Phosphorous acid, mixed 2,4-bis(1,1-dimethylpropyl)phenyl and 4-(1,1-dimethylpropyl)phenyl triesters

Endpoint summary

Description of key information

ORAL

The acute oral toxicity of DVS005u was determined to be LD50 > 2000 mg/kg according to a study performed in accordance with GLP and to the standardised guidelines OECD 420 and EU Method B.1.

DERMAL

The acute dermal toxicity of DVS005u was determined to be LD50 > 2000 mg/kg according to a study performed in accordance with GLP and to the standardised guidelines OECD 402 and EU Method B.3.

INHALATION

In accordance with point 8.5.5, Column 2, adaptation of Annex VII, testing by the inhalation route is deemed inappropriate as exposure to humans via inhalation is unlikely to occur as the substance does not have a high vapour pressure, and will not be used in a manner likely to produce aerosols or droplets of an inhalable size.

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:

12th January 2010 to 2nd February 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of GLP inspection: 15th September 2009 Date of Signature on GLP certificate: 26th November 2009

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK
- Age at study initiation: At the start of the study the animals were eight to twelve weeks of age.
- Weight at study initiation: The bodyweight variation did not exceed ± 20% of the initial/mean bodyweight of any previously dosed animal(s).
- Fasting period before study: overnight fast immediately before dosing
- Housing: The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): (2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK) was allowed ad libitum throughout the study.
- Water (e.g. ad libitum): free access to mains drinking water
- Acclimation period: acclimatisation period of at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): The rate of air exchange was at least fifteen changes per hour.
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

IN-LIFE DATES: From: Day 1 To: Day 14

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: For the purpose of the study the test material was freshly prepared, as required, as a solution in arachis oil BP.
- Amount of vehicle (if gavage): Not stated
- Justification for choice of vehicle: Arachis oil was the preferred vehicle as the test material did not dissolve/suspend in distilled water.
- Lot/batch no. (if required): Not stated
- Purity: Not stated

- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

Doses:

Following a sighting test at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test material, as a solution in arachis oil BP, at a dose level of 2000 mg/kg bodyweight.

No. of animals per sex per dose:

1 female at 300mg/kg; 5 females at 2000 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, body weight.

Preliminary study:

A sighting test at a dose level of 300 mg/kg was performed.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

other: Not reported

Mortality:

There were no deaths.

Clinical signs:

other: There were no signs of systemic toxicity. Pale faeces were noted in one animal.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information: The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System- Unclassified).

Executive summary:

Introduction. The study was performed to assess the acute oral toxicity of the test material in the Wistar strain rat. The method was designed to meet the requirements of the following:

-  OECD Guidelines for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001)

-   Method B1 bis Acute Toxicity (Oral) of CommissionRegulation (EC) No. 440/2008

Method. Following a sighting test with one female at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test material, as a solution in arachis oil BP, at a dose level of 2000 mg/kg bw. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity. Pale faeces were noted in one animal.

Bodyweight. All animals showed expected gains in bodyweight.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000mg/kg bodyweight (Globally Harmonised Classification System-Unclassified).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

One study with Klimisch score of 1, therefore quality of database is acceptable.

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:

20th January 2010 and 10th February 2010.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Principles of method if other than guideline:

Due to technician error, the dermal reaction observations for four females on Day 4 and four males on Day 11 were not recorded. These deviations were considered not to affect the purpose or integrity of the study, as no evidence of dermal irritation was noted pre or post Day 4 for females or pre or post Day 11 for males.

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of GLP inspection: 15/09/09 Date of Signature on GLP certificate: 26/11/09

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK.
- Age at study initiation: eight to twelve weeks of age.
- Weight at study initiation: at least 200g
- Fasting period before study: none
- Housing: individually in suspended solid-floor polypropylene cages
- Diet (e.g. ad libitum): 2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK ad libitum
- Water (e.g. ad libitum): mains drinking water ad libitum
- Acclimation period: At least 5 days under laboratory conditions, after health examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10 % of the total body surface.

In the absence of data suggesting the test material was toxic, one male and one female rat were initially treated with the test material at a dose level of 2000 mg/kg.

The calculated volume of test material, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body
surface area) using a graduated syringe. A piece of surgical gauze, approximately 10 cm x 8 cm in size, was placed over the treatment area and semi-occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 hour exposure period. Shortly after dosing the
dressings were examined to ensure that they were securely in place.

After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened
with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.

As no mortalities were noted a further group of animals (four males and four females) was similarly treated with the test material at a dose level of 2000 mg/kg bodyweight to give a total of five males and five females. After the 24 hour contact period the bandages were carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test material. These animals were returned to group housing for the remainder of the test period.

The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

Rationale: Dermal administration was used as this is one possible route of human exposure during manufacture, handling and use of the test item.

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

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: individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was performed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 95% confidence limits not reported.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: Increased respiratory rate and/or hunched posture were noted in two animals. No other signs of systemic toxicity were noted. There were no signs of dermal irritation.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

None.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Executive summary:

Introduction: The study was performed to assess the acute dermal toxicity of the test material in the Wistar strain rat. The method was designed to meet the requirements of OECD Guidelines for the Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008.

Method: Initially, two animals (one male and one female) were given a single, 24 hour, semi-occluded dermal application of the undiluted test material to intact skin at a dose level of 2000 mg/kg bodyweight. Based on the results of the initial test, a further group of eight animals (four males and four females) was similarly treated. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Results:

Mortality: There were no deaths.

Clinical Observations: Increased respiratory rate and/or hunched posture were noted in two animals. No other signs of systemic toxicity were noted.

Dermal Irritation:  There were no signs of dermal irritation.

Bodyweight: All animals showed expected gains in bodyweight over the study period.

Necropsy: No abnormalities were noted at necropsy.

Conclusion: 

The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg. bodyweight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

One study with Klimisch score of 1, therefore quality of database is acceptable.

Additional information

Acute oral toxicity

The key study (Sanders, 2010) was conducted in line with GLP and standardised guidelines with a sufficient level of detail to assess the quality of the study. Female Wistar rats were exposed to the test material first in a sighting test to 300 mg/kg, then at 2000 mg/kg following the fixed dose procedure. No mortalities or systemic signs of toxicity were observed at the higher dose level, therefore the LD50 is determined to be > 2000 mg/kg. The study was performed to a good standard and was assigned a reliability score of 1 using the principles for assessing data quality as set out in Klimisch (1997).

Acute dermal toxicity

The key study (Sanders, 2010) was conducted in line with GLP and standardised guidelines with a sufficient level of detail to assess the quality of the study. Male and female Wistar rats were exposed 2000 mg/kg of the test material following the standard acute method. No mortalities or systemic signs of toxicity were observed at the higher dose level, therefore the LD50 is determined to be > 2000 mg/kg. Slight deviations from the standard guideline were recorded, however these were not thought to have any effect on the outcome to the study, or affect the reliability of the results. The study was performed to a good standard and was assigned a reliability score of 1 using the principles for assessing data quality as set out in Klimisch (1997).

Justification for selection of acute toxicity – oral endpoint

One key study available.

Justification for selection of acute toxicity – dermal endpoint

One key study available.

Justification for classification or non-classification

Acute oral toxicity

The acute oral toxicity study indicated that the toxicity of the test material is above the limits of classification. The test material does not require classification in line with Regulation 1272/2008.

Acute dermal toxicity

The acute dermal toxicity study indicated that the toxicity of the test material is above the limits of classification. The test material does not require classification in line with Regulation 1272/2008.