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Administrative data

Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
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
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
Adopted December 17, 2001
Deviations:
no
Qualifier:
according to guideline
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 or test system 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:
other: 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.
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.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
7-day range-finding tolerability study
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
24 October 2008 to 29 January 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Guideline:
other: In-house 7-day repeated oral dose protocol
Principles of method if other than guideline:
In-house protocol. The notified chemical in the vehicle, corn oil, was administered orally by gavage once daily for 7 consecutive days to 3 groups of test animals at the dose levels of 100, 300 and 1,000 mg/kg bw/day. A concurrent control group received vehicle only on a comparable regimen. The dose volume was 5 mL/kg bw for all groups. Following 7 days of dose administration, all test animals were euthanized for gross necropsies.

During the study, all test animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily at the time of dosing and approximately 1 and 4 hours post-dosing and detailed physical examinations were performed weekly. Individual body weight and food consumption were recorded on study Days 0 and 7.
GLP compliance:
no
Remarks:
The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot no. Q151-170
- purity: 99.0%
Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
This species and strain of animal is recognized as appropriate for subchronic toxicity studies. The Sprague Dawley rat was selected because it is a widely used strain for which significant historical control data are available.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 8 weeks old at the initiation of dose administration
- Weight at study initiation: 281 g to 322 g for males and from 182 g to 233 g for females at the initiation of dosing
- Housing: housed individually
- Diet: ad libitum throughout the study
- Water: ad libitum throughout the study
- Acclimation period: 14-day acclimation/pretest period

DETAILS OF FOOD AND WATER QUALITY:
Food: PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 meal
Water: Reverse osmosis-treated (on-site) drinking water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.3°C to 21.5°C
- Humidity (%): 40.4% to 49.9%
- Air changes (per hr): a minimum of 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 29 October 2008 To: 5 November 2008
Route of administration:
oral: gavage
Details on route of administration:
The dose volume for all groups was 5 mL/kg.
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test article formulations were volume/volume (test article/vehicle) mixtures. The test article formulations were prepared daily as single formulations for each dosage level, divided into aliquots for daily dispensation and stored at room temperature. The test article formulations were stirred continuously throughout the preparation, sampling and dose administration procedures. Due to the nature of the vehicle, the pH was not measured.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The accuracy and stability of the test substance at 3 concentrations was confirmed using High Pressure Liquid Chromatography (HPLC). The results indicated that the three formulations used for dose levels 100, 300, and 1000 mg/kg bw were within +/- 10% of the target concentrations. Also the traces revealed a clear peak for the test substance and no incipient peaks.
Duration of treatment / exposure:
once daily for 7 consecutive days
Frequency of treatment:
once daily for 7 consecutive days
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
The notified chemical in the vehicle, corn oil, was administered orally by gavage once daily for 7 consecutive days to 3 groups of test animals at the dose levels of 100, 300 and 1,000 mg/kg bw/day. A concurrent control group received vehicle only on a comparable regimen. The dose volume was 5 mL/kg bw for all groups. Following 7 days of dose administration, all test animals were euthanized for gross necropsies.
Positive control:
None
Observations and examinations performed and frequency:
During the study, all test animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily at the time of dosing and approximately 1 and 4 hours post-dosing and detailed physical examinations were performed weekly. Individual body weight and food consumption were recorded on study Days 0 and 7.
Sacrifice and pathology:
A gross necropsy was conducted for all animals. The necropsies included examination of the external surface, all orifices, and the cranial, thoracic, abdominal and pelvic cavities, including viscera.
Other examinations:
None
Statistics:
All statistical tests were performed using appropriate computing devices or programs.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Test substance related clinical observations noted in the 1,000 mg/kg bw/day group as early as study Day 0 and throughout 7-day dosing period included impaired muscle coordination and/or impaired equilibrium in both sexes of the test animals with higher frequency in females. Hypoactivity, decreased respiration rate and prostration were noted in females on study Day 0. These effects did not persist to the 4-hour post-dosing observation on study Days 0 to 6 for males and study Days 4 to 6 for females. These effects were considered by the study authors as adverse since they persisted throughout the 7-day dosing period at approximately 1 hour post-dosing. No significant clinical observations were recorded in the 100 and 300 mg/kg bw/day groups.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A test substance related effect on body weight was noted in test substance treated animals, showing a trend towards slightly lower body weight gains. However, this effect was not considered by the study authors as adverse.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related effects on food consumption.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant macroscopic findings noted.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Key result
Dose descriptor:
NOAEL
Remarks:
7 days
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
mortality
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Organ:
not specified
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
Based on the results of this study, adverse toxicity of the test substance administered orally (gavage) to rats for 7 consecutive days was observed at 1000 mg/kg/day as evidenced by clinical observations noted following dosing throughout the 7-day dosing period. The test article was well tolerated in male and female rats at 100 and 300 mg/kg/day.
Executive summary:

The test substance in the vehicle, corn oil, was administered orally by gavage once daily for 7 consecutive days to 3 groups (Groups 2-3) of rats. Dosage levels were 100, 300 and 1000 mg/kg/day. A concurrent control group (Group 1) received the vehicle on a comparable regimen. The dose volume was 5 mL/kg for all groups. Each group (Groups 1-4) consisted of 5 animals/sex. Following 7 days of dose administration, all rats were euthanized.

 

All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily at the time of dosing and approximately 1 and 4 hours post-dosing, and detailed physical examinations were performed weekly. Individual body weight and food consumption were recorded on study days 0 and 7. All carcasses were discarded following examination and collection of gross lesions.

 

All animals survived to the scheduled necropsy. There were no test article-related effects on food consumption and there were no significant macroscopic findings. There were no significant clinical observations in the 100 and 300 mg/kg/day groups.

 

Test article-related clinical observations noted in the 1000 mg/kg/day group as early as study day 0 and throughout the 7-day dosing period included impaired muscle coordination and/or impaired equilibrium in males and females; hypoactivity, decreased respiration rate, and prostration were also noted in females on study day 0. These effects did not persist to the 4-hour post-dose observation on study days 0-6 for males and study days 4-6 for females. These clinical observations were considered adverse, especially since they persisted throughout the 7-day dosing period at approximately 1-hour post-dosing.

 

A test article-related effect on body weight included a trend towards slightly lower body weight gains noted in all test article-treated groups compared to the control group. However, the changes in body weights were not of a magnitude to be considered adverse.

 

Based on the results of this study, adverse toxicity of the test substance administered orally (gavage) to rats for 7 consecutive days was observed at 1000 mg/kg/day as evidenced by clinical observations noted following dosing throughout the 7-day dosing period. The test article was well tolerated in male and female rats at 100 and 300 mg/kg/day.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 October 2007 to 14 January 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
Only 8% of the body surface was covered
GLP compliance:
no
Remarks:
The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Q14A-14
- Purity: 99%
Species:
rat
Strain:
other: Crl:CD(SD)
Details on species / strain selection:
The Sprague-Dawley rat was used because it is a widely used strain for which significant historical control data are available.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Females nulliparous and non-pregnant: yes
- Age at study initiation: The animals were approximately 58 days old at the initiation of dose administration.
- Weight at study initiation: individual body weights ranged from 260 g to 298 g for males and from 190 g to 220 g for females.
- Housing: housed individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68.2°F to 70.6°F (20.1°C to 21.4°C)
- Humidity (%): 33.6% to 52.2%
- Air changes (per hr): minimum of 10 fresh air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 10 October 2007 To: 9 November 2007
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
The test was conducted as non-GLP study. The test substance at the level of 0.91 mL/kg bw (equivalent to 1,300 mg/kg bw based on the density of 1.432 g/mL) was dosed to individual animals via dermal application to clipped dorsum under occlusive conditions once daily for a minimum of 6 hours per day for 28 consecutive days.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were typically within 4% of expected concentration. Examination of the HPLC chromatograms showed OFPMA eluting near 1.55 minutes as expected, and revealed no incipient peaks.
Duration of treatment / exposure:
A minimum of 6 hours per day for 28 consecutive days.
Frequency of treatment:
28 consecutive days
Dose / conc.:
1 300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes
Positive control:
None
Observations and examinations performed and frequency:
All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily. Detailed clinical examinations were performed weekly.
Sacrifice and pathology:
Pathology evaluations were performed on all animals on the day of scheduled necropsy (Day 28 of the study). Complete necropsies were conducted on all animals.
Other examinations:
Application sites were examined once per week at the time of the detailed physical examination and treated and untreated skin was examined macroscopically and microscopically. Individual body weights and food consumption were recorded weekly. Ophthalmic examinations were performed during study weeks -2 and 3. Blood and urine samples for clinical pathology evaluations (hematology, coagulation, serum chemistry and urinalysis) were collected from all animals on the day of the scheduled necropsy (study day 28).
Statistics:
All statistical tests were performed using appropriate computing devices or programs.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related effects noted on clinical findings, including dermal observations.
Dermal irritation:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related effects noted on clinical findings, including dermal observations.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male in test group was found dead on Day 13 of the study. The cause of the death was undetermined. Due to lack of significant indication of toxicity in the treated animals, this death was considered by the study authors to be likely not test substance related
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related effects noted on body weights.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related effects noted in haematology or coagulation parameters.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Lower total protein (-5%) and globulin (-9%) levels were recorded as treatment related alterations in serum chemistry parameters in the test substance treated males. The values for the total protein and globulin were within historical control ranges for the laboratory and hence study authors considered the alterations as non-adverse.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no test substance-related effects noted in urinalysis parameters.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
One statistically significant difference was observed when the vehicle control and test article-treated groups were compared. Mean thymus relative to final body weight was lower (13.4%) than the vehicle control group in the treated group males but was within the WIL historical control range (version 2.4) for male rats 9-12 and 13-15 weeks of age. This alteration was a function of a slightly lower (but also within the historical control ranges) mean absolute thymus weight and slightly higher mean final body weight in the treated group males and not an effect of test article administration.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
White area(s) were seen in the liver from 1 of 10 males and females in the treated group compared to none in the vehicle control group. These foci correlated to areas of hepatocellular necrosis seen histologically. However, smaller foci of necrosis, that went undetected at necropsy, were seen microscopically in vehicle control group rats, indicating that the white areas and hepatocellular necrosis were incidental changes unrelated to test article administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance related effects noted in selected organs and microscopic tissue samples. Minimal to mild acute inflammation of the urinary bladder was observed in 2 of 10 test substance treated females and was considered by the study authors to be related to the administration of the test substance and to be non-adverse. No test substance related microscopic findings were noted on treated skin tissues.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
1 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects noted at the dose level of 1300 mg/kg bw/day via dermal route
Critical effects observed:
no
Conclusions:
Repeated dermal application of test substance to rats for 6 hours daily for 28 consecutive days was well-tolerated with no physical observations of toxicity. Evidence of systemic, non-adverse effects attributable to the test article was limited to lower total protein and lower globulin in treated males on study day 28. Although, the microscopic finding of minimal or mild acute inflammation of the urinary bladder observed in 2 treated females is considered to be related to test article administration, it does not appear to be adverse.
Executive summary:

The test article was administered via dermal application to clipped dorsum (approximately 8% of total body surface area) once daily for a minimum of 6 hours per day for 28 consecutive days to 1 group (Group 2) of rats. The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape. Elizabethan collars were applied to restrict access to the wrapped dosing site. The dosage level was 1300 mg/kg/day. A concurrent vehicle control group (Group 1) received the vehicle on a comparable regimen. The dose volume was 1.3 mL/kg for Group 1 and 0.91 mL/kg for Group 2. Each group consisted of 10 animals/sex. Following 28 days of dose administration, all animals were euthanized and necropsied.

 

All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily, and detailed physical examinations were performed weekly. Application sites were examined once per week at the time of the detailed physical examination and treated and untreated skin was examined macroscopically and microscopically. Individual body weights and food consumption were recorded weekly. Ophthalmic examinations were performed during study weeks -2 and 3. Clinical pathology evaluations (hematology, coagulation, serum chemistry and urinalysis) were performed on all animals on the day of the scheduled necropsy (study day 28). Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsy. Selected tissues were examined microscopically from all animals.

In the test article-treated group, one male was found dead on study day 13. While the cause of death was undetermined, due to overall lack of significant indications of toxicity in the treated animals, this death was probably not test article-related. There were no test article-related effects on clinical findings, including dermal observations, nor any test article-related effects on body weights, food consumption, hematology, coagulation or urinalysis parameters or organ weights were noted. There were no test article-related macroscopic findings. There were no test article-related microscopic findings on treated skin.

 

Test article-related non-adverse alterations in serum chemistry parameters included lower total protein and glucose levels in the treated males when compared to the vehicle control group. A test article-related but non-adverse microscopic finding was minimal or mild acute inflammation of the urinary bladder observed in 2 treated females.

Repeated dermal application of test substance to rats for 6 hours daily for 28 consecutive days was well-tolerated with no physical observations of toxicity. Evidence of systemic, non-adverse effects attributable to the test article was limited to lower total protein and lower globulin in the treated males on study day 28. Although, the microscopic finding of minimal or mild acute inflammation of the urinary bladder observed in 2 treated females is considered to be related to test article administration, it does not appear to be adverse.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

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