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Description of key information

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and reported study, conducted according to internationally accepted technical guidelines and in compliance with GLP in recognized contract research organization. Fully adequate for assessment.
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
of 1996
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
of 1996
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Wistar rats, strain: Crl:(WI) BR (outbred, SPF-Quality) with appropriate range of bodyweight at study start.
Females were nulliparous and non-pregnant.
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation (day of dosing): Approx. 7 weeks.
- Weight at study initiation (day of dosing): Males: mean: 255 g, minimum 252 g, maximum 260 g
Females: mean: 177 g, minimum 170 g, maximum 181 g.
- Fasting period: Overnight (for a maximum of 20 hours) prior to dosing until 3-4 hours post administration.
Water was available.
- Housing: Group housing with 3 animals/Macrolon type IV cage.
- Diet (ad libitum): Commercially available standard pelleted laboratory animal diet (from Altromin, code VRF 1).
- Water (ad libitum): Tap water
- Acclimation period: At least 5 days before start of dosing under laboratory conditions.


ENVIRONMENTAL CONDITIONS

Animals were housed in a controlled environment with optimal conditions considered to be approximately 15 air changes per hour, 21±3°C, 30-70% relative humidity, and 12 hours artificial fluorescent light and 12 hours darkness per day.

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DOSE VOLUME APPLIED:

A dose volume of 1.68 mL unchanged test substance per kg bodyweight was administered by oral gavage. In view of a specific gravity of 1.19, the administered dose volume corresponds to a dose of 2000 mg unchanged test substance per kg body weight.

CLASS METHOD - Rationale for the selection of the starting dose:
Starting at the limit dose of 2000 mg/kg, in retrospect, proved to be appropriate, as no animals died at this dose.
Doses:
2000 mg/kg bw (3 males + 3 females)
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
Post-dosing observation period was 14 days during which mortality/survival and clinical signs were recorded at: 0, 2 and 4 hours after dosing on day 1 and twice daily (mortality/survival) or once daily (clinical signs) thereafter until day 15. Body weight of each animal was recorded on day 1 (prior to dosing) and on days 8 and 15. At the end of the 14-day post-dosing observation period (day 15), all animals were killed by asphyxiation with oxygen/carbon dioxide and necropsied. Macroscopic pathology findings were recorded.
Statistics:
Not applicable, as there were no deaths and only one dose group. In addion, the acute toxic class method is not intended for the calculation of a precise LD50 value.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: No deaths at the limit dose of 2000 mg/kg
Mortality:
Dose level Mortality Date of treatment
2000 mg/kg 0/3 (f) 09 January 2001
2000 mg/kg 0/3 (m) 11 January 2001
Clinical signs:
other: Clinical signs of systemic toxicity were not evident.
Gross pathology:
Necropsy of each animal at the end of the 14-day post treatment observation period did not reveal any macroscopic pathology findings.
Interpretation of results:
not classified
Remarks:
Migrated information no mortality at the limit dose of 2000 mg/kg Criteria used for interpretation of results: EU
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and reported study fully adequate for assessment. The study was conducted according to internationally accepted technical guidelines and in compliance with GLP in a recognized contract research organization.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
of 1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
of 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
of 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Test Data for Registration of Agricultural Chemicals, Acute dermal toxicity (2-1-2), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Sprague Dawley rats, strain: Crl:CD(SD) with appropriate range of bodyweight at study start.
- Source: Charles River (UK) Ltd.
- Age on the day of dosing (Day 1): 8 to 12 weeks.
- Weight on Day 1 (prior to dosing): Males: minimum 351 g, maximum 366 g,
Females: minimum 235 g, maximum 240 g.
- Housing Inside a barriered rodent facility in solid floor polycarbonate cages with a stainless steel mesh lid:
Day before dosing until Day 9: Individually.
Remainder of acclimation & post dose periods: In groups of 5 by sex.

- Bedding material: Autoclaved woodflakes.
- Cage enrichment: Chew block + plastic shelter
- Diet (ad libitum): Standard rodent diet (Rat and Mouse No. 1 Maintenance Diet)
without antibiotic, chemotherapeutic or prophylactic agent.
- Water (ad libitum): Pottable drinking water from the public supply.
- Acclimation period: 6 days before dosing.

Routine analysis of the batch of diet used, water and chew blocks did not provide evidence of contamination that might have prejudiced the study.
ENVIRONMENTAL CONDITIONS

Air conditioned room kept at positve pressure without re-circulation of the filtered fresh air supplied to the room.
Controlled environment, environmental conditions were set at:
- Temperature (°C): 21 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
Deviations from these target ranges were not reported.

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Preparation: On the day before exposure the dorso-lumbar region clipped free of hair using veterinary clippers.
- Area of treated skin: Ca. 50 mm x 50 mm corresponding to approx. 10% of total body surface.
- Type of wrap used: Porous gauze, held in place with non-irritating dressing, further covered with waterproof dressing encircled firmly around the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
Occlusive treatment of the clipped, intact skin lasted 24 hours. Then the dressings were removed, the treated area of skin washed with acetone, rinsed with warm water (30 - 40°C) and blotted dry with absorbent paper, to remove any residual test substance.

TEST MATERIAL AND DOSE PREPARATION
- Administered Dose: 2000 mg/kg bw administered as unchanged test substance (no vehicle used).
- Dose volume: 2.15 mL per kg body weight (specific gravity of the unchanged test substance = 0.930)

RATIONALE FOR DOSE SELECTED:
Pronounced acute dermal toxicity was not expected. Starting at the limit dose of 2000 mg/kg, in retrospect, proved to be appropriate, as no animals died at this dose.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw (5 males + 5 females)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following the end of the 24-hour treatment period: 14 days
- Frequency of observations and weighing:
Deaths and overt signs of toxicity: Frequently after dosing on Day 1 and subsequently twice daily (morning and afternoon) until termination on Day 15
Skin reactions (detailed in Table 1): After removal of the dressings once daily for 14 days (Day 2 to Day 15).
Weighing of each animal: Day 1 (prior to application for dose calculation) and on Days 8 and 15.
- Necropsy performed: Yes, of all animals.

Statistics:
Statistical analysis is nappropriate for this study, as there were no deaths and only one dose group.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No deaths at the limit dose of 2000 mg/kg.
Mortality:
There were no premature deaths.
Clinical signs:
other: Brown staining on the head in four females and urine staining in the perigenital area in one female were first noted on Day 2 (the day after dosing) and had completely resolved in all animals by Day 10. Dermal reactions noted were erythema very slight in
Gross pathology:
Necropsy of each animal did not reveal any macroscopic pathologic abnormalities at termination of the study.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

.

Justification for classification or non-classification

In both, the acute oral and the acute dermal toxicity studies, all animals survived the limit dose of 2000 mg/kg b.w. Therefore, classification of WS400128 for acute oral or dermal toxicity is not required [REGULATION (EC) 1272/2008 and DIRECTIVE 67/548/EEC].

 

Non-classification of WS400128 by the inhalation route was justified by the very low vapour pressure of WS400128, making inhalation exposure of humans unlikely.