Lithium phosphorodifluoridate

Endpoint summary

Description of key information

Acute toxicity of the test item to rats was determined in two studies using different exposure routes (oral and dermal). Both studies were conducted in accordance with the relevant OECD guideline and to GLP. Mortality was observed in studies and severe corrosive effects were noted in the dermal study at 1000 mg/kg and 2000 mg/kg. The LD50 value ranges were determined as 1000 - 2000 mg/kg for the acute dermal study and 50 - 300 mg/kg for the acute oral study. For the purpose of the Chemical Safety Assessment, LD50 cut-off values published in the OECD guidelines 423 - oral, were used. The LD50 cut-off value is stated as 200 mg/kg (oral) for the testing schedule conducted in the study. Although, there was no mortality in the 1000 mg/kg group to assess acute dermal toxicity there was severe corrosive effects therefore the LD50 value is conservatively set at 1000 mg/kg.

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

CRL

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young healthy adult rats, 8 weeks old
- Weight at study initiation: 165-188 g
- Fasting period before study: overnight
- Housing: 3 animals/cage (Cage type: Type II polypropylene/polycarbonate, Bedding: Lignocel® Bedding for Laboratory Animals)
- Diet (e.g. ad libitum): ssniff® SM R/M “Autoclavable complete diet for rats and mice-breeding and maintenance”, produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany ad libitum,
- Water (e.g. ad libitum): tap water from the municipal supply, as for human consumption from 500 ml bottle ad libitum.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1 - 23.0 °C
- Humidity (%): 31-61%
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/mL and 5 mg/mL
- Lot/batch no. (if required): 3450611

MAXIMUM DOSE VOLUME APPLIED: 10mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The initial dose level was selected by the study director to be that which is most likely to produce mortality in some of the dosed animals. Based on the information provided by Sponsor, 300 mg/kg bw was selected to be the starting dose.

Doses:

300 mg/kg bw and 50 mg/kg bw (additional confirmation test at 50 mg/kg bw)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Statistics:

None.

Preliminary study:

Initially, three females (Group 1) were treated at a dose level of 300 mg/kg bw the test substance. The test item caused the death of all animals in this group.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Based on:

test mat.

Mortality:

Treatment with test item caused the death of 3/3 animals at a dose level of 300 mg/kg bw.

Treatment with test item did not cause mortality at a dose level of 50 mg/kg bw.

Clinical signs:

other: Treatment with test item caused decreased activity, hunched back, piloerection, and decreased body temperature and prone position at a dose level of 300 mg/kg bw. Treatment with test item did not cause any test item related effect at a dose level of 50 m

Gross pathology:

Three females were found dead on Day 0 or 1. Necropsy was performed on 3/3 animals dosed at 300 mg/kg bw. Dark/red discoloration of the non-collapsed lungs and thymus did not indicate cause of death for these animals and rather were agonal/post mortem in nature than test item-related in this animals.

No macroscopic observations were noted at a dose level of 50 mg/kg bw.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item was found to be between 50 and 300 mg/kg bw in female CRL:(WI) rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

200 mg/kg bw

Quality of whole database:

All toxicological studies on the test substance have been conducted in accordance to OECD (or equivalent) guideline and GLP-compliant. Therefore the quality of the database is regarded as high quality.

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:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

CRL:(WI) rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult rats
- Weight at study initiation: Males between 259g and 293g, Females between 205g and 256g
- Fasting period before study: none
- Housing :Individual caging (Cage type: Type II. polypropylene/polycarbonate Bedding: Laboratory bedding:
Lignocel Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH+Co.KG
- Diet (e.g. ad libitum): ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany ad libitum
- Water (e.g. ad libitum): tap water from the municipal supply, as for human consumption from 500 ml bottle ad libitum.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1 - 25°C
- Humidity (%): 30-51%
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12h dark' / 12h light

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back of each animal
- % coverage: 10
- Type of wrap if used: semi-occlusive plastic wrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24h

TEST MATERIAL
- For solids, paste formed: moisten with water when applied to skin

Duration of exposure:

20 hours

Doses:

Sighting study: 50, 200, 1000, 2000 mg/kg bw
Main study: 1000 mg/kg bw

No. of animals per sex per dose:

Sighting study: 1 animal per dose
Main study: 4 females, 5 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed on the day of treatment at 1 and 5 hours after application of the test item and once each day for 14 days thereafter. Observations included the skin and fur, eyes and mucous membranes, the respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The body weights were recorded on Day 0 (before test item administration) and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Statistics:

None

Preliminary study:

As the animal treated at a dose level of 2000 mg/kg bw in the sighting period, showed severe signs of a corrosive effect, the animal was euthanized and the dose level for the main period was defined as 1000 mg/kg bw.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 000 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Administration of the test item at a dose level of 1000 mg/kg body weight did not cause mortality, however due to the severe corrosive effects caused by the administration of the test item, two male animals were euthanized due to ethical reasons.

Clinical signs:

other: No systemic clinical signs were observed after treatment with the test item or during the 14-day observation period. Piloerection observed in case of 2 animals is suspected to be associated with the general bad condition of the animal caused by the severe

Gross pathology:

Test-item related, diffuse, grey discoloration of the skin at the site of application could be detected in 2/3 male and 1/5 female rats. In 1/5 male and 4/5 female rats, there was no evidence of the test item-related observations at a dose level of 1000 mg/kg bw at necropsy.

Other findings:

LOCAL DERMAL SIGNS
Administration of the test item at a dose level of 1000 mg/kg bw caused necrotic skin surface, wounds, scabs, erythema, oedema and scaled skin. Full recovery of the local signs was observed in case of 1/5 male and 4/5 females. Local signs were irreversible within the observation period in case of one female and two males. In case of two male animals, necrotic tissues on an extended surface was observed on the exposed skin area, therefore the animals were euthanized for animal welfare reasons in consultation with the clinical veterinarian.

Severe corrosive effects were seen in the 2000 mg/kg bw test group and irreversible local effects on the skin within the observation period in case of one female and two males (1000 mg/kg bw).

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute dermal median lethal dose (LD50) of the test item was found to be higher than 1000 mg/kg body weight in male and female CRL:(WI) rats. Severe corrosive effects were seen in the 2000 mg/kg bw test group and irreversible local effects on the skin was observed.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

All toxicological studies on the test substance have been conducted in accordance to OECD (or equivalent) guideline and GLP-compliant. Therefore the quality of the database is regarded as high quality.

Justification for classification or non-classification

Based on the LD50 available for acute oral toxicity and acute dermal toxicity determined in OECD guideline studies, the substance is classified as Acute Tox 3. (oral) - H301 and Acute Tox 4. (dermal) - H311 in accordance with the CLP Regulation (EC1272/2008, as amended).