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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-08-23-2018-02-07
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:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
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:
Due to technical reason, relative humidity values (maximum of 80 %) outside the expected range of 30-70 % were recorded during the acclimation period or experimental phase. This deviation has no presumed impact on the outcome or integrity of the study
GLP compliance:
yes (incl. QA statement)
Remarks:
June 2015
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dioctyl hydrogen phosphate
EC Number:
221-485-7
EC Name:
Dioctyl hydrogen phosphate
Cas Number:
3115-39-7
Molecular formula:
C16H35O4P
IUPAC Name:
Dioctyl hydrogen phosphate
Constituent 2
Chemical structure
Reference substance name:
Octyl dihydrogen phosphate
EC Number:
223-638-3
EC Name:
Octyl dihydrogen phosphate
Cas Number:
3991-73-9
Molecular formula:
C8H19O4P
IUPAC Name:
octyl dihydrogen phosphate
impurity 1
Chemical structure
Reference substance name:
Trioctyl phosphate
EC Number:
217-305-1
EC Name:
Trioctyl phosphate
Cas Number:
1806-54-8
Molecular formula:
C24H51O4P
IUPAC Name:
trioctyl phosphate
impurity 2
Chemical structure
Reference substance name:
Octanol
EC Number:
249-405-6
EC Name:
Octanol
Cas Number:
29063-28-3
Molecular formula:
C8H18O
IUPAC Name:
octan-1-ol
Test material form:
liquid

Test animals

Species:
rat
Strain:
other: CLR:(WI) Wistar rats
Sex:
female
Details on test animals or test system 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: 8 weeks old
- Weight at study initiation: 194 - 220 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 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7 - 24.9 °C
- Humidity (%): 33 - 80 %
- 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: A limit of 2000 mg/kg bw dose was selected by the Sponsor
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
All animals were subjected to a necropsy and a macroscopic examination. The animals were exsanguinated after verification of narcosis following an injection of pentobarbital sodium (Release; Lot No.: 106075, Expiry Date: July 2018, Produced by: Wirtschaftsgenossenschaft deutscher Tierärzte eG, Siemensstr. 14, 30827 Garbsen, Germany). After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.
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:
Clinical signs were observed in all animals treated at the dose level of 2000 mg/kg bw and included decreased activity (6/6), hunched back (6/6) and piloerection (6/6).
Body weight:
There was no treatment-related effects on body weight or body weight gain during the observation period.
Gross pathology:
Multifocal thickness of the non-glandular mucosa of the stomach observed in 3/6 females was considered to be test item-related.

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 was found to be above 2000 mg/kg bw in female CRL:(WI) rats.
Executive summary:

The single-dose oral toxicity of reaction mass of dioctyl hydrogen phosphate and octyl dihydrogen phosphate 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.

Reaction mass of dioctyl hydrogen phosphate and octyl dihydrogen phosphate was not acutely orally toxic to female rats up to 2000 mg/kg bw under the conditions of this study.