Registration Dossier

Administrative data

Description of key information

The OCED 423, Acute Oral, LD50 is > 2000 mg/kg bw.

The OECD 402, Acute Dermal, LD50 is > 2000 mg/kg bw.

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
Study period:
09 August 2013 to 20 January 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant with OECD test guideline and GLP
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
To minimise the number of animals used, Group 2 animals were administered at 2000 mg/kg instead of 300 mg/kg. There were no adverse signs so a third group of rats were treated at the same dose level (2000 mg/kg) to complete the study.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- lot/batch No.of test material: E00031-633
- Retest date of the lot/batch: 04 Febuary 2013
- Purity test date: >/= 99%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient temperature, in the dark
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS:
- Source: Charles River, Maragate, UK
- Age at study initiation: 8 to 11 weeks old
- Weight at study initiation: 196.2 to 227.7 g
- Fasting peroid before study: overnight before dosing
- Housing: Housed in groups of 3
- Diet: ad libitum (except fasting period before study)
- Water: ad libitum
- Acclimatisation: At least 9 days before dosing

ENVIRONMENTAL CONDITIONS:
- Temperature: Approximately 20 °C
- Humidity: Approximately 52% to 67%
- Photoperiod: 12 hours light/dark cycle (light hours 0700 to 1900 h)
- Air Changes: 10 air changes per hour
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
TEST ITEM
- Purity: 99%

MAXIMUM DOSE VOLUME APPLIED: 2.1 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: 300 mg/kg is recommended by the OECD 423 guidelines.
Doses:
300 mg/kg followed by 2000 mg/kg
No. of animals per sex per dose:
Three groups of three females
Control animals:
no
Details on study design:
- Housing: The rats were housed in groups of three, 9 days before dosing. Food and water were available ad libitum, except food was withdrawn overnight before dosing. Environmental conditions were monitored and recorded every 15 minutes.
- Observations and weighing: The rats were examined five times on the day of dosing, followed by daily observations up to Day 15. The body weight of the rats were recorded on Day 1 (before dosing), Day 8 and Day 15.
- Necropsy: All animals were euthanised on Day 15
Statistics:
None
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no unscheduled deaths at both 300 mg/kg and 2000 mg/kg dose levels.
Clinical signs:
There were no clinical signs of reaction to treatment in any animal thoughout the study period.
Body weight:
The body weight gains observed were considered acceptable for rats of that age and strain.
Gross pathology:
Dark discolouring to lung lobes were found in two animals dosed at 2000 mg/kg. As this finding is occationally noted in rats of this strain at these laboratories, it is regarded as a background finding and not a result of treatment. No other abnormalities were recorded.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the study, the median lethal dose level (LD50) of EXP0700332 in Sprague-Dawley rats was considered to exceed 2000 mg/kg.
This study is considered to be relevant, reliable and adequate for risk assessment and for classification purposes.
Executive summary:

The objective of this OECD 423 study was to assess the adverse effects of EXP0700332 after a single oral gavage administration to Sprague-Dawley rats. The test item was administered to three groups of rats, comprising of three females, with one group being tested at 300 mg/kg and the two remaining groups being tested at 2000 mg/kg. The dose volume was based on the density and purity of the test item, and the individual doses were based on the individual body weight of the animals on the day of dosing. The animals were observed daily for 14 days after dosing and their body weights recorded before dosing and on Days 8 and 15. The following parameters and endpoints were evaluated in this study: clinical signs, body weights, body weight changes and gross necropsy findings.

All animals survived the treatment with no adverse clinical signs or macroscopic findings recorded for any animal. Body weight gains were considered to be acceptable for rats of this age and strain. The median lethal dose level (LD50) of EXP0700332 in Sprague-Dawely rats was considered to be in excess of 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Klimisch 1 study was conducted in accordance with the OECD guidelines and GLP.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
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
Study period:
09 August 2013 to 28 November 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- lot/batch No.of test material: E00031-633
- Retest date of the lot/batch: 30 January 2013
- Purity test date: >/= 99%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient temperature, in the dark
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS:
- Source: Charles River UK Limited, Manston Road, Maragate, Kent, UK
- Age at study initiation: 8 to 10 weeks old
- Weight at study initiation: Males between 325.3 and 353.0 g; females between 231.4 and 251.3 g
- Idenitification: Manual ear punch
- Preparation: Hair was clipped from dorsal area of the trunk, avoiding abrading the skin, the day before dosing
- Fasting period before study: Not specified
- Housing: In groups of 5 of the same sex and the beginning of acclimatisation and then transferred into single housing before dosing.
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENT:
- Cage: Suspended polycarbonate cages with stainless steel. Woodshavings as bedding.
- Temperature: Approximately 20°C
- Humidity: Approximately 52% to 67%
- Photoperiod: 12 hour light/dark cycle (light hours 0700 h to 1900 h)
- Air changes: At least 10 air changes per hour
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The test item was applied directly onto the clipped dorsal area and spread uniformally. The test item was then covered with semi-occlusive tape and secured with non-irritating occlusive tape.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males and 5 females per dose
Control animals:
not required
Details on study design:
- Preparation: Animals housed separately and clipped before dosing
- Observations: All animals were checked for clinical changes at least 4 times on the day of dosing and daily for 14 days thereafter. Mortality/moribundity checks were performed twice a day.
- Body weight: Days 1 (before dosing), 8 and 15.
- Necropsy: All animals were euthanised on Day 15.
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no unscheduled deaths.
Clinical signs:
There were no signs of reaction to treatment during any of the observation timepoints.
Body weight:
Weight gain was considered acceptable for rats of this age and strain.
Gross pathology:
One female (No. 7) was found to have dark foci to all lobes of the lungs. As this observation is common in this strain of rat, it is not considered to be related to the test item.
Interpretation of results:
GHS criteria not met
Conclusions:
As all animals survived and the median lethal dose (LD50) is greater than 2000 mg/kg, this study is considered to be relevant, reliable and adequate for risk assessment and for classification purposes.
Executive summary:

The purpose of this study is to evaluate the adverse effects of EXP0700332 following dermal exposure for 24 hours. Male and female Sprague-Dawley rats were housed in groups up to five animals of the same sex, then separated into single housing and clipped before dosing. The dose of the test item was calculated on the day of dosing. 2000 mg/kg of test item was applied topically to each animal on the clipped dorsal area and spread as evenly as possible. The dosed area was then covered with a gauze patch which was secured with semi-occlusive tape and non-irritating occlusive tape, wrapped around the trunk. The females were dosed 5 days after the males. After 24 hours, the patches and tape were removed and the dosing sites were delinated and cleaned with mineral oil. The animals were observed for 14 days thereafter for signs of reaction. The body weight of the rats were recorded weekly and all animals were subjected to necropsy examinations on Day 15. There were no clinical signs of reaction to treatment, no unscheduled deaths, no abnormal findings in the necropsy and the body weights of all animals were considered acceptable for rats of this strain and age.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Klimisch 1 study was conducted in accordance with the OECD guidelines and GLP.

Additional information

Acute Oral

A key study conducted in accordance with the OECD 423 guideline and GLP reported that there were no deaths following oral administration of the test substance among rats dosed at 300 and 2000 mg/kg. No adverse clinical signs or macroscopic abnormalities were recorded in any animal and no signs of systemic toxicity were noted during the study. The acute median lethal oral dose was found to exceed 2000 mg/kg, therefore the test material was considered to have no significant acute toxic risk if swallowed.

Acute Dermal

A limit test study was conducted in accordance with the OECD 402 guideline and GLP. The study reported that there were no deaths following dermal administration of the test substance among rats dosed at 2000 mg/kg. No adverse clinical signs, macroscopic abnormalities and no signs of systemic toxicity were observed during the study. The acute median lethal dermal dose was found to exceed 2000 mg/kg, therefore the test material was considered to have no significant acute toxic risk.

Acute Inhalation

In accordance with Rule 8.5 of Annex VIII of the REACH Regulation, a study of the acute inhalation toxicity is not required, since studies of acute toxicity via oral exposure and via dermal exposure have been provided. Furthermore, the potential for inhalation exposure to occur is considered negligible.

Justification for classification or non-classification

Acute Oral:

As the LD50 was > 2000 mg/kg/ bw and no clinical signs were observed, no classification for acute oral toxicity is required.

Acute Dermal:

The LD50 was > 2000 mg/kg bw and no clinical signs were observed, therefore no classification for acute dermal toxicity is required.

Acute Inhalation:

No acute inhalation toxicity data are available. Based on the low toxicity via both the oral and dermal routes of exposure, no classification for acute inhalation toxicity is proposed.