Registration Dossier

Administrative data

Description of key information

Two acute toxicity studies were carried out for the oral and dermal route.  In a study according to OECD Guideline 401 (Acute toxicity oral) the LD50 oral was determined to be greater than 5000 mg/kg bw. 
Testing by the inhalation route was waived as exposure of humans is unlikely taking in to account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. The vapour pressure of LZ649 is 0.24 Pa and no particle size distribution study was performed as the substance is a liquid. Furthermore, the second likely route of human exposure is by dermal route. Therefore a dermal study was performed. On this basis an acute inhalation study is not required.
In a study according to OECD Guideline 402 (Acute Dermal Toxicity) the LD50 dermal was determined to be greater than 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:
December 1984 - January 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study conducted in accordance with international guidelines.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Ten male and 10 female Wistar-derived rats of the Cr1:(WI)BR strain obtained from Charles River (UK) Ltd., Margate, were used for the study.
On the day before treatment the weight of the males was between 210 and 224 g, those of the females between 195 and 206 g. The animals were
acclimatised to the laboratory environment for at least 3 days. Before starting the study all animals were examined for signs of ill health or injury.
All animals appeared healthy and no animals were discarded. The animals were housed in a single air conditioned room maintained at a temperature
and relative humidity of 19 to 25°C and 40 to 70% respectively. Fluorescent lighting was automatically controlled to give a cycle of 12 hours light
and 12 hours darkness. Environmental conditions were recorded twice daily on week-days and once daily at week-ends.
Animals were housed in groups of 5 by sex in grid floor stainless steel cages. Water bottles were cleaned at intervals during the study.
With the exception of an overnight fast prior to dosing the animals were allowed free access to food (SQC Rat and Mouse Maintenance Diet No.1,
Expanded; Special Diets Services Ltd., Witham). Mains water was provided at all times and dispensed from glass water bottles. The diet and drinking
water were considered not to contain any contaminant at a level that might have affected the objectives or integrity of the study.
The food was re-introduced immediately after treatment.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Doses:
Screening study:
---------------
50, 250, 1000, 2000 and 5000 mg/kg

Single dose level study:
---------------------
5000 mg/kg
No. of animals per sex per dose:
Screening study:
---------------
50, 250, 1000, 2000 and 5000 mg/kg (five groups), each of 2 rats (1 male, 1 female)

Single dose level study:
---------------------
One group of 10 rats (5 males, 5 females)
Control animals:
no
Details on study design:
The test article preparations were administered once only by oral gavage using a metal stomach tube (14 gauge x 8 cm long,
Stand Medicals Ltd., Manchester) attached to a disposable plastic syringe. Fresh formulations of the test article were made for each
study.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities occurred in the screening study. In the single dose level Study all animals survived the study period.
Clinical signs:
All animals appeared normal throughout the study period.
Body weight:
All animals showed body weight gain at the end of the observation period.
Gross pathology:
All animals were subjected to necropsy. No abnormalities were noted.
Other findings:
No other findings were observed.

Single dose level study:

Appearance, behaviour and general observations:

All animals were observed for overt signs of toxicity or behavioural changes at 1/4, 1, 2 and 4 hours after treatment and subsequently once daily for 14 days. All observations were recorded.

Body weight:

Individual body weights were recorded on the day before treatment (day-1), on the day of treatment, and on days 7 and 14. Necropsy:

All animals were subjected to a gross necropsy examination. No tissues were retained. The animals were killed by exposure to high levels of carbon dioxide.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of P5306 in the Wistar-derived rat was estimated to be greater than 5000 mg/kg bodyweight.
Executive summary:

The acute oral toxicity study was performed from Dezember 1984 - January 1985 according to OECD Guideline 401 and GLP.

No mortalities occurred throughout the study period. No clinical signs were observed. All animals were subjected to necropsy. No abnormalities were noted. The acute oral median lethal dose (LD50) of P5306 in the Wistar-derived rat was estimated to be greater than 5000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
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:
24 November - 15 December 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study conducted in accordance with international guidelines.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CD (Crl:CD ‘SD’)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: a reputable supplier
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: 335 to 371g for males, and 248 to 274g for females

- Housing: They were housed individually from Day -1 until Day 5 when they were returned to group housing (in groups of five rats of the same sex)., were housed in solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding. Cages, food hoppers, water bottles and bedding were changed at appropriate intervals.
- Diet (e.g. ad libitum): free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet), except for overnight prior to and approximately four hours after dosing.
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes.
- Acclimation period: 5 days
- During the acclimatisation and study periods, each cage of animals was provided with a soft white untreated chew block for environmental
enrichment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):19 to 23°C
- Humidity (%):40 to 70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): Artificial lighting was controlled to give a cycle of 12 hours continuous light and 12 hours continuous dark per 24 hours.

IN-LIFE DATES: From: 29 September 2011 To: 20 December 2011
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
One day prior to treatment, hair was removed from the dorso-lumbar region of each rat with electric clippers taking care to avoid damaging the skin, exposing an area equivalent to approximately 10% of the total body surface area.
The test substance was applied by spreading it evenly over the prepared skin. The treatment area (approximately 50 mm x 50 mm) was covered with
porous gauze held in place with a non-irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the
animal.
Treatment in this manner was performed on Day 1 (day of dosing) of the study only.
At the end of the 24 hours exposure period the dressing was carefully removed and the treated area of skin was washed with warm water (30 - 40°C), to remove any residual test substance. The treated area was blotted dry with absorbent paper.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bodyweight.
No. of animals per sex per dose:
5 Males and 5 Females.
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: twice daily for any mortalities, the weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other:
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity, where appropriate, of the
clinical signs and the time were recorded at each observation.
Preliminary study:
No
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths and no systemic response to treatment in any animal.
Clinical signs:
No dermal reactions were observed in any animal during the study.
Body weight:
A bodyweight loss was recorded for one female on day 15 (A10). Low bodyweight gains were noted for one female on Day 8 (A10), three females (A6, A7 & A9) on Day 15. Bodyweight stasis was recorded for one female on Day 8 (A6). All other animals were considered to have achieved satisfactory
bodyweight gains throughout the study.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.
Other findings:
No other findings.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute median lethal dermal dose (LD50) to rats of LZ649 was demonstrated to be greater than 2000 mg/kg bodyweight. LZ649 is included in Category 5 or unclassified, according to the Globally Harmonised System (UNITED NATIONS, 2005)
Executive summary:

The acute dermal toxicity study was performed in year 2011 according to OECD Guideline 402 and GLP. There were no deaths and no systemic response to treatment in any animal. No dermal reactions were observed in any animal during the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15. Therefore, the acute median lethal dermal dose (LD50) to rats of LZ649 was demonstrated to be greater than 2000 mg/kg bodyweight. LZ649 is included in Category 5 or unclassified, according to the Globally Harmonised System (UNITED NATIONS, 2005)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

An acute oral toxicity study was performed from Dezember 1984 - January 1985 according to OECD Guideline 401 and GLP.

No mortalities occurred throughout the study period. No clinical signs were observed. All animals were subjected to necropsy. No abnormalities were noted. The acute oral median lethal dose (LD50) of P5306 in the Wistar-derived rat was estimated to be greater than 5000 mg/kg bodyweight.

In accordance with column 2 of Annex VIII (required in Section 8.5.2) of REACH Regulation 1907/2006 testing by the inhalation route is appropriate if exposure of humans is likely taking in to account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. The vapour pressure of LZ649 is 0.24 Pa and no particle size distribution study was performed as the substance is a liquid. Furthermore, the second likely route of human exposure is by dermal route. Therefore a dermal study was performed. On this basis an acute inhalation study is not required.

The acute dermal toxicity study was performed in year 2011 according to OECD Guideline 402 and GLP. There were no deaths and no systemic response to treatment in any animal. No dermal reactions were observed in any animal during the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15. Therefore, the acute median lethal dermal dose (LD50) to rats of LZ649 was demonstrated to be greater than 2000 mg/kg bodyweight. LZ649 is included in Category 5 or unclassified, according to the Globally Harmonised System (UNITED NATIONS, 2005)


Justification for selection of acute toxicity – oral endpoint
GLP compliant study conducted in accordance with international guidelines. Reliable study without restrictions.

Justification for selection of acute toxicity – dermal endpoint
GLP compliant study conducted in accordance with international guidelines. Reliable study without restrictions.

Justification for classification or non-classification

Based on the data available the substance is not classified according to Regulation 1272/2008/EEC (CLP) and according to Directive 67/548/EEC (DSD).