Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-10-25 - 2017-12-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study according to OECD guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
December 2001
*Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris
*EPA Health Effects Test Guidelines (OPPTS 870.1100), United States, EPA 712-C-98-190 (1998)
Deviations:
yes
Remarks:
The actual range for humidity was 33 – 80 % (instead of 30-70% in the guideline). However, these minor differences of the environmental parameters were considered not to adversely affect the results of integrity of the study
GLP compliance:
yes (incl. certificate)
Remarks:
June 2015
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Name: 2,2’ -Dihydroxy-4-methoxybenzophenone
Batch/Lot Number: CM70314A1
Description:Yellow powder
Expiry Date: 14 March 2019
Purity: 99.8%
Storage Conditions: Room Temperature, protected from light

Test animals

Species:
rat
Strain:
other: CLR:(WI) Wistar rats
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 11 weeks old
- Weight at study initiation: 243-286 g
- Fasting period before study: On the night before treatment, the animals were fasted. The food but not water was withheld during an overnight period. The food was made available again at about 3 hours after the treatment.
- Housing: standard housing conditions ; 3 animals / cage, Type II polypropylene/polycarbonate cages, “Lignocel 3/4-S Hygienic Animal Bedding” and “Arbocel crinklets natural” nest building material produced by J. Rettenmaier & Söhne GmbH & Co.KG (D-73494 Rosenberg, Germany) were available to animals during the study.
- Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.

- Diet: ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany (Batch no.: 262 21592, expiry date: 31 January 2018), ad libitum
- Water : tap water from the municipal supply, as for human consumption from 500 ml bottles, ad libitum
- Acclimation period: At least 28 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-23.3 °C
- Humidity (%): 32-68%
- Air changes (per hr): 15 – 20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 am to 6.00 pm

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The selection of the vehicle was made during trial formulations with the test item.
- Lot/batch no.: BCBS1795V

CLASS METHOD
- Rationale for the selection of the starting dose: The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose.
Doses:
2000 mg/kg
No. of animals per sex per dose:
6
Details on study design:
- Duration of observation period following administration: 14 days

- Clinical Observations
Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

- Body Weight Measurement
The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0), Day 7 and Day 14.
 
- Necropsy
Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia (Euthasol 40%; Lot No.: 16B095, Expiry date: 31 January 2019, produced by: Produlab Pharma B.V., Forellenweg 16, 4941 SJ Raamsdonksveer, The Netherlands). After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed.
Statistics:
No statistics were performed.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Test item did not cause mortality at a dose level of 2000 mg/kg bw.
Clinical signs:
At the dose level of 2000 mg/kg bw, slightly noisy respiration was observed from Day 1 up to Day 4 in 1 out of 6 animals. From Day 5, all animals were symptom-free until the end of the observation period.
Body weight:
There was no treatment-related effects on body weight or body weight gain during the observation period.
Gross pathology:
There was no evidence of the macroscopic changes at a dose level of 2000 mg/kg bw in any animal.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item 2,2’ -Dihydroxy-4-methoxybenzophenone was found to be above 2000 mg/kg bw in female CRL:(WI) rats.
Executive summary:

The single-dose oral toxicity of 2,2'-Dihydroxy-4 -methoxybenzophenone was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008of30 May2008, B.1.tris) in CRL:(WI) rats and GLP conditions.

Two groups of three females were treated at the dose level of 2000 mg/kg bw resulting in no mortality. No treatment-related adverse effects were noted.

2,2'-Dihydroxy-4 -methoxybenzophenone was not acutely orally toxic to female rats up to 2000 mg/kg bw under the conditions of this study.