Registration Dossier

Administrative data

Description of key information

Oral LD50 (rat) > 5000 mg/Kg bw

Inhalation LC50 (rat) >6100 mg/m³

Dermal LD50 (rabbit) > 2000 mg/Kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989/03/01-1989/03/15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 401: GLP .
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
only one dose tested
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River France
- Sex: Males (5); Females (5)
- Weight at study initiation: 102-146 g
- Housing: individual
- Diet (e.g. ad libitum): Biosure LAD 1, ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 50%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
A single dose of P-D 20/26 (5g/kg) was administered by oral gavage.
Doses:
5 g/kg
No. of animals per sex per dose:
Male (5), Female (5)
Control animals:
no
Details on study design:
The acute oral toxicity of P-D 20/26 was investigated in a group of 5 male and 5 female rats. Each animal received a single oral dose of 5 g/kg administered by oral gavage. The condition of all animals was observed over a 14 day period following dosing.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No mortality was observed in any of the animals treated with 5 g/kg P-D 20/26.
Clinical signs:
Pilo-erection was observed in all rats within five minutes of dosing and throughout the remainder of Day 1. There were no other clinical signs and recovery, as judged by external appearance and behavior, was complete by Day 2.
Body weight:
All surviving animals showed an increase in body weight over their initial values at the end of the observation period.
Gross pathology:
Terminal autopsy findings were normal.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 for P-D 20/26 following oral gavage was >5 g/kg . Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

The acute toxicity of P-D 20/26 was evaluated in rats via oral gavage at a dose of 5 g/kg bw. Observations were made as to the nature, onset, severity, and duration of toxicological signs once per day for a total of 14 days. All animals survived the entire observational period and displayed a low incidence of clinical symptoms.  The animals displayed little or no abnormalities. The LD50 for P-D 20/26 following oral gavage was >5 g/kg. Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977-06-16 to 1977-06-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 401: pre-GLP
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: individually
- Diet (e.g. ad libitum): ad libitum except for 18 hours prior to dosing
- Water (e.g. ad libitum):ad libitum



Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
15g/kg
No. of animals per sex per dose:
5 males and 5 females/dose
Control animals:
no
Details on study design:
Rats were observed for mortality and toxic effects immediately and 1, 2, 4, and 6 hours after dosing and daily for 14 days. Necropsies were performed on all rats. Weights were recorded pretest and weekly
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 15 000 mg/kg bw
Mortality:
No mortatlity
Clinical signs:
During the first 24h after hyperactivity to noise, dilated pupils, and slight lethargy were observed. Chromorhinorrhea was observed in 4 males and 1 female on day 1 after exposure and alopecia in anogenital region was observed in all females on Day 14 after exposure.
Gross pathology:
Red ovaries in 3/5 females; portions of uterus red in 2/5 females.
Other findings:
Slight alopecia in anogenital area in 9/10 animals
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 following oral gavage of MRD 77-12 is greater than 15g/kg. Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

MRD 77-12 was administered via oral gavage to ten albino Wistar rats (5 males and 5 females) at a dose of 15.0 g/kg to assess the acute oral toxicity.  Animals were observed for mortality and toxic effects immediately and 1, 2, 3, 4, and 6 hours after dosing and daily for 14 days.  Necropsies were performed on all rats.  No deaths or clinical signs of toxicity were observed.  Slight alopecia in the anogential area was observed in 9/10 animals and darkened ovaries in 3/5 female animals were observed at necropsy.  The oral LD50 for MRD 77-12 was greater than 15.0 g/kg. Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Two key read across studies available from structural analogues.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report equivalent or similar to OECD guideline 403 : GLP.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: 9-11 weeks
- Weight at study initiation: 245-325 g
- Housing:individually
- Diet (e.g. ad libitum): ad libitum during non-exposure, food withheld while in chamber
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-76
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Exposure apparatus: 150 liter stainless steel inhalation chamber
- Exposure chamber volume: 150 liter
- Temperature, humidity, pressure in air chamber: 75° F, 48%, slight negative pressure to the room


TEST ATMOSPHERE
- Brief description of analytical method used: calibrated infrared monitor
- Samples taken from breathing zone: no



CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
actual vapor concentration of6100 mg/m3
No. of animals per sex per dose:
10 animals/dose (5 males; 5 females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Day 0, 7, and 14
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
>= 6 100 mg/m³ air (analytical)
Exp. duration:
4 h
Mortality:
None
Clinical signs:
other:
Body weight:
Body weight appeared normal throughout experiment. One female lost 2 grams during the Day 7-14 post-exposure observation period.
Gross pathology:
All animals appeared normal.
Other findings:
N/A
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LC50 for acute inhalation exposure to MRD-94-979 vapor is greater than 6100 mg/m3. Classification as an acute inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

MRD-94-979 was administered via individual inhalation chambers for four hours to ten Sprague-Dawley rats (5 males, 5 females) to an average actual vapor concentration of 6100 mg/m3 for four hours to assess acute inhalation toxicity. Animals were observed for fourteen days following exposure.  There were no mortality or gross pathological alterations noted in any of the animals.  Based on the conditions of this study, The LC50 for acute inhalation exposure to MRD-94-979 vapor is greater than 6100 mg/m3.  Classification as an acute inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1995-09-20 to 1995-10-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 403: GLP
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc., Kingston, New York USA
- Age at study initiation: Males, approximately 6 weeks; Females, approximately 7 weeks
- Weight at study initiation: Males, 155 to 168 grams; Females, 157 to 177 grams
- Fasting period before study: none
- Housing: Single housed during the study period. Suspended stainless steel and wire mesh.
- Diet (e.g. ad libitum): Certified Rodent Diet #5002, from PMI Feeds, Inc., Richmond, Indiana, ad libitum, during non-exposure periods. Food withheld while animals were in chamber.
- Water (e.g. ad libitum): Automatic watering system, ad libitum, during non-exposure periods. Water withheld while animals were in chamber.
- Acclimation period: 8 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-76 degrees F while in animal room; 71-74 degrees F while in exposure chamber
- Humidity (%): 40-70% relative humidity while in animal room; 82-95% relative humidity while in exposure chamber
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark


IN-LIFE DATES: From: 1995-09-21 To: 1995-10-05
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 150 liter stainless steel and acrylic whole-body inhalation exposure chamber.
- System of generating particulates/aerosols: The test atmosphere was generated using a Laskin nebulizer and a 3-neck round-bottom flask as a reservoir for the liquid test material. Compressed air was supplied to the nebulizer at approximately 4-5 psi back-pressure, producing a liquid droplet aerosol within the 3-neck flask. The aerosol was mixed with additional room air and then drawn into the exposure chamber.
- Method of particle size determination: Sierra Instruments Model 210 Cascade Impactor. Preweighed glass fiber filters were used to collect the aerosol on each stage. A bulk estimation technique was employed to characterize the particle size distribution of the test atmosphere. The change in weight of the filter for each stage was measured and the cumulative percent of the sample collected on each stage was calculated. This information plus the stage constants for the impactor were used to calculate the 15.9%, 50.0% and 84.1% particle sizes, the geometric standard deviation, and the estimated percent of the aerosol less than or equal to 1, 10, and 15 microns in size.
- Temperature, humidity, pressure in air chamber:

TEST ATMOSPHERE
- Brief description of analytical method used: Analytical chamber concentrations were determined during each hour of the exposure by drawing a known volume of the test atmosphere through a sample train consisting of a glass-fiber filter for collection of non-volatile aerosol and a charcoal sorbent tube for collection of volatile hydrocarbons (vapor).

Non-volatile aerosol concentrations were first determined gravimetrically by dividing filter weight gain by the sample volume. The filters and the charcoal tubes were then analyzed by GC/FID. Total hydrocarbons and individual hydrocarbons (full scan) were reported for both sample types. Total analytical chamber concentrations were reported as the sum of the gravimetric aerosol and total hydrocarbon vapor results.

PARTICLE SIZA DATA
-Mass median equivalent aerodynamic diameter (50% size): 3.4 microns
-Gravimetric standard deviation: 2.1
-Percent <= 15 microns: 98.0%
-Percent <= 10 microns: 93.3%
-Percent <= 1 micron: 4.6%

Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gravimetrically (aerosol); GC/FID (vapor)
Duration of exposure:
4 h
Concentrations:
5991 mg/m3 (5428 mg/m3 aerosol, 562 mg/m3 vapor)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Approximately 15 minute intervals during the first hour of exposure and once each hour thereafter through the termination of exposure.
- Necropsy of survivors performed: yes
Statistics:
Means and standard deviations for body weight and body weight change by group and sex
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 991 mg/m³ air (analytical)
Exp. duration:
4 h
Remarks on result:
other: No mortalities.
Mortality:
No mortalities occurred.
Clinical signs:
other:
Body weight:
All animals displayed increases in body weight over their initial (Day 0) values.
Gross pathology:
All ten animals were free of internal macroscopic abnormalities at post-mortem examination.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LC50 for acute inhalation exposure (aerosol atmosphere) to MRD-95-289 is greater than 5991 mg/m3 (5428 mg/m3 aerosol, 562 mg/m3 vapor). This finding does not warrant classification of Isopar M as an acute inhalation toxicant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

To assess acute inhalation toxicity, MRD-95 -289 was administered via individual whole-body inhalation chambers for four hours to ten Crl:CDBR rats at a total chamber concentration of 5991 mg/m3 (5428 mg/m3 aerosol, 562 mg/m3 vapor). Animals were observed for fourteen days following exposure. There were no mortality or gross pathological alterations in the animals, with the exception of two animals that displayed scabs and one with a necrotic and truncated tail. Based on the conditions of the study, the LC50 for acute inhalation exposure to an aerosol atmosphere of MRD-95 -289 is greater than 5991 mg/m3.

This finding does not warrant classification of MRD-95 -289 as an acute inhalation toxicant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
6 100 mg/m³
Quality of whole database:
One key and one weight of evidence study available from structural analogues.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992/11/10-1992/11/24
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles: GLP
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
; 1987 Guidelines
Deviations:
yes
Remarks:
occlusive dressing used
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products
-Sex: Male (3); Female (3)
- Age at study initiation: 12-13 weeks
- Weight at study initiation: Male: 2.01 to 2.21 kg; Female: 2.17 to 2.48 kg
- Housing: individually housed
- Diet (e.g. ad libitum): AgwayCertified Diet RCA Rabbit, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8-day acclimatization

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-70
- Humidity (%): 40 to 60
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day prior to application the trunk of each animal was clipped free of hair. For each treated animal, 5000 mg/kg of MRD-92-405 was applied to the trunk beneath a gauze patch and secured by an occlusive wrap to prevent evaporation. The whole patch assembly was held in place with tape. The patches were left in position for approximately 24 hours. Residual test material was removed and animals were observed 1, 2.5, and 4 hours after dosing and once per day thereafter for a total of 14 days.
Duration of exposure:
24 hours
Doses:
5000 mg/kg: (3) males; (3) female
No. of animals per sex per dose:
Animals: (3) males; (3) female
Control animals:
no
Details on study design:
SCORING SYSTEM: Draize scale
- Dermal response observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Differences between treated and control group mean values for bodyweight gain were analysed by Student's t-test. Where individual variance ratios were significant (P <0.05 or less), Cochrans approximation was applied (Snedecor and Cochran, Statistical Methods, 6th Ed. Iowa State. 1973). Where zero variance was found in one or more groups, intergroup comparison was performed by the Wilcoxon Rank Sum Test.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
There were no animal deaths prior to study termination.
Clinical signs:
Well-defined erythema was noted upon removal of the test patches in all animals exposed to MRD-92-405, with edema noted in two animals. At Day 14, three animals were noted as having very slight erythema and only one animal was noted as having well-defined erythema. Clinical signs during the test period were minimal. Five animals were free of any clinical signs; one animal displayed decreased food consumption on day 11.
Body weight:
All animals gained body weight over their Day 0 values
Gross pathology:
One animal was free of macroscopic abnormalities. Five animals were observed with desquamation.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 of MRD-92-405 was > 5000 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

Three male and three female rabbits were exposed to MRD-92-405 for 24h via an occluded patch.  Dermal evaluations occurred at 24 hours post patch removal and once daily until the study termination at day 14. Exposure had no affect on viability; all animals survived the exposure.  The LD50 of MRD-92-405 was > 5000 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989/01/27 - 1989/02/10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 402: GLP .
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River France
-Sex: Male (5); Female (5)
- Weight at study initiation: 209 to 254 g
- Housing: individually housed
- Diet (e.g. ad libitum): Labsure LAD 1, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 71%
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day prior to application the trunk of each animal was clipped free of hair. For each treated animal, 2000 mg/kg of P-D 20/26 was applied to the trunk beneath a gauze patch and secured by an occlusive wrap to prevent evaporation. The whole patch assembly was held in place with tape. The patches were left in position for approximately 24 hours. Residual test material was removed and animals were observed soon after dosing and twice per day thereafter for a total of 14 days.
Duration of exposure:
24 hours
Doses:
2000 mg/kg: (5) males; (5) female
No. of animals per sex per dose:
Animals: (5) males; (5) female
Control animals:
no
Details on study design:
SCORING SYSTEM: Draize scale
- Dermal response observations: daily
- Other examinations performed: clinical signs, body weight
Statistics:
Differences between treated and control group mean values for bodyweight gain were analysed by Student's t-test. Where individual variance ratios were significant (P <0.05 or less), Cochran's approximation was applied (Snedecor and Cochran, Statistical Methods, 6th Ed. Iowa State. 1973). Where zero variance was found in one or more groups, intergroup comparison was performed by the Wilcoxon Rank Sum Test.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no animal deaths prior to study termination.
Clinical signs:
Well-defined erythema accompanied by slight oedema was observed in all five males and one female after removal of the dressings. A small amount of test substance remained on the skin site in these animals. Slight erythema only was observed in the remaining four females. All skin irritation reactions had resolved by Day 4 of the study.
Body weight:
Slightly low bodyweight gains were recorded on Day 5 for two males and on Day 15 for four males and one female. All other rats achieved anticipated bodyweight gains throughout the study.
Gross pathology:
Terminal autopsy findings were normal.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 of P-D 20/26 was > 2000 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

Five male and five female rabbits were exposed to P-D 20/26 for 24h via an occluded patch.  Dermal evaluations occurred at 24 hours post patch removal and twice daily until the study termination at day 14. Exposure had no affect on viability; all animals survived the exposure.  The LD50 of P-D 20/26 was > 2000 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report equivalent or similar to OECD guideline : GLP
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton
- Age at study initiation: 19 weeks
- Weight at study initiation: 3.14-3.51
- Housing: individual
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 50 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-71
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12


Details on dermal exposure:
TEST SITE
- Area of exposure: shoulder region to lumbar region
- Type of wrap if used: gauze and plastic sleeve


REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing, wiped with gauze
- Time after start of exposure: 24h
Duration of exposure:
The test material was applied to the skin at the appropriate dose, covered with a gauze patch, secured with tape, and covered with a plastic sleeve. After ca. 24h of exposure, the plastic sleeve, tape and gauze patch were removed. The skin was then wiped (but not washed) with gauze and water to remove any remaining test material.
Doses:
The test material was applied to the skin at the appropriate dose, covered with a gauze patch, secured with tape, and covered with a plastic sleeve. After ca. 24h of exposure, the plastic sleeve, tape and gauze patch were removed. The skin was then wiped (but not washed) with gauze and water to remove any remaining test material.
No. of animals per sex per dose:
6 animals/dose (3 males; 3 females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:2, 4, 24 hours after dosing and daily for 14 days
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight
Statistics:
The means and standard deviations of the body weights were calculated.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 3 160 mg/kg bw
Mortality:
none
Clinical signs:
There was an overall low incidence of clinical in-life observations noted during the study. Observations included nasal discharge, dry rales, alopecia. Topical exposure elicited very slight to well defined erythema in all animals and very slight edema in four animals. Desquamation was noted in five animals during the study. By Day 14, all animals were clear of erythema and edema
Body weight:
3/6 test animals gained weight during the 14 day test period.
Gross pathology:
N/A
Other findings:
N/A
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The dermal LD50 for MRD-83-349 is greater than 3160 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

The acute dermal toxicity of MRD-83-349 was evaluated in rabbits following topical occlusive exposure.  Test material was applied as a single dose of 3160 mg/kg to the clipped backs of 3 male and 3 female rabbits, covered with a gauze patch, and secured with non-irritating tape and a plastic sleeve.  The test material remained in contact with the skin for 24 hours.  Observations were made as to the nature, onset, severity, and duration of toxicological signs 2, 4, and 24 hours after dosing and once per day thereafter, for a total of 14 days.  Dermal responses were evaluated 24 hours after topical application and on Days 3, 7, 10, and 14 according to the Draize method of scoring.  Application of MRD-83-349 at a dose level of 3160 mg/kg showed no evidence of systemic toxicity under the conditions of this study and all animals survived to study termination.  There were no deaths or treatment-related clinical signs.  Topical exposure elicited very slight to well defined erythema in all animals and very slight edema in four animals.  Desquamation was noted in five animals during the study.  By Day 14, all animals were clear of erythema and edema.  Based on the results of this study, the dermal LD50 for MRD-83-349 is greater than 3160 mg/kg.  Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Three key read across studies available from structural analogues.

Additional information

There is no acute oral, inhalation, or dermal toxicity data available for Hydrocarbons, C14-C20 (even numbered), n-alkanes, isoalkanes, <2% aromatics. However, data is available for structural analogues, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics; Hydrocarbons, C11-C14, n-alkanes, <2% aromatics, Hydrocarbons, C11-C14, isoalkanes, cyclics, <2% aromatics; Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics; Hydrocarbons, C12-C16, isoalkanes, cyclics, <2% aromatics; C14-C16, n-Paraffins, Hydrocarbons, C14-C17, n-alkanes, <2% aromatics; and isohexadecane. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Oral

Hydrocarbons, C11-C14, isoalkanes, cyclics, <2% aromatics

In a key study (ExxonMobil, 1989), the acute toxicity of the test material was evaluated in rats via oral gavage at a dose of 5 g/Kg bw. Observations were made as to the nature, onset, severity, and duration of toxicological signs once per day for a total of 14 days. All animals survived the entire observational period and displayed a low incidence of clinical symptoms.  The animals displayed little or no abnormalities. The LD50 of the test material following oral gavage was >5 g/Kg.

Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics

In a key study (ExxonMobil, 1977), the test material was administered via oral gavage to ten albino Wistar rats (5 males and 5 females) at a dose of 15.0 g/Kg to assess the acute oral toxicity.  Animals were observed for mortality and toxic effects immediately and 1, 2, 3, 4, and 6 hours after dosing and daily for 14 days.  Necropsies were performed on all rats.  No deaths or clinical signs of toxicity were observed.  Slight alopecia in the anogential area was observed in 9/10 animals and darkened ovaries in 3/5 female animals were observed at necropsy. The oral LD50 for the test material was greater than 15.0 g/Kg.

C14-C16 n-Paraffins

In a supporting toxicity study (Conoco, Inc., 1982), C14-C16 n-Paraffins was tested for acute oral toxicity in COX-SD rats in an acute dose assay. Animals were fasted overnight prior to treatment. The test substance, a liquid, was administered as supplied. The assay was conducted on a group of 10 rats (5 males, 5 females) with doses of 4750 mg/Kg b.w. or 5250 mg/Kg b.w. administered by gavage in a single oral dose. Examinations for mortality, clinical signs and body weight gain were performed during the 14-day observation period. All surviving animals were necropsied at the end of the observation period. One male died at the lowest test substance dose while no mortality was observed at the highest dose. Hypoactivity of the animals was observed within 24 hours post-treatment but not after. Diarrhea, diuresis, wet skin and fur of anogenital region and general weakness were also noted at both doses within one to three days post-treatment. Body weight gain was not affected by treatment. At necropsy, macroscopic examination of main organs showed no abnormalities. As the acute oral LD50was found greater than 5250 mg/Kg b.w. under the conditions of the test, C14-C16 n-Paraffins are not classified according to the criteria of CLP Regulation 1272/2008.

Hydrocarbons, C14-C17, n-alkanes, <2% aromatics

In a supporting study (Cepsa, 1984), the test material (Hydrocarbons, C14-C17, n-alkanes, <2% aromatics) was tested for acute oral toxicity in HC/CFY rats in a limit dose assay. The assay was conducted on a group of 10 rats (5 males, 5 females) with a dose of 5000 mg/Kg b.w. administered by gavage, as supplied, in a single oral dose (maximum dose volume of 6.4 mL/Kg b.w). Examinations for mortality, clinical signs and body weight gain were performed during the 14-day observation period. All surviving animals were necropsied at the end of the observation period. No deaths occurred. Pilo-erection was observed in all animals shortly after dosing but not at 72-hour observation period. Body weight gain was not affected by treatment. At necropsy, macroscopic examination of main organs showed no abnormalities. As the acute oral LD50was found greater than 5000 mg/Kg b.w. under the conditions of the test, the test material was not classified according to the criteria of CLP Regulation 1272/2008.

 

Isohexadecane

In a supporting study (INEOS, 1980), the toxicity of isohexadecane in Sprague-Dawley rats was tested by gavage of the undiluted liquid test substance as supplied. The animals were observed for 4 weeks after treatment. At the end of observation period, they were killed and a necropsy was performed. The test doses were 2.15, 4.64, 10.0, 21.15, 31.6 and 46.4 mL/Kg bw. Five males and five females were tested at the three lower doses while 10 rats of both sexes were treated at the three higher dose groups. No mortality was observed at any tested dose. Sublethal effects were noted such as oily secretion in the area of anus for tested dose from 4.64 mL/kg bw to 46.4 mL/kg bw. Moreover, 28% and 11% daily food intake decrease was recorded in females treated at 31.6 mL/kg bw on the first and the second day of observation, respectively. The same effects (32% and 49% food intake decreases) were observed at the 24 and 48-hour observation periods in females treated with the highest dose. Decrease of body weight intake was also observed on first observation day in treated females at 46.4 mL/kg bw, corresponding to 37 g/kg bw. No LD50 was determined.

Inhalation

Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics

In a key study (ExxonMobil, 1995), the test material was administered via individual inhalation chambers for four hours to ten Sprague-Dawley rats (5 males, 5 females) to an average actual vapor concentration of 6100 mg/m3 for four hours to assess acute inhalation toxicity. Animals were observed for fourteen days following exposure. There were no mortality or gross pathological alterations noted in any of the animals. Based on the conditions of this study, the LC50 for acute inhalation exposure to the test material vapor is greater than 6100 mg/m3. 

Hydrocarbons, C12-C16, isoalkanes, cyclics, < 2% aromatics

In a key study (ExxonMobil, 1997), to assess acute inhalation toxicity, the test material (Hydrocarbons, C12-C16, isoalkanes, cyclics, < 2% aromatics) was administered via individual whole-body inhalation chambers for four hours to ten Crl:CDBR rats at a total chamber concentration of 5991 mg/m3 (5428 mg/m3 aerosol, 562 mg/m3vapor). Animals were observed for fourteen days following exposure. There were no mortality or gross pathological alterations in the animals, with the exception of two animals that displayed scabs and one with a necrotic and truncated tail. Based on the conditions of the study, the LC50 for acute inhalation exposure to an aerosol atmosphere of the test material was greater than 5991 mg/m3. This finding does not warrant classification of MRD-95 -289 as an acute inhalation toxicant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

C14-C16 n-Paraffins

In a supporting study (Conoco, Inc., 1982), the toxicity of C14-C16 n-Paraffins was tested in COX-SD rats exposed by inhalation. Five males and five females were exposed to the test substance in the form of a mist at a delivery flow concentration of approximately 5.8 mg/L of air at a total flow rate of 9 L/min. The animals were observed for 2 weeks after treatment. At the end of observation period, they were killed and a pathology investigation was performed. No mortality occured during the study. Moderate rales were noted in 2 animals on day 2 to 7, that lasted 9 days or until termination. Moderate thinness was also recorded in 2 animals from day 1 or 2 and lasted 3 to 6 days. Necropsy showed slight congestion of the lungs in 2 rats and a slight decrease of visceral fatty tissues in one animal. As the acute LC50 by inhalation was found to be greater than 5.8 mg/L under the conditions of the test, C14-C16 n-Paraffins are not classified according to the criteria of EU GHS.

Dermal

Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics

In a key acute dermal toxicity study (ExxonMobil, 1984), the acute dermal toxicity of the test material was evaluated in rabbits following topical occlusive exposure. Test material was applied as a single dose of 3160 mg/Kg to the clipped backs of 3 male and 3 female rabbits, covered with a gauze patch, and secured with non-irritating tape and a plastic sleeve. The test material remained in contact with the skin for 24 hours. Observations were made as to the nature, onset, severity, and duration of toxicological signs 2, 4, and 24 hours after dosing and once per day thereafter, for a total of 14 days. Dermal responses were evaluated 24 hours after topical application and on Days 3, 7, 10, and 14 according to the Draize method of scoring. Application of the test material at a dose level of 3160 mg/Kg showed no evidence of systemic toxicity under the conditions of this study and all animals survived to study termination. There were no deaths or treatment-related clinical signs. Topical exposure elicited very slight to well defined erythema in all animals and very slight edema in four animals. Desquamation was noted in five animals during the study. By Day 14, all animals were clear of erythema and edema. Based on the results of this study, the dermal LD50 for the test material was determined to be greater than 3160 mg/Kg. 

Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics

In a key acute dermal toxicity study (ExxonMobil, 1993), three male and three female rabbits were exposed to the test material (Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics) for 24h via an occluded patch. Dermal evaluations occurred at 24 hours post patch removal and once daily until the study termination at day 14. Exposure had no effect on viability; all animals survived the exposure. The LD50 was > 5000 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Hydrocarbons, C11-C14, isoalkanes, cyclics, < 2% aromatics

In a key acute dermal toxicity study (Cepsa Quimica, 1989), five male and five female rabbits were exposed to the test material (Hydrocarbons, C11-C14, isoalkanes, cyclics, < 2% aromatics) for 24h via an occluded patch. Dermal evaluations occurred at 24 hours post patch removal and twice daily until the study termination at day 14. Exposure had no effect on viability; all animals survived the exposure. The LD50was > 2000 mg/kg. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

C14 -C16 n-paraffins

In a supporting study (Conoco, Inc., 1982), the acute dermal toxicity of C14 -C16 n-paraffins was determined in male and female adults New Zealand White rabbits. The test substance was applied at 500 or 2000 mg/Kg b.w. concentration on abraded skin of rabbits exposed for 24 hours by an occlusive dressing. At the end of exposure, the remaining test substance was wiped by means of absorbent paper. Examinations for mortality, clinical signs and body weight gain were performed during the 14-day observation period. All surviving animals were necropsied at the end of the observation period. No deaths nor clinical signs occurred during the observation period. Body weight gain was not affected by treatment.

At the 24 hour observation interval, all of the animals showed very slight to marked erythema and edema of the skin at the treatment site. The initial dermal reaction was followed by thickening and/or wrinkling, fissuring, dryness and desquamation of which residual effects persisted in each through termination of the study. As the acute dermal LD50 was greater than 2000 mg/Kg b.w. under the test conditions, C14 -C16 n-paraffins are not classified according to the criteria of CLP Regulation 1272/2008.

Hydrocarbons, C14-C17, n-alkanes, <2% aromatics

In a supporting study (Petroquimica, 1984), the test material (Hydrocarbons, C14-C17, n-alkanes, <2% aromatics) was tested for acute dermal toxicity in HC/CFY (remote Sprague-Dawley) rats in a limit dose assay according to OECD guideline 402. The test substance, a liquid, was administered undiluted as supplied. A 10% total body surface of hair was removed from the dorso-lumbar region with clippers in every animal. The assay was conducted on a group of 10 rats (5 males, 5 females) with a dose of 2000 mg/Kg b.w. administered by spreading in a single dermal dose (maximum dose volume of 2.6 mL/Kg b.w). After test substance application an occlusive patch was held in place for 24 hours. Skin was washed with water at the end of the 24-hour exposure period. Examinations for mortality, clinical signs and body weight gain were performed during the 14-day observation period. All surviving animals were necropsied at the end of the observation period. No deaths and clinical signs occurred during the observation period. Body weight gain was not affected by treatment. At necropsy, macroscopic examination of main organs showed no abnormalities.

Slight to well-defined and slight oedema was observed at the site of treatment in all animals. Reversibility was generally observed by day 6 with the exception of one animal showing slight oedema until Day 9. All rats developed small, slightly raised erythematous areas at the dose site on the day 6. Then, small focal scab formations persisted from day 9 to day 15 in all rats except two females which had recovered by day 14. Two small areas of necrosis were observed at the treatment site on two males on day 2 but not on day 6 and day 9, respectively. As the acute dermal LD50 was greater than 2000 mg/Kg b.w. under the test conditions, the test material is not classified according to the criteria of CLP Regulation 1272/2008.

Justification for classification or non-classification

Based on available read across data, Hydrocarbons, C14-C20 (even numbered), n-alkanes, isoalkanes, <2% aromatics is minimally toxic via ingestion where the LD50 is >5000 mg/Kg, via dermal exposure where the LD50 is >2000 mg/Kg, and by inhalation where the LC50 >6100 mg/m3. These findings do not warrant classification under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Hydrocarbons, C14-C20 (even numbered), n-alkanes, isoalkanes, <2% aromatics is classified under EU CLP guidelines as a Category 1 aspiration hazard based on its physical and chemical properties (hydrocarbon fluid, viscosity ≤ 20.5 mm2/s).