Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From September 9, 2015 to October 1, 2015
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)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Animal supply and acclimatisation
- Supplier: Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy
- Age and body weight at study initiation: 6-7 weeks old; 150-174 g
- Date of arrival: September 03, 2015
- Weight range at arrival: from 160 to 168 g
- Acclimatisation period: At least 5 d

Animal husbandry
- Animals per cage: 3 during the study; up to 5 during acclimatisation
- Housing: Polisulphone solid bottomed cages measuring 59.5x38x20 cm with nesting material provided into suitable bedding bags
- Diet: 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)
- Diet supply: ad libitum throughout the study except for the dosing procedure

Environmental conditions
- Water: ad libitum
- Air changes: Approximately 15 to 20 air changes per h
- Temperature: 22±2°C
- Humidity: 55±15%
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
Fasting procedure: Food was removed from the cages overnight prior to dosing (Day 1) and was made available approximately 4 h after dosing.
Dosing method: The formulated test substance was administered, by gavage, at a dose volume of 10 mL/kg using a plastic feeding tube attached to a graded syringe
Dose preparation: The test substance was suspended in vehicle i.e. 0.5% aqueous solution of carboxymethylcellulose in concentration of 200 mg/mL.
Doses:
2,000 mg/kg bw
No. of animals per sex per dose:
6
Control animals:
not specified
Details on study design:
- Dosing: First group of 3 female animals was dosed at a level of 2,000 mg/kg bw. No mortality was observed. A second group of 3 female animals was then dosed at the same dose level. No further doses were investigated since the objective of the study had been achieved.
- Duration of observation period following administration: 14 d.
- Frequency of observations: Mortality and morbidity-All animals were checked twice daily.
- Body weight: All animals were weighed at allocation to the study (Day 1), on the day of dosing (Day 1) and on Days 2, 8 and 15. Body weight change calculated for Days 2, 8 and 15 of the dosing phase was relevant to Day 1 of the phase.
- Termination: Animals were sacrificed on Day 15 by carbon dioxide narcosis
- Necropsy: Necropsy was carried out on all animals (gross necropsy examination for both external and internal abnormalities, with particular attention to the gastro-intestinal tract).
- Clinical signs observation: Approximately 0.5, 2 and 4 h after dosing and daily thereafter for 14 d.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
No clinical signs were observed in any of the treated animals.
Body weight:
Changes in body weight observed during the study were within the expected range for this strain and age of animals.
Gross pathology:
No abnormalities were observed at necropsy examination performed on all animals at the end of the observation period.
Interpretation of results:
other: CLP criteria not met
Conclusions:
The LD50 of the test substance was determined to be ≥2,000 mg/kg bw.
Executive summary:

A study was conducted to assess the acute oral toxicity of the test substance in rats according to OECD Guideline 423, EU Method B.1 and EPA OPPTS 870.1100, in compliance with GLP. In this study, groups of females were administered the test substance by gavage in a stepwise manner. Treated animals were then observed for mortality, clinical signs and body weight changes for 14 d and were then culled and subjected to gross pathological examination. In the first step, the test substance was administered to a group of 3 females at 2,000 mg/kg bw. A second group of 3 females was then dosed at the same level. No mortality and no signs of toxicity were observed. No abnormalities were recorded at necropsy. Based on the findings of the study, the oral LD50 of the test substance was determined to be >2,000 mg/kg bw (Caruso R, 2015).

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From September 21, 2015 to October 06, 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Hsd: Sprague Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy
- Age at study initiation: 6-8 wk
- Weight at study initiation: 176 – 200 g
- Housing: Clear polysulphone H-Temp solid bottomed cages (Techniplast Gazzada S.a.r.l., Buguggiate, VA, Italy) measuring 59.5_38_20 cm during acclimatization period and 42.5_26.6_18.5 cm during the study with nesting material provided into suitable bedding bags, Up to 5 of one sex during acclimatisation; individually caged during the study

- Diet (e.g. ad libitum): 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 5 d

ENVIRONMENTAL CONDITIONS
- Temperature: 22±2°C
- Humidity: 55±15%
- Photoperiod: 12 h dark/12 h light
- IN-LIFE DATES: From: September 21, 2015 To: October 06, 2015
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the dorsal surface of the trunk
- % coverage: approximately 10% of body surface
- Type of wrap if used: elastic adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing: After exposure, the adhesive bandage and gauze patch were removed. The treatment area was cleaned by gentle swabbing of the skin with cotton wool soaked with lukewarm water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 2,000 mg/kg
Duration of exposure:
24 h
Doses:
2,000 mg/kg bw
No. of animals per sex per dose:
05
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: immediately after the dossing, 1, 2 and 4 h after dosing, and daily thereafter.
- Necropsy of survivors performed: yes.
- Clinical signs: immediately after the dossing, 1, 2 and 4 h after dosing, and daily thereafter.
- Body weight: on the day of dosing (Day 1) and on Days 2, 8 and 15.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred throughout the observation period.
Clinical signs:
No clinical signs were observed in male or female animals during the 14 d post-dose observation period.
Body weight:
Body weights and body weight changes were within the expected range for this species and age of animals at the end of the study.
Gross pathology:
No abnormalities were found in any animal at necropsy examination performed at termination of the study.
Interpretation of results:
other: CLP criteria not met
Conclusions:
The acute dermal LD50 of the test substance was found to be >2,000 mg/kg in Hsd:Sprague-Dawley CD rats.
Executive summary:

A study was conducted to assess the acute dermal toxicity of the test substance in Hsd:Sprague-Dawley rats according to OECD Guideline 402, EU Method B.3 and EPA OPPTS 870.1200,in compliance with GLP. A group of 10 rats (five males and five females) received the test substance at a dose level of 2,000 mg/kg bw dermally through semiocclusive exposure for a period of 24 h. Exposed animals were observed for mortality, clinical signs and body weight changes for 14 d and were then killed and subjected to gross pathological examination. No mortality and clinical signs were noted during the observation period. The body weight changes recorded during the study were within the expected range for this species and age. No significant abnormalities were found at necropsy in the animals at termination of the study. No abnormalities were observed at the treated site. Under the study conditions, the acute dermal LD50 of the test substance was found to be >2,000 mg/kg (Longobardi C, 2015a).

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion