Registration Dossier

Administrative data

Description of key information

The acute oral LD50 of the substance is greater than 2000 mg/kg bw.

The NOAEL for nose-only vapour inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm.

Testing by the dermal route does not need to be conducted as the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects after dermal exposure are predicted.

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:
June 24, 2008 to August 28, 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
Adopted December 17, 2001
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
yes
Specific details on test material used for the study:
Purity: 99%
Specific Gravity: 1.49
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Boyertown, PA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: ~8-9 weeks
- Weight at study initiation: 196-212 grams
- Fasting period before study: 16-20 hours prior to dosing
- Housing: 1/cage
- Diet: ad libitum, except for 16-20 hours prior to dosing
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: June 25, 2008 To: July 10, 2008
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 0.26-0.28 mL
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 females/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed 0.5, 1, 2, and 4 hours postdose and once daily for 14days for toxicity and pharmacological effects. All animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly and at termination.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality reported
Mortality:
All animals survided the 2000 mg/kg oral dose
Clinical signs:
Instances of wetness of the anogenital area, ataxia, prostration, flaccid muscle tone and coma were noted on the day of dosing. All animals appeared normal from day 1 through day 14.
Body weight:
body weight changes were normal in 4/5 animals. One animal lost weight during the second week of the observation period.
Gross pathology:
Necropsy results were normal.
Interpretation of results:
GHS criteria not met
Conclusions:
All animals survived the 2000 mg/kg oral dose with transient clinical signs observed during the day of dosing. The symptoms occurred quickly after dosing and were transient in nature. The acute oral LD50 is greater than 2000 mg/kg bw.
Executive summary:

The acute oral toxicity of the substance was investigated following a GLP compliant OECD Guideline 425 study. In total, five female non-pregnant and nulliparous Wistar albino rats were dosed with 2000 mg/kg bw of OFPMA according to up-and-down procedure. The rats were observed at 0.5, 1, 2, and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects. All animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly and at termination. All animals were examined for gross pathology.

 

All animals survived the 2000 mg/kg bw oral dose with transient clinical signs observed during the day of dosing. Instances of wetness of the anogenital area, ataxia, prostration, flaccid muscle tone and coma were noted on the day of dosing. The symptoms occurred quickly after dosing and were transient in nature. All animals appeared normal from day 1 through day 14. Body weight changes were normal in 4/5 animals. One animal lost weight during the second week of the observation period. Necropsy results were normal.

 

The acute oral LD50 of the substance is greater than 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The database is robust given the number and type of studies available, and consistency of findings

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Remarks:
5-day tolerability study
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 July 2009 to 31 August 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Guideline:
other: In-house nose-only inhalation study
Principles of method if other than guideline:
In-house protocol. The test substance was administered to test animals via nose-only inhalation for 6 hours per day for 5 consecutive days at targeted dose levels of 42, 84 and 168 ppm. A concurrent control group was exposed to filtered air on a comparable regimen. On the day following the fifth exposure, all test animals were euthanized and subjected to necropsy.
GLP compliance:
yes
Test type:
other: 5-day tolerability study
Limit test:
no
Specific details on test material used for the study:
- Source and lot/batch No.of test material: Lot no. 900638318
- Purity: 99.7%
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 7-9 weeks of age at initiation of exposures
- Weight at study initiation: Males - 206-251 g; Females - 147-181 g
- Housing: housed individually
- Diet: ad libitum throughout the study except during restraint acclimation, exposure periods, and prior to the scheduled necropsy.
- Water: ad libitum throughout the study except during restraint acclimation, exposure periods, and prior to the scheduled necropsy.
- Acclimation period: 12 days acclimation/pretest period; 5 days in nose-only exposure tubes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2 °C to 21.8 °C
- Humidity (%): 43.1% to 47.5%
- Air changes: a minimum of 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 26 July 2009 To: 31 July 2009
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
other:
Remarks:
nitrogen gas mixed with filtered air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Vapors of the test substance were generated using 1-, 2-, and 3-jet Collison nebulizer for Exposure Systems 2, 3, and 4, respectively as follows: Using a regulator compressed nitrogen was supplied to the nebulizer to generate an aerosol of the test substance. Additional test substance was manually added to the nebulizer during the exposure as needed. Prior to entering the nose-only system, all test substance aerosol was vaporized or removed by a liquid trap. A siphon was placed in-line prior to the nose-only system to adjust the concentration as needed. Using a rotameter-type flow meter, a portion of the test substance atmosphere was siphoned to the in-house vacuum source. Filtered supply air was mixed with the test substance atmosphere prior to entering the nose-only system. Control animals were exposed to compressed nitrogen mixed with filtered supply air using an exposure regimen equivalent to the test substance exposures. Aerosol formation was not observed in any test substance exposure system.

TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed exposure concentrations were determined at approximately 35-minute intervals using a gas chromatograph (GC)
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 h
Remarks on duration:
The test substance or compressed air (control group) was administered as a daily 6-hour nose-only in halation exposure for 5 consecutive days.
Concentrations:
Nominal: 81, 169, 219 ppm; Targeted: 42, 84, 168 ppm; Actual: 40, 89, 168 ppm

The test substance exposure concentrations were selected by the Sponsor based on toxicity information from structurally related materials and levels needed to provide adequate safety margins based on estimated human exposure levels.
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes
Remarks:
concurrent control group was exposed to filtered air on a comparable regimen
Details on study design:
All animals were observed twice daily, once in the morning and once in the afternoon, for mortality and moribundity.

Clinical examinations were performed 3 times daily, prior to exposure, during exposure (at the approximate midpoint), and approximately 0-1 hour following the end of exposure (designated as 1-hour post-exposure for report presentation purposes).

Individual body weights were recorded during the pretest period, prior to randomization, and prior to the first (study day 0) and last (study day 4) exposures. Final body weights (fasted) were recorded on the day of the scheduled necropsy.

Individual food consumption was recorded for 1 week during the pretest period and on study days 0 and 4.

A complete necropsy was conducted on all animals. The following were collected: kidneys, larynx, liver, and lungs.

Liver and lung weights were recorded at scheduled necropsy.
Statistics:
All statistical tests were performed using appropriate computing devices or programs.
Key result
Sex:
male/female
Dose descriptor:
other: NOAEL
Remarks:
5 days
Effect level:
168 ppm
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: 5-day tolerability study
Mortality:
No mortality observed
Clinical signs:
other: All clinical findings in the test substance-treated groups were noted with similar incidence in the control group, were limited to single animals, were not noted in a dose-related manner and/or were common findings for laboratory rats of this age and stra
Body weight:
No effects observed
Gross pathology:
There were no test substance-related macroscopic findings at the scheduled necropsy. All macroscopic findings noted were considered to be spontaneous and/or incidental in nature and unrelated to test substance administration.
Other findings:
There were no test substance-related microscopic findings. All findings observed were consistent with normal background lesions in clinically normal rats of the age and strain used on this study and were considered spontaneous and/or incidental in nature and unrelated to test substance administration.
No effects observed for organ weight findings.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations ≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest exposure concentration tested.
Executive summary:

The test substance was administered via nose-only inhalation for 6 hours per day for 5 consecutive days to 3 groups (Groups 2, 3, and 4) of rats. Target exposure concentrations were 42, 84, and 168 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to filtered air on a comparable regimen. Each group consisted of 5 animals/sex. On the day following the fifth exposure, all animals were euthanized and subjected to necropsy.

The animals were observed twice daily for mortality and moribundity. Clinical examinations were performed 3 times daily (prior to exposure, at the approximate exposure midpoint, and approximately 0 to 1 hour following the end of exposure), and detailed physical examinations were performed for randomization and during the exposure phase on study days 0 and 4. Individual body weights and food consumption were recorded at least weekly during the pretest phase and on study days 0 and 4. Complete necropsies were performed on all animals, and the liver, lungs, and kidneys were weighed at the scheduled necropsy. The kidneys, larynx, liver, lungs, nasal cavity (with turbinates), pharynx, trachea, and urinary bladder were examined microscopically from all animals in the control and 168 ppm group (Groups 1 and 4, respectively). Gross lesions were examined microscopically from all animals (when possible).

There were no test substance-related effects on survival or clinical observations. There were no apparent test substance-related effects on body weights, body weight changes, food consumption, organ weights, or macroscopic and microscopic findings at any exposure concentration.

Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest vapour exposure concentration tested. Applying the ideal gas law, the NOAEL for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 2 mg/L, the highest vapour exposure concentration tested.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The database is robust given the number and type of studies available, and consistency of findings.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral Toxicity:

The acute oral toxicity of the substance was investigated following a GLP compliant OECD Guideline 425 study. In total, five female non-pregnant and nulliparous Wistar albino rats were dosed with 2000 mg/kg bw of OFPMA according to up-and-down procedure. The rats were observed at 0.5, 1, 2, and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects. All animals were observed twice daily for mortality. Body weights were recorded immediately pre-test, weekly and at termination. All animals were examined for gross pathology.

 

All animals survived the 2000 mg/kg bw oral dose with transient clinical signs observed during the day of dosing. Instances of wetness of the anogenital area, ataxia, prostration, flaccid muscle tone and coma were noted on the day of dosing. The symptoms occurred quickly after dosing and were transient in nature. All animals appeared normal from day 1 through day 14. Body weight changes were normal in 4/5 animals. One animal lost weight during the second week of the observation period. Necropsy results were normal.

 

The acute oral LD50 of the substance is greater than 2000 mg/kg bw.

 

Inhalation Toxicity

The test substance was administered via nose-only inhalation for 6 hours per day for 5 consecutive days to 3 groups (Groups 2, 3, and 4) of rats. Target exposure concentrations were 42, 84, and 168 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to filtered air on a comparable regimen. Each group consisted of 5 animals/sex. On the day following the fifth exposure, all animals were euthanized and subjected to necropsy.

 

The animals were observed twice daily for mortality and moribundity. Clinical examinations were performed 3 times daily (prior to exposure, at the approximate exposure midpoint, and approximately 0 to 1 hour following the end of exposure), and detailed physical examinations were performed for randomization and during the exposure phase on study days 0 and 4. Individual body weights and food consumption were recorded at least weekly during the pre-test phase and on study days 0 and 4. Complete necropsies were performed on all animals, and the liver, lungs, and kidneys were weighed at the scheduled necropsy. The kidneys, larynx, liver, lungs, nasal cavity (with turbinates), pharynx, trachea, and urinary bladder were examined microscopically from all animals in the control and 168 ppm group (Groups 1 and 4, respectively). Gross lesions were examined microscopically from all animals (when possible).

 

There were no test substance-related effects on survival or clinical observations. There were no apparent test substance-related effects on body weights, body weight changes, food consumption, organ weights, or macroscopic and microscopic findings at any exposure concentration.

 

Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations ≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest vapour exposure concentration tested. Applying the ideal gas law, the NOAEL for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 2 mg/L, the highest vapour exposure concentration tested.

 

Dermal Toxicity

Testing by the dermal route does not need to be conducted as the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects after dermal exposure are predicted.

Justification for classification or non-classification

The acute oral LD50 of the substance is greater than 2000 mg/kg bw. Therefore, the substance does not fulfil the criteria for acute oral toxicity classification according to European CLP Regulation (EC) No 1272/2008 (as amended).

 

Testing by the dermal route does not need to be conducted as the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects after dermal exposure are predicted. Therefore, the substance does not fulfil the criteria for acute dermal toxicity classification according to European CLP Regulation (EC) No 1272/2008 (as amended).

 

The acute NOAEL following 6-hour exposure to the vapour was 168 ppm (approximately 2 mg/L); the highest vapour exposure concentration tested. No deaths and no clinical signs were reported. Therefore, the substance does not fulfil the criteria for acute inhalation toxicity classification according to European CLP Regulation (EC) No 1272/2008 (as amended).

 

An assessment of the whole database supports the non-classification for STOT SE. The clinical symptoms observed following single oral exposure occurred quickly after dosing and were transient in nature. Additionally, there were no test substance-related clinical observations following inhalation of vapours for six hours a day for five consecutive days at a maximum of 168 ppm. Overall, the transient nature of the reported clinical signs and consideration of the database as a whole do not fulfil the criteria for STOT SE classification according to European CLP Regulation (EC) No 1272/2008 (as amended).