Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute Oral LD50 = 6318 mg/Kg in rats (OECD TG 401)

Acute Dermal LD50 >2000 mg/Kg in rabbits (OECD TG 402)

Acute Inhalation LC50 >4688 mg/m3 (OECD TG 403)

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:
From November 14, 1994 To January 5, 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report in agreement with OECD guideline 401-GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
other: Crl:CDBR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc
- Age at study initiation: Males: Approximately 8-10 weeks; Females: Approximately 9-12 weeks
- Fasting period before study: Approximately 16 hours
- Weight at study initiation: Males: 217 to 317 grams; Females: 185 to 273 grams
- Housing: Individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:7-22days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): maintained range 20-24.4
- Humidity (%): maintained range 40-70
- Photoperiod (hrs dark / hrs light): 12hrs dark / 12 hrs light


IN-LIFE DATES: From: November 16, 1994 To: January 5, 1995
Route of administration:
other: oral intubation via syringe
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data
Doses:
5000mg/kg; 6000mg/kg; 7500 mg/kg; 10000 mg/kg
No. of animals per sex per dose:
10 animals per dose (5 male; 5 female)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were made as to the nature, onset, severity, and duration of toxicological signs at 1, 2, 4, and 6 hours after dosing, and once per day thereafter for a total of 14 Days. Body weights were recorded on the day prior to dosing (pretest), the day of dosing (Day 0), on Day 7, and on Day 14, and at death for those which succumbed.
- Necropsy of survivors performed: yes
Statistics:
The means and standard deviations of the body weights and body weight changes, by sex and group were calculated .

The oral median lethal dose (LD50) was calculated using the standard Litchfield-Wilcoxon technique (Litchfield and Wilcoxon, 1949) with equal weighting of the data values. If the fraction surviving was zero, the value was transformed to 1-(1/4n). If the fraction surviving was 1, it was transformed to the 1/4n, where 'n' is the number of animals in the dose group. The regression line was fitted by the least squares technique, using probit on log dose values.

The Litchfield-Wilcoxon recommended test for "goodness of fit" was performed. The significance level (probability) of the lack of fit test was calculated . If the probability is >0.05, the standard Litchfield-Wilcoxon technique was used to generate the confidence intervals for the slope and LD50. If the probability is 0.05 or less, then the modified Litchfield-Wilcoxon technique was used for calculating the confidence intervals.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 7 093 mg/kg bw
95% CL:
> 6 142 - < 8 190
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 5 558 mg/kg bw
95% CL:
> 4 592 - < 6 726
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 6 318 mg/kg bw
95% CL:
> 5 668 - < 7 044
Mortality:
5000 mg/kg: 0 males; 2 females
6000 mg/kg: 2 males; 3 females
7500mg/kg: 3 males; 5 females
10000 mg/kg: 5 males; 5 females
Clinical signs:
other: Adverse clinical effects were observed in all groups and were observed primarily during the first week of the study. Abnormal clinical signs noted during the study included hypoactivity; hypothermia; abnormal stool production; oral, nasal, and ocular dis
Gross pathology:
All animals which survived to study termination were free of abnormalities at postmortem examination (seven animals at the 5000 mg/kg dose level, five at the 6000 mg/kg dose level, and 2 at the 7500 mg/kg dose level), with the exception of one 5000 mg/kg male with alopecia.

Postmortem observations noted in the animals which died prior to scheduled termination examination included: staining of the fur; discolored kidneys, stomach and liver; and/or abnormal contents, discoloration or distention of the gastrointestinal tract or urinary bladder. These findings were considered to be treatment-related.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 for MRD-94-953 following oral intubation of (MRD-94-953) was established at 7093 mg/kg for males, 5558 mg/kg for females, and 6318 mg/kg combined. Classification 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 oral toxicity and LD50 of MRD-94-953 administered via oral intubation were evaluated in Crl:CDBR rats.  The dose levels were 5000, 6000, 7500, and 10000 mg/kg.  Each dose group consisted of 5 animals/sex.  Animals were observed daily for 14 days post dosing.  Overt signs of toxicity were apparent at a dose level of 5000 mg/kg and higher.  Mortality was observed at all dose levels tested and all of the animals that succumbed following administration of MRD-94-953 died within 3 days of dosing.  The incidence of death was considered dose related.  All animals which survived to study termination were free of abnormalities at postmortem examination (seven animals at the 5000 mg/kg dose level, five at the 6000 mg/kg dose level, and 2 at the 7500 mg/kg dose level), with the exception of one 5000 mg/kg male with alopecia.  All surviving animals displayed increases in body weight over their Day 0 values. The LD50for this study was established at 7093 mg/kg for males, 5558 mg/kg for females, and 6318 mg/kg combined. 

Based on the results of this study, the oral LD50 for this material is greater than 5000mg/kg.  MRD-94-953 and classification as an acute 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:
1990/10/22-1990/11/06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to OECD 420 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:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: Approximately 9 - 10 weeks
- Weight at study initiation: Males (260-295 g), Females (201-228 g)
- Fasting period before study: approximately 16h
- Housing: individual
- Diet (e.g. ad libitum): Purina certified rodent chow, ad libitum
- Water (e.g. ad libitum): Automatic watering system, ad libitum
- Acclimation period: 7d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test material MRD-90-884 was diluted in corn oil and administered at the appropriate dose levels by a single oral intubation via syringe and a no. 16 stainless steel straight, ball-tipped feeding needle.
Doses:
500 mg/kg, 1500 mg/kg, 5000 mg/kg
No. of animals per sex per dose:
Male (5), Female (5); total animals (30)
Control animals:
no
Details on study design:
Duration of observation period following administration: 1, 2, 4, and 6 h after dosing and once per day thereafter for a total of 14 days
Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The means and standard deviations of the body weights and body weight changes were calculated. LD50 was calculated using the standard Litchfield-Wilcoxon technique with equal weighting of the data points.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
10 650 mg/kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
5 210 mg/kg bw
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
7 050 mg/kg bw
Remarks on result:
other: combined LD50
Mortality:
No mortality was observed in the 500 or 1500 mg/kg doses. In the 5000 mg/kg dose group, two males were found dead on day 2; two females were found dead on day 3, and a final female death noted on day 4.
Clinical signs:
other: No abnormal clinical in-life observations were noted for the majority of animals in either the 500 or 1500 mg/kg doses; only a single incidence ano-genital staining and a single oral/ocular discharge were noted. In the 5000 mg/kg group the most frequentl
Gross pathology:
No abnormal pathological observations were noted for the animals in either the 500 or 1500 mg/kg dosed groups. The animals that succumbed prior to study termination exhibited staining of the lungs and of the fur, abnormalities of the stomach and gastro-intestinal tract, liver discoloration and distension, and abnormal contents of the cecum and urinary bladder. Four of the five survivors in this group displayed no abnormalities, while the remaining animals exhibited alopecia.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 for males is 10650 mg/kg and the LD50 for female animals is 5210 mg/kg. The combined estimated LD50 (both sexes) is 7050mg/kg. This finding does not warrant classification as an acute oral 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:

The acute toxicity of MRD-90-884 was evaluated in rats via oral gavage at doses of 500 mg/kg, 1500 mg/kg, or 5000 mg/kg fasted body weight. Observations were made as to the nature, onset, severity, and duration of toxicological signs at 1, 2, 4, and 6 hours after dosing and once per day for a total of 14 days. Animals in the 500 or 1500 mg/kg dose groups survived the entire observational period and displayed a low incidence of clinical symptoms. Two males and three female animals in the 5000 mg/kg dosing group did not survive the study and died on days 2 - 4. The most frequently noted in-life clinical abnormalities were ano-genital staining, oral/nasal discharges, decreased appetite, hypoactivity, and prostration. Gross postmortem examination of the animals that succumbed prior to study termination revealed staining of the lungs and of the fur, and abnormalities of the stomach, gastro-intestinal tract, liver and bladder.  The surviving animals displayed little or no abnormalities. The surviving animals had no observable abnormalities. It is estimated that the LD50 for males is 10650 mg/kg and the LD50 for female animals is 5210 mg/kg. The combined estimated LD50 (both sexes) is 7050mg/kg. This finding does not warrant classification as an acute oral 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:
adverse effect observed
Dose descriptor:
LD50
Value:
6 318 mg/kg bw
Quality of whole database:
Two key (one substance specific and one read across to structural analogue) studies along with one substance specific supporting study available for assessment.

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:
1995/09/20-1995/10/04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 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
Limit test:
yes
Species:
rat
Strain:
other: Crl:CDBR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Source: Charles River Laboratories Inc.
Sex: Male (5), Female (5) for each species
Age at study initiation: 7 weeks
Weight at study initiation:
Males: 145-171g
Females: 146 - 177g
Housing: Single housed
Diet (e.g. ad libitum): PMI Feeds, Inc. Certified Rodent Diet #5002 ad libitum during non-exposure period; withheld during exposure
Water (e.g. ad libitum): automatic watering system, ad libitum
Acclimation period: 7d and animals were examined once a day for viability

ENVIRONMENTAL CONDITIONS
Temperature (°F): 68-76
Humidity (%): 40-70%
Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The test material was generated using a single barrel Laskin nebulizer. Compressed air was supplied to the nebulizer at 5-7 psi back pressure, producing a droplet aerosol that was mixed with room air and drawn into the exposure chamber. Particle size was determined via a Sierra Instruments Model 210 Cascade Impactor. DATA: Exposure Concentration (average actual): 4778 mg/m3
Exposure Concentration (nominal): 11321 mg/m3
Chamber Size: 150L
ATM Pressure: slightly negative pressure to the room
Temperature: 25°C
Air Flow Rate: 30 (L/min)
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetrically (aerosol), GC/FID (vapour)
Duration of exposure:
4 h
Concentrations:
4778 mg/m3 (analytical)
11321 mg/m3 (nominal))
Chamber Size: 150L
ATM Pressure: slightly negative pressure to the room
Temperature: 25°C
Air Flow Rate: 30 (L/min)
No. of animals per sex per dose:
Male (5), Female (5) for each species
Control animals:
no
Details on study design:
The animals were individually housed in a 150L stainless steel whole body inhalation chamber that was under a slight negative pressure to the room and had an air flow of 30 L/min. The exposure was 4 hours plus equilibration time (~23 min) and air flow, temperature, and humidity were continuously monitored. Animals were observed for mortality and obvious toxic signs at 15 min intervals for the first hour of exposure and then once each hour until the termination of the exposure. Body weights for each animal were recorded prior to exposure and on days 7 and 14. A gross necropsy was performed on every animal.
Statistics:
Mean and Standard Deviation of body weight and body weight change by group and sex.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4 778 mg/m³ air (analytical)
Mortality:
One male animal was found dead on day 2 post-exposure. This animal was observed as prostrate with wet fur, oral and nasal discharge, wet rales, and little sign of stool or food consumption.
Clinical signs:
other:
Body weight:
All animals gained body weight over their initial values.
Gross pathology:
A dead animal was observed with dark red nasal turbinates and bright red lungs, red material in the stomach mixed with ingesta, wet/matted fur, and nasal discharge. Surviving animals were observed having small seminal vesicles, scabs, red foci in the lungs and thymus. One male and all five females were free of abnormalities.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LC50 is >4.778 mg/L for aerosolized MRD-95-246. 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:

Five male and five female rats were exposed to 4778 mg/m3 (4.778 mg/L, analytical)/ 11321 mg/m3 (11.3 mg/L, nominal) aerosol of test material MRD-95-246 for 4 hours. Animals were observed for 14 days. One male animal was found dead on day 2 post-exposure.  The majority of abnormalities were noted during the first 2 days of the 14 day observational period.  These abnormalities included wet/matted fur, oral/nasal discharge, reddening of the eyelids and extremities, anogenital staining, and alopecia.  One male and all five females were free of abnormalities by day 14 and surviving animals continued to gain weight through day 14. The LC50 is >4.778 mg/L for aerosolized MRD-95-246. 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:
key study
Study period:
From November, 15, 1994 to December 1, 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report in general agreement with OECD guideline 403-GLP
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
only one dose tested
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 Laboratories Inc.
- Age at study initiation: approximately 8-10 weeks
- Weight at study initiation: 225-296 grams
- Housing: individually
- Diet (e.g. ad libitum): ad libitum during non-exposure periods. Food withheld while animals were in chamber
- Water (e.g. ad libitum): ad libitum during non-exposure periods. Food withheld while animals were in chamber
- Acclimation period: eight days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): maintained range 20-24.4
- Humidity (%): maintained range of 40-70
- Photoperiod (hrs dark / hrs light): 12hrs dark / 12hrs light


IN-LIFE DATES: From: November 17, 1994 To: December 1, 1994
Route of administration:
inhalation: vapour
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 inhalation chamber
- Exposure chamber volume: 150 liter
- Method of holding animals in test chamber:
- Source and rate of air: chamber operated under slight negative pressure to the room at an airflow of approximately 30.0 liters per minute
- Method of conditioning air:
- System of generating vapor: test material was delivered by a syringe pump to the inside of a heated glass counter current vapor generator
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber: approximately 23.8 C


TEST ATMOSPHERE
- Brief description of analytical method used: vapor concentrations were determined during exposure by drawing chamber air through a calibrated infrared monitor. chamber concentrations were recorded at approximately 1 hour intervals and averaged to yield the mean chamber concentration for exposure
- Samples taken from breathing zone: yes



CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: highest attainable vapor concentration
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
average actual vapor concentration of 4688 mg/m3 (± 72 mg/m3)
No. of animals per sex per dose:
10 animals (5 males; 5 females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed in chamber during exposure at 15, 30, and 45 minutes and at 1, 2, 3, and 4 hours. Animals were observed once daily for 14 days. Body weights were measured before exposure and on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other:
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4 688 mg/m³ air (analytical)
Remarks on result:
other: no mortality or gross systemic toxicity observed at this dose
Clinical signs:
other:
Body weight:
Body weight gain for all animals appeared normal throughout the observation period with the exception of one female whose weight remained unchanged from day 7 to day 14
Gross pathology:
all animals appeared normal at the gross postmortem examination
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LC50 for acute inhalation exposure to MRD-94-953 vapor is greater than the highest obtainable vapor concentration (4688 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:

The acute inhalation toxicity of MRD-94-953 was evaluated in ten Sprague-Dawley rats.  Animals were exposed for four hours to the maximum attainable vapor concentration of the test material (4688mg/m3) in individual inhalation chambers. Animals were observed for 14 days.  There were no mortality or gross pathological alterations noted in any of the animals.  Based on the conditions of this study, the LC50for vapors of MRD-94-953 are greater than 4688mg/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 conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
4 688 mg/m³ air
Quality of whole database:
Two key (one substance specific and one read across to structural analogue) studies along with one read across supporting study available for assessment.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From November 14, 1994 To November 29, 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report in agreement with OECD test guideline 402-GLP
Qualifier:
according 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: HRP Inc., Denver, PA
- Age at study initiation: Males: approximately 13 weeks; females: approximately 10 weeks
- Weight at study initiation: 2.05-2.43kg
- Housing: individually
- Diet (e.g. ad libitum): Based on recommendations of the animal supplier, in an effort to improve the health of the animals, the amount of feed administered to the animals was limited on a daily basis.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3-21.1 °C
- Humidity (%): 40 to 60 percent relative humidity
- Photoperiod (hrs dark / hrs light): 12hrs dark /12 hrs light


IN-LIFE DATES: From: November 15, 1994 To: November 29, 1994
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal surface from the shoulder region to the lumbar region
- % coverage: at least 10% of the body surface
- Type of wrap if used: the gauze patch was secured to the trunk of the animal with a plastic sleeve


REMOVAL OF TEST SUBSTANCE
- Washing (if done): reverse osmosis water and paper towels
- Time after start of exposure: approximately 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg



Duration of exposure:
24 hours
Doses:
2000mg/kg dose
No. of animals per sex per dose:
5 males; 5 females (nulliparous and non-pregnant)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made at 2 and 4 hours after dosing, and daily thereafter for a total of 14 days.
Body weights were recorded once prior to dosing initiation; on Days 0, 7, 14; and on the day of sacrifice. Dermal responses were evaluated on Day 1 (30 to 60 minutes after patch removal) and on Days 3, 7, and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: Clinical observations were made as to the nature, onset, severity, and duration of toxicological signs; Dermal responses were evaluated according to the Draize method of scoring.
Statistics:
Statistical analyses included means and standard deviations of body weights and body weight change by group and sex.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: no evidence of systemic toxicity under the conditions of this study at this dose
Clinical signs:
other: All animals survived to study termination. There were no treatment-related clinical signs. At the 2 and 4 hour observations, one female had mucoidal stool. At the Day 1 observation, one female was noted with a reddened nictitating membrane. These find
Gross pathology:
At the postmortem examination, four males and two females were noted with desquamation and/or eschar on the dose site which was consistent with their inlife dermal observations. The remaining male and three females had no macroscopic abnormalities.
Other findings:
Topical application of the test material elicited dermal irritation in all animals. At the Day 1 observation, eight animals had well-defined erythema and two animals had moderate/severe erythema. At the Day 3 observation, five animals had well-defined erythema, two animals had moderate/severe erythema, and one animal had severe erythema. At the Day 7 observation, four animals had very slight erythema, three animals had well-defined erythema, and one animal had severe erythema. On Day 14, three animals had very slight erythema, one animal had well-defined erythema, and four animals had severe erythema/slight eschar formation.

Edema was observed in all animals. At the Day 1 observation, one animal had very slight edema, one animal had slight edema, and eight animals had moderate edema. At the Day 3 observations, one animal had very slight edema and four animals had slight edema. Edema was not observed in any animal on Day 7. At the Day 14 observation, one animal had slight edema.

Other dermal observations included atonia, cracking, desquamation, eschar, exfoliation, fissuring, and leathery texture of the dose site.

Severe dermal irritation from mechanical damage at undamming was observed in all ten animals at sleeve removal and in nine animals at the Day 1 observation. This irritation was not scored.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the dermal LD50 for MRD-94-953 is greater than 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:

The acute toxicity of MRD-94-953 was evaluated following its application to the clipped backs of ten New Zealand White rabbits.  A single dose of 2000 mg/kg of the test material was applied to not less than 10% of the body surface, covered with a gauze patch, and secured with non-irritating tape and a plastic sleeve.  Clinical observations were performed 2 and 4 hours after dosing, and once per day thereafter for a total of 14 days.  Dermal responses were evaluated on Days 1, 3, 7, and 14 according to the Draize method of scoring.  Body weights were recorded the day prior to dosing, the day of dosing (Day 0), and on Days 7 and 14.  Application of MRD-94-953 at a dose level of 2000 mg/kg showed no evidence of systemic toxicity under the conditions of this study and all animals survived to study termination.  There were no treatment-related clinical signs.  Dermal irritation was the most significant finding and was observed in the majority of animals throughout the study. 

 

Based on the results of this study, the dermal LD50 for MRD-94-953  is greater than 2000 mg/kg in the rabbit. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labelling 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:
Two key (one substance specific and one read across to structural analogue) studies along with one substance specific supporting study available for assessment.

Additional information

There is data available for Hydrocarbons, C10, aromatics, >1% naphthalene. This data is supported by information available for structural analogues, Hydrocarbons, C10-C13, aromatics, >1% naphthalene andHydrocarbons, C10, aromatics. 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.

Acute Oral Toxicity

 

Hydrocarbons, C10, aromatics, >1% naphthalene

The acute oral toxicity and LD50of the test material (Hydrocarbons, C10, aromatics, >1% naphthalene) administered via oral intubation were evaluated in Crl:CDBR rats (ExxonMobil, 1995a). The dose levels were 5000, 6000, 7500, and 10000 mg/Kg. Each dose group consisted of 5 animals/sex. Animals were observed daily for 14 days post dosing. Overt signs of toxicity were apparent at a dose level of 5000 mg/Kg and higher. Mortality was observed at all dose levels tested and all of the animals that succumbed following administration of the test material died within 3 days of dosing. The incidence of death was considered dose related. All animals which survived to study termination were free of abnormalities at post-mortem examination (seven animals at the 5000 mg/Kg dose level, five at the 6000 mg/Kg dose level, and 2 at the 7500 mg/Kg dose level), with the exception of one 5000 mg/Kg male with alopecia. All surviving animals displayed increases in body weight over their Day 0 values. The LD50 for this study was established at 7093 mg/Kg for males, 5558 mg/Kg for females, and 6318 mg/Kg combined. 

 

In a supporting acute oral toxicity study (Shell, 1977b) in rats, the LD50 for the test material (Hydrocarbons, C10, aromatics, >1% naphthalene) was determined to be ≥10000 mg/Kg. Classification is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Hydrocarbons, C10-C13, aromatics, >1% naphthalene

In a key read across study (ExxonMobil, 1991), the acute toxicity of the test material (Hydrocarbons, C10-C13, aromatics, >1% naphthalene) was evaluated in rats via oral gavage at doses of 500 mg/Kg, 1500 mg/Kg, or 5000 mg/Kg fasted body weight. Observations were made as to the nature, onset, severity, and duration of toxicological signs at 1, 2, 4, and 6 hours after dosing and once per day for a total of 14 days. Animals in the 500 or 1500 mg/Kg dose groups survived the entire observational period and displayed a low incidence of clinical symptoms. Two males and three female animals in the 5000 mg/Kg dosing group did not survive the study and died on days 2 - 4. The most frequently noted in-life clinical abnormalities were ano-genital staining, oral/nasal discharges, decreased appetite, hypoactivity, and prostration. Gross post-mortem examination of the animals that succumbed prior to study termination revealed staining of the lungs and of the fur, and abnormalities of the stomach, gastro-intestinal tract, liver and bladder. The surviving animals displayed little or no abnormalities. The surviving animals had no observable abnormalities. It is estimated that the LD50 for males is 10650 mg/Kg and the LD50 for female animals is 5210 mg/Kg. The combined estimated LD50 (both sexes) is 7050mg/Kg. This finding does not warrant classification as an acute oral toxicant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

 

Acute Inhalation Toxicity

Hydrocarbons, C10, aromatics, >1% naphthalene

The acute inhalation toxicity of the test material (Hydrocarbons, C10, aromatics, >1% naphthalene) was evaluated in ten Sprague-Dawley rats (ExxonMobil, 1995b). Animals were exposed for four hours to the maximum attainable vapor concentration of the test material (4688 mg/m3) in individual inhalation chambers. Animals were observed for 14 days. There were no mortality or gross pathological alterations noted in any of the animals.  Based on the conditions of this study, the LC50for vapors of Hydrocarbons, C10, aromatics, >1% naphthalene are greater than 4688 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).

 

Hydrocarbons, C10-C13, aromatics, >1% naphthalene

Five male and five female rats were exposed to 4778 mg/m3(4.778 mg/L, analytical)/ 11321 mg/m3(11.3 mg/L, nominal) aerosol of test material (Hydrocarbons, C10-C13, aromatics, >1% naphthalene) for 4 hours (ExxonMobil, 1997). Animals were observed for 14 days. One male animal was found dead on day 2 post-exposure. The majority of abnormalities were noted during the first 2 days of the 14 day observational period. These abnormalities included wet/matted fur, oral/nasal discharge, reddening of the eyelids and extremities, anogenital staining, and alopecia. One male and all five females were free of abnormalities by day 14 and surviving animals continued to gain weight through day 14. The LC50is >4.778 mg/L for aerosolized Hydrocarbons, C10-C13, aromatics, >1% naphthalene. 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).

 

Hydrocarbons, C10, aromatics

In a supporting study (Carpentar et al., 1977), the acute inhalation toxicity LC50s for male rats, cats, and dogs were determined to be >6.3 mg/L, >8.2 mg/L, and >1 mg/L, respectively following a 6 hour whole body exposure to the test material (Hydrocarbons, C10, aromatics). Classification as an acute inhalation toxicant is therefore not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Acute Dermal Toxicity

Hydrocarbons, C10, aromatics, >1% naphthalene

In a key study (ExxonMobil, 1995c), the acute toxicity of the test material (Hydrocarbons, C10, aromatics, >1% naphthalene) was evaluated following its application to the clipped backs of ten New Zealand White rabbits. A single dose of 2000 mg/Kg of the test material was applied to not less than 10% of the body surface, covered with a gauze patch, and secured with non-irritating tape and a plastic sleeve. Clinical observations were performed 2 and 4 hours after dosing, and once per day thereafter for a total of 14 days. Dermal responses were evaluated on Days 1, 3, 7, and 14 according to the Draize method of scoring. Body weights were recorded the day prior to dosing, the day of dosing (Day 0), and on Days 7 and 14. Application of the test material at a dose level of 2000 mg/Kg showed no evidence of systemic toxicity under the conditions of this study and all animals survived to study termination. There were no treatment-related clinical signs. Dermal irritation was the most significant finding and was observed in the majority of animals throughout the study. Based on the results of this study, the dermal LD50for Hydrocarbons, C10, aromatics, >1% naphthalene was determined to be greater than 2000 mg/Kg in the rabbit. Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP).

 

In supporting acute dermal toxicity study in rabbits (ExxonMobil, 1975), the dermal LD50for the test material (Hydrocarbons, C10, aromatics, >1% naphthalene) was determined to be 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).

 

Hydrocarbons, C10-C13, aromatics, >1% naphthalene

In a supporting study (ExxonMobil, 1975), three male and three female rabbits were exposed to the test material (Hydrocarbons, C10-C13, aromatics, >1% naphthalene) for 24 hours via an occluded patch. Dermal evaluations occurred at 24 hours post patch removal and on days 7 and 14. Exposure had no effect on viability; all animals survived the exposure. It was concluded that the LD50in this situation 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).

 

Based on available data, Hydrocarbons, C10, aromatics, >1% naphthalene has a low order of acute toxicity by the oral, dermal, and inhalation routes of exposure and is not classifiable under EU CLP.

Justification for classification or non-classification

Based on available data, Hydrocarbons, C10, aromatics, >1% naphthalene does not warrant classification as an acute oral, dermal, or inhalation toxicant under the new Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP). On the basis of available physical and chemical property data (hydrocarbon fluid, viscosity ≤ 20.5 mm2/s), Hydrocarbons, C10, aromatics, >1% naphthalene is classified under EU CLP guidelines as a Category 1 aspiration hazard (H304).