects were considered not to have affected the conclusion of the study.
Body weight:
Overall body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study and were therefore considered not indicative of toxicity.
The incidence of slight body weight loss or reduced body weight gain on between Days 8 and 15 in two females were considered not indicative of toxicity, based on the absence of any corroborative findings in these animals.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
GHS criteria not met
Remarks:
Not classified according to Regulation (EC) No. 1272/2008.
Conclusions:
The dermal LD50 value of Ethylene glycol dibenzoate in Wistar rats was established to exceed 2000 mg/kg body weight. Based on this result, the test item is not classified according to GHS and Regulation (EC) No. 1272/2008.
Executive summary:

The dermal LD50 value of Ethylene glycol dibenzoate in Wistar rats was established to exceed 2000 mg/kg body weight. Based on this result, the test item is not classified according to GHS and Regulation (EC) No. 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for classification or non-classification

Based on the results from an acute oral and dermal study ethylene glycol dibenzoate does not required classification.