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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21 September 2016 - 18 October 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2017

Materials and methods

Test guidelineopen allclose all
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:
(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.
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Appearance: White powder

Test animals

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. 8 weeks old)
- Weight at study initiation: 145-163 g
- Fasting period before study: Animals were deprived of food overnight prior to dosing
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- 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

ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 18 – 24
- Humidity (%): 40 - 70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Deviations from the minimum level of daily mean relative humidity occurred.
As laboratory historical data do not indicate an effect of the deviations, the study integrity was not adversely affected.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes.

Frequency: single dosage, on Day 1.

VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at Charles River Den Bosch and on test substance data supplied by the sponsor.

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

DOSAGE PREPARATION
The preparations (w/w) were kept at room temperature 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 (1.036 g/mL).
No correction was made for purity of the test item. The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

CLASS METHOD
- Rationale for the selection of the starting dose: Based on anticipated mortality at the next higher dose.
Doses:
- 300 mg/kg body weight
- 2000 mg/kg body weight
No. of animals per sex per dose:
- 300 mg/kg body weight: 6 (2 groups of three females in a stepwise manner)
- 2000 mg/kg body weight: 3
Control animals:
no
Details on study design:
The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 300 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7).
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: All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities 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).

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- At 300 mg/kg bw, no mortality occurred
- At 2000 mg/kg bw, two animals were found dead on Day 1 and one animal was killed in extremis on Day 1
Clinical signs:
- At 300 mg/kg bw, hunched posture, piloerection, ptosis and/or uncoordinated movements were noted for all animals on Day 1
- At 2000 mg/kg bw, lethargy, ventral-lateral recumbency, hunched posture, slow breathing, exophthalmos and/or shallow respiration were noted for all animals on Day 1
Body weight:
The mean body weight gain shown by the surviving 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.

Applicant's summary and conclusion

Interpretation of results:
other: Category 4 based on GHS and CLP criteria
Conclusions:
In an acute oral toxicity study with the substance in female rats, performed according to OECD/EC test guidelines, an LD50 of > 300 - < 2000 mg/kg bw was determined. Based on this result, SPM20200 is classified for acute toxicity by the oral route (Category 4) with Harmful if swallowed (H302). According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.
Executive summary:

The acute oral toxicity of SPM20200 was determined in accordance with OECD 423 (2001) and according to GLP principles. The substance was administered by oral gavage to three subsequent groups of three female Wistar rats at 300 and 2000 mg/kg body weight. At 300 mg/kg bw, no mortality occurred. At 2000 mg/kg bw, two animals were found dead and the third animal was killed in extremis on Day 1. At 2000 mg/kg bw, lethargy, ventral-lateral recumbency, hunched posture, slow breathing, exophthalmos and/or shallow respiration were noted for all animals on Day 1. At 300 mg/kg bw, hunched posture, piloerection, ptosis and/or uncoordinated movements were noted for all animals on Day 1. No abnormalities were found at macroscopic post mortem examination of the animals. The acute oral toxicity (LD50) was determined to be > 300 - < 2000 mg/kg bw. Based on this result, the substance is classified for acute toxicity by the oral route (Category 4) with Harmful if swallowed (H302). According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.