Dialkyl C18 and C18-unsaturated phosphonates

Endpoint summary

Description of key information

- LD50/Oral/Rat is > 2000 mg/kg bw.

- LD50/Dermal/Rat 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:

04 July to 19 July 2017.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was a GLP-compliant OECD guideline study.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Alkenyl phosphonate
- Expiration date of the lot/batch: 09 September 2017
- Purity test date: 08/06/2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25 ºC, below 70 RH%)
- Stability under test conditions: yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH.
- Age at study initiation: 10 weeks old
- Weight at study initiation: 225 – 238 g
- Fasting period before study: yes
- Housing: 3 animals / cage (Type II. polypropylene/polycarbonate).
- Food consumption (e.g. ad libitum): ad libitum
- Water consumption (e.g. ad libitum): ad libitum
- Acclimation period: 21-22 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 – 24.3 °C
- Humidity (%): 31 – 70 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12hr/12hr

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): BCBS1795V
- Purity: no data

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

DETAILS ON STUDY DESIGN
- Duration of observation period following administration: 14 days
- Frequency of observations: 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.
- Frequency of weighing: The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter.
- Necropsy of survivors performed: yes on day 15
- Other examinations performed: macroscopic examination at necropsy (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organ with obvious abnormalities)

Statistics:

no data

Preliminary study:

Not applicable.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

Alkenyl phosphonate did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: There were no systemic clinical signs noted in any animal throughout the study.

Gross pathology:

There was no evidence of the macroscopic observations at necropsy at a dose level of 2000 mg/kg bw.

None.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item Alkenyl phosphonate was found to be above 2000 mg/kg bw in female Crl:WI rats. Therefore, no classification is required according to EU criteria.

Executive summary:

In an acute oral toxicity study (OECD 423, Kr.1, GLP),Two groups of three female Crl:WI rats were treated with Alkenyl phosphonate at a dose level of 2000 mg/kg (Group 1 and Group 2). The test item was administered formulated in PEG 400 at a concentration of 200 mg/mL at a dose volume of 10 mL/kg bw. Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.tris. Animals were observed for 14 days.

Alkenyl phosphonate did not cause mortality at a dose level of 2000 mg/kg bw. There were no systemic clinical signs noted in any animal throughout the study. There were no treatment related body weight changes. Body weight gains of Alkenyl phosphonate treated animals during the study showed no indication of a test item-related effect. There was no evidence of the macroscopic observations at necropsy at a dose level of 2000 mg/kg bw.

Under the conditions of this study, the acute oral LD₅₀value of the test item Alkenyl phosphonate was found to be above 2000 mg/kg bw in female Crl:WI rats. Therefore, no classification is required according to EU criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

GLP guideline study, well conducted (OECD 423, Kr.1).

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

Study period:

18 July to 01 August 2017.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Due to technical reasons, temperature values (maximum of 25.7 °C) outside the expected range of 22 ± 3 °C were recorded during the study. However, this minor deviation was considered not to adversely affect the results of or integrity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Alkenyl phosphonate
- Expiration date of the lot/batch: 09 September 2017
- Purity test date: 08/06/2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25 ºC, below 70 RH%)
- Stability under test conditions: yes

Species:

rat

Strain:

Wistar

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: Between 223 g and 271 g
- Fasting period before study: yes
- Housing: Individual caging
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.1 – 25.7 °C
- Humidity (%): 31 – 67 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 10% area of the total body surface.
- Type of wrap if used: Sterile gauze pads were placed on the skin of rats to cover the test item. These gauze pads were kept in contact with the skin using a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap for 24 hours.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): YES
- Time after start of exposure: 24 hours.

Duration of exposure:

24 hours.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the body weights were recorded on Day 0 (before test item administration) and on Days 7 and 14 just before necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Statistics:

None.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

Alkenyl phosphonate did not cause mortality at the dose level of 2000 mg/kg bw.

Clinical signs:

other: There were no systemic clinical signs noted in any animal throughout the study.

Gross pathology:

At necropsy, a few crusts were seen on the skin at the lumbar area in 3 male and 3 female animals. Besides this, there was no evidence of macroscopic observations at a dose level of 2000 mg/kg bw.

Other findings:

Very slight to well-defined erythema in 10/10 animals (Day 1-5 or 1-6), very slight to slight oedema in 9/10 animals (Day 1-6) and crust in 9/10 animals were seen at the treated area after treatment with the test item. Besides these, no other local dermal signs were observed during the 14 days observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the acute dermal median lethal dose (LD50 value) of the test item Alkenyl phosphonate was found to be above 2000 mg/kg bw in male and female rats. Therefore, Alkenyl phosponate is not classified according to EU criteria.

Executive summary:

The acute toxicity of Alkenyl phosphonate was investigated following administration of a single dermal dose to rats, in compliance with OECD Guideline No. 402. A limit test was carried out at 2000 mg/kg body weight (bw) in both sexes (5 rats/sex). The test item was applied as a single dermal 24-hour exposure followed by a 14 day observation period.

No mortality occurred following dosing and no clinical signs were observed. Very slight to well-defined erythema in 10/10 animals (Day 1-5 or 1-6), very slight to slight oedema in 9/10 animals (Day 1-6) and crust in 9/10 animals were seen at the treated area after treatment with the test item. Besides these, no other local dermal signs were observed during the 14 days observation period. Slight body weight loss was observed in three females following treatment, but the animals recovered the lost weight during the second week of the observation period. The body weight of the other treated animals during the study showed no indication of a test item-related effect. At necropsy, a few crusts were seen on the skin at the lumbar area in 3 male and 3 female animals. Besides this, there was no evidence of macroscopic observations at a dose level of 2000 mg/kg bw.

Under the conditions of this study, the acute dermal median lethal dose (LD₅₀value) of the test item Alkenyl phosphonate was found to be above 2000 mg/kg bw in male and female. Therefore, no classification is required according to EU criteria.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

GLP guideline study, well conducted (OECD 402, Kr.1).

Additional information

Oral route:

Two studies are available, one was selected as a key study (Kr.1, GLP, CiToxLAB, 2017) and the other one was selected as a supporting study (Kr.4, Not GLP, Industrial Biology Laboratories, 1967).

In the key study (OECD 423, Kr.1, GLP), two groups of three female Crl:WI rats were treated with Alkenyl phosphonate at a dose level of 2000 mg/kg. Alkenyl phosphonate did not cause mortality at a dose level of 2000 mg/kg bw. There were no systemic clinical signs noted in any animals throughout the study. There were no treatment related body weight changes. Body weight gains of Alkenyl phosphonate treated animals during the study showed no indication of a test item-related effect. There was no evidence of the macroscopic observations at necropsy at a dose level of 2000 mg/kg bw. Based on these results, the LD50 is > 2000 mg/kg bw.

In the supporting study (Kr.4, Not GLP), the LD50/rat is greater than 64 mL/kg.

Inhalation route:

No data is available for this route of administration.

Dermal route:

Two studies are available, one was selected as a key study (Kr.1, GLP, CiToxLAB, 2017) and the other one was selected as a supporting study (Kr.4, Not GLP, Industrial Biology Laboratories, 1967).

In the key study (OECD 402, Kr.1, GLP), a limit test was carried out at 2000 mg/kg body weight (bw) in both sexes (5 rats/sex). The test item was applied as a single dermal 24-hour exposure followed by a 14 day observation period.

No mortality occurred following dosing and no clinical signs were observed. Slight body weight loss was observed in three females following treatment, but the animals recovered the lost weight during the second week of the observation period. The body weight of the other treated animals during the study showed no indication of a test item-related effect. At necropsy, few crusts were seen on the skin at the lumbar area in 3 male and 3 female animals. Besides this, there was no evidence of macroscopic observations at a dose level of 2000 mg/kg bw. Based on these results, the LD50 is > 2000 mg/kg bw.

In the supporting study (Kr.4, Not GLP), the LD50/rabbit > 8000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
The study was a GLP-compliant OECD guideline study.

Justification for selection of acute toxicity – inhalation endpoint
Likely route of human exposure is more in favor of acute dermal toxicity study than inhalation one.

Justification for selection of acute toxicity – dermal endpoint
The study was a GLP-compliant OECD guideline study.

Justification for classification or non-classification

Harmonized classification:

No harmonized classification is available according to the Regulation (EC) No 1272/2008.

Self-classification:

- Acute oral toxicity:

Based on the results of the key study (OECD 423, Kr.1, GLP), the LD50/rat is > 2000 mg/kg bw. Therefore, no classification is required according to EU criteria.

- Acute inhalation toxicity:

No classification is possible due to lack of data.

- Acute dermal toxicity:

Based on the results of the key study (OECD 402, Kr.1, GLP), the LD50/rat is > 2000 mg/kg bw. Therefore, no classification is required according to EU criteria.