Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Sub-acute oral NOAEL = 60 mg/kg bw/d; OECD 407 (equivalent); Plutnick (1985)
Sub-acute dermal NOAEL = 100 mg/kg bw/d; OECD 410 (equivalent); Ward, 1983)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
Charles River Breeding Labs Inc., Lakeview Facility, NJ

- Age at study initiation:
Approximately 10 to 11 weeks

- Weight at study initiation:
Males: 354 - 410 g; Females: 217 - 259 g

- Housing:
Individual during the study (group housed 5/sex/cage during acclimation)

- Diet (e.g. ad libitum):
Purina Certified Rodent Chow (mash) ad libitum

- Water (e.g. ad libitum):
Automatic watering system ad libitum

- Acclimation period:
34 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
Monitored twice daily; maintained range of 68 to 76 degrees Fahrenheit

- Humidity (%):
Monitored twice daily; maintained range to 40 to 70% relative humidity

- Photoperiod (hrs dark / hrs light):
Approximately 12 hourd light and 12 hours dark by automatic timer.

IN-LIFE DATES: From: Day 1 To: Day 30
Route of administration:
other: Oral: syringe and a No. 16 stainless steel ball-tipped feeding needle
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was diluted to a 25% (w/v) solution in vehicle by the Compound Preparation Department. Dose levels were generated based on the results of a Rangefinding Study conducted from August 13th 1984 to September 28th 1984 (not recorded). Fresh dosing solutions were prepared daily during the first week of dosing and weekly thereafter until study termination.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
30 Days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
10 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
30 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
60 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
10 Male, 10 Female per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale:
Dose levels were generated based on the results of a Rangefinding Study conducted from August 13th 1984 to September 28th 1984 (not recorded)
Positive control:
Not applicable
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Clinical observations were made daily for the nature, onset and duration of the toxicological signs throughout the study.

BODY WEIGHT: Yes
- Time schedule for examinations:
Recorded during the week prior to dosing (pretest), at dosing initiation (Day 0), and weekly thereafter, on Monday. Body weights were also recorded at the scheduled sacrifice and at death for animals which succumbed prior to study termination.


HAEMATOLOGY: Yes
- Time schedule for collection of blood:
Blood samples were collected from the abdominal aorta after an overnigh fast (food was removed at approximately 1600 hours on the previous day) on the day of scheduled sacrifice.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: All survivors
- Parameters checked are as follows:
erythrocyte count
haematocrit
haemoglobin
leukocyte count (total and differential (d))
mean corpuscular volume
mean corpuscular haemoglobin
mean corpuscular haemoglobin conentration
platelet count
reticulocyte count (a)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
Blood samples were collected from the abdominal aorta after an overnigh fast (food was removed at approximately 1600 hours on the previous day) on the day of scheduled sacrifice.
- Animals fasted: Yes
- How many animals: All survivors
- Parameters checked are as follows:
albumin
blood urea nitrogen
calcium
cholesterol
creatinine
electrolytes (Na+, K+, Cl-)
gamma glutamyl transpeptidase
glucose
inorganic phosphorus
serum glutamic pryuvic transaminase (c)
total bilrubin
total protein
triglyceride
Sacrifice and pathology:
TERMINATION
After a minimum of 30 days of oral administration of MRD-82-178 all surviving animals were weighed, anesthetized by methoxyfluorane and sacrificed by exsanguination.

NECROPSY:
The necropsy included a physical examination of the external surface, all orifices, the carcass, the cranial cavity, the thoracic, abdominal and pelvic cavities with their associated organs and tissues, and the tissues and organs of the neck.
The following organs were weighed prior to fixation for all animals sacrificed at termination:
adrenals
kidneys
liver
testes

The following tissues and organs were taken and preserved in 10% neutral buffered formalin for all animals:
all gross lesions
liver
kidneys
testes
stomach
jejunum
caecum
rectum
heart
spleen
adrenals
esophagus
duodenum
ileum
colon

Preserved tissues from control and high dose groups were processed, sectioned, stained (hematoxylin and eosin) and mounted on glass slides for histopathological examination to be arranged by the sponsor. Tissues from the low and mid dose groups were processed to the paraffin block stage only.
Other examinations:
Not applicable.
Statistics:
The following parameters were statistically analysed for significant differences:
mean quantitative haematology
mean serum chemistry parameters
mean organ weights
mean organ relative organ weights
mean body weights, by weighing period
mean food consumption
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
A survival bar graph is presented in Table 2 (attached). Nine animals either died or were euthanised prior to study termination; 1 male and 2 females from Group IV, 3 females from Group III, 2 females from Group II and 1 female from Group I. Two of these animals were confirmed as dosing accidents at necropsy.

The incidence of in-life observations is presented in Table 1 (attached). Individual in-life observations are presented in Appendix G (attached).

There was an overall low incidence of clinical in-life observations noted in all groups; however, wet and dry rales were noted at a higher incidence for the treated group animals. Red nasal discharge, dry red nasal discharge, alopecia, truncated tail, red ocular discharge, ataxia, oral discharge, dyspnea, staining of the ano-genital area, urinary staining, hypothermia, small amount of stool, clear ocular discharge, fecal staining, eye partially closed and hypoactivity were also noted in treated and/or control animals with no apparent pattern.

BODY WEIGHT AND WEIGHT GAIN
Individual animal weights by time, sex and dose are presented in Appendix H and the mean values with statistics are presented in Table 3.

There was an increase in mean body weight for all groups over the course of the study. The treated male groups gained weight at the same rate as the controls while the female treated groups gained at a slower rate than the controls. The female Group III mean body weight was significantly different from the controls on Day 7 only.

HAEMATOLOGY
Individual quantitive haematology parameters are presented in Appendix L and the mean haematology parameters with statistics are presented in Table 7. The individual qualitative haematology parameters are presented in Appendix M.

There was slight difference among the haemaglobin means for the groups of males, but this difference was not statistically nor biologically significant. There were no other statistically significant differences between treated and control mean haemotology values.

CLINICAL CHEMISTRY
The individual serum chemistry values are presented in Appendix N and the mean serum chemistry values with statistics is presented in Table 8.

There was a statistical difference among the male group means for inorganic phosphorus, but this difference showed a lack of fit to linear response and was not statistically nor biologically significant. There were no other statistically significant differences noted between the treated and control group mean serum chemistry values.

ORGAN WEIGHTS
Mean organ weights by dose and sex are presented un Table 5 and the mean relative organ weight values are presented in Table 6. Individual animal organ weights are presented in Appendix J with the relative organ weights listed in Appendix K.

There were no significant differences between treated and control male mean organ or relative organ weights nor were there any significant differences between female treated and control mean organ weights. The Group III and IV female mean relative adrenal weights were, however, increased when compared to the control value. This response exhibited a linear relationship to dose, and was statistically significant for Group IV only.

GROSS PATHOLOGY
Individual necropsy observations are presented in Table 9.

The most frequently noted observations at gross necropsy examination were discoloration of the stomach mucosa and dilated renal pelves. Stomach discoloration was noted in 1 control animal and 4 Group IV animals, while dilated renal pelves were not the same control animal, 2 Group II animals and 3 Group IV animals. Abnormalities of gastro-intestinal tract (esophagus, stomach, ileum and jejunum) were also noted more frequently than other observations, notably in the treated groups animals which died prior to study termination.
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; haematology and clinical chemistry.
Critical effects observed:
not specified
Conclusions:
The objective of this study was to evaluate the effects of MRD-82 -178 when administered by the oral route, via gavage, daily, for a minimum of 30 days.
The NOAEL was found to be 60 mg/kg/day.
Executive summary:

The objective of this study was to evaluate the effects of MRD-82 -178 when administered by the oral route, via gavage, daily, for a minimum of 30 days. Eighty Sprangue-Dawley rats were divided in 4 groups of 10 males and 10 females each. Dose levels were generated based on the results of the Rangefinding Study conducted prior to study initiation. Group I was used as a control which received vehicle only. Groups II, III and IV received doses of 10, 30 and 60 mg/kg of MRD-82 -178, respectively.

Observations were made as to the nature, onset, severity and duration of toxicological signs daily for the duration of the study. Body weights were recorded prior to dosing, at dosing initiationm and weekly thereafter during the test period. Body weights were also recorded at death for animals which succumbed prior to study termination. Food consumpotion was measured weekly. Serum chemistry and haemotology studies were performed on all surviving animals at termination.

After at least 30 days of oral administration of MRD-82 -178, all surviving animals were weighed, anesthetised by methoxyfluorane, and blood samples collected from the abdominal aorta; animals were killed by exsanguination. Necropsies were performed and required organs and tissues were collected and weighed.

Nine animals died prior to study termination; two of these animals were confirmed at necropsy as dosing accidents.

There was an overall low incidence of clinical in-life observations noted in the treated and control groups. However, rales and emaciation were noted at a slightly higher incidence for treated group animals than for control group animals.

There were no significant differences noted between male control and treated mean animal weights or mean food consumption during the study. The female treated group animals appeared to gain weight at a lower rate than the controls. The Group III female body weights on Day 7 were significantly less than the control group. The mean food consumption values for the treated females were also less than the control values. This decrease was statistically significant for the Week 1 food consumption interval.

There was no statistically nor biologically significant differences in mean haemotology or serum chemistry values between the treated and control groups. There were no significant differences in male organ weight or relative organ weight mean values between the treated and control groups. The mean femal organ weight values showed no differences between the treated and control groups. However, the Group II and IV female mean relatice adrenal weights were increased when compared to the control value. This response was linearly related to dose, and was statistically significant for Group IV only.

Gross postmortem examination revealed a slightly higher incidence of discolouration of the stomach mucosa and dilate renal pelvis in the high dose animals when compared to controls. Gastro-intestinal tract abnormalities were also limited to animals in the treated groups.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Dosing inititated: January 24 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dutchland Laboratories, Incorporated, Denver, PA
- Age at study initiation: Approx 16 weeks
- Weight at study initiation: 2.98 - 4.06 kg
- Housing: Individual stainless steel cage
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow (pellets), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 Days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65 to 71 degrees Fahrenheit
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark


Type of coverage:
not specified
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: 10 x 20 cm
- Type of wrap if used: surgical tape and guaze.
- Time intervals for shavings or clipplings: Twice per week.



TEST MATERIAL
Test dilutions were prepared weekly by diluting the appropriate amounts of substance with distilled water. The volume of dosing solution applied to each animal was 2 ml/kg.




USE OF RESTRAINERS FOR PREVENTING INGESTION: Elizabethan-type collars.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
5 days per week for at least 4 weeks. Male rabbits received a total of 21 applications and females 22 applications.
Frequency of treatment:
The test material was applied directly to the gauze 5 days per week.
Remarks:
Doses / Concentrations:
0% (w/v)
Basis:
other: control group
Remarks:
Doses / Concentrations:
1.0% (w/v)
Basis:
analytical per unit area
Remarks:
Doses / Concentrations:
5.0% (w/v)
Basis:
analytical per unit area
No. of animals per sex per dose:
10 males and 10 females per group.
Dose group I = 0%
Dose group II = 1.0%
Dose group III = 5.0%
Control animals:
yes, concurrent vehicle
Details on study design:
Doses determined by preliminary study.

Animals determined to be unsutiable for inclusion on this study because of poor health, outlying body weights or other abnormalities were excluded from selection.
Positive control:
No.
Observations and examinations performed and frequency:
Each animal was observed daily during the 4 week dosing period for dermal and systemic toxicological responses. Clinical laboratory studies were conducted on blood samples collected pretest and at termination.
Sacrifice and pathology:
Gross necropsies were performed and specific organs retained.
Statistics:
The following parameters were statistically analyzed for significant differences.
- mean terminal hematology parameters.
- mean terminal clinical chemistry parameters.
- mean organ weights.
- mean organ to body weight ratio's.
- mean body weights, by weighing period.
- mean food consumption.
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Dermal irritation: The incidence and severity of dermal irritation increased with dose. Mild dermal irritation was observed in many of the low dose group animals. Irritation was more severe in the high dose groups.

Supplemental dermal observations of desquamation, necrosis and eschar were noted in several animals of the high dose group.

In-life observations: Four animals died prior to termination of the study. One Group I male was sacrificed for humane reasons on Day 21, and 1 female of group I was found dead on Day 29. 2 Group III males were found dead on Day 5 and on Day 28 respectively.

Food consumption: There were no treatment related effects on food consumption patterns.

Body weights: Mean body weights for all groups increased over the course of the study.

Hematology parameters: There were statistically significant differences from control in the Group III male MCH, Group II female platelet and Group II female MCHC values. It is unlikely that these differences are biologically significant.

Clinical Chemistry parameters: There were statistically significant differences from control noted in Group II male and female total blirubin, Group III female alkaline phosphatase, Group III male chloride and Group III female calcium values. The decreased calcium mean is attritutable to 1 abnormally low female value; the other mean values fall within the normal biological range for these parameters.

Necropsy Observations: The most common findings observed during gross postmortem examination were renel and pulmonary discolourations. The incidence of these findings was similar in all 3 groups and not considered treatment related.

Organ weights: A statistically elevation in mean adrenal gland weight and mean adrenal to body weight ratio was noted in Group II and III males.





Dose descriptor:
dose level: 5.0% w/v
Effect level:
1 - 5 other: % w/v dose of substance causing dermal irritation.
Sex:
male/female
Basis for effect level:
other: By study termination, 5.0% test substance had elicited moderate to severe irritation in the females but only mild irritation in the majority of males.
Critical effects observed:
not specified
Conclusions:
With the exception of primary dermal irritation, topical adminstration of the test substance at 2 concentrations to male and female rabbits for a period of approximately 4 weeks did not appear to produce toxicological change in the parameters and organs examined, which could unequivocally be related to treatment.
Executive summary:

The objective of this study was to evaluate the dermal irritation potential and systemic toxicity of 2 concentrations of test material MRD-82 -178 following repeated topical application. The material was applied to the dorsal surface of rabbits 5 days per week for at least 4 weeks. 60 New Zealand White rabbits were divided into 3 groups of 10 males and 10 females each. Group I was used as a control. Groups II and III received 2 ml/kg administrations of 1.0 and 5.0% (w/v) test substance. Each animal was observed daily for dermal and systemic toxicological responses. Clinical laboratory studies were conducted on blood samples collected pre-test and at termination. Gross necropsies were performed and specific organs retained.

Four animals died prior to study termination: 1 male and 1 female in the control group and 2 males in the high dose group.

The incidence and severity of dermal irritation increased with dose. By study termination, 5.0% test substance had elicited moderate to severe irritation in the females but only mild irritation in the majority of males.

There was an overall low incidence of in-life observations noted in all 3 groups, with none appearing to be treatment related. There were no treatment related effects on food consumption patterns. Mean body weights for all groups increased over the course of the study.

Statistically significant differences were noted in a small number of mean terminal hematology and clinical chemistry values. It is unlikely that any of these differences are biologically significant.

A review of the in-life, clinical laboratory and gross necropsy findings did not reveal any significant signs of toxicity, other than primary irritation, which could be directly attributed to the administration of MRD-82 -178.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Dosing inititated: January 24 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dutchland Laboratories, Incorporated, Denver, PA
- Age at study initiation: Approx 16 weeks
- Weight at study initiation: 2.98 - 4.06 kg
- Housing: Individual stainless steel cage
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow (pellets), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 Days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65 to 71 degrees Fahrenheit
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark


Type of coverage:
not specified
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: 10 x 20 cm
- Type of wrap if used: surgical tape and guaze.
- Time intervals for shavings or clipplings: Twice per week.



TEST MATERIAL
Test dilutions were prepared weekly by diluting the appropriate amounts of substance with distilled water. The volume of dosing solution applied to each animal was 2 ml/kg.




USE OF RESTRAINERS FOR PREVENTING INGESTION: Elizabethan-type collars.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
5 days per week for at least 4 weeks. Male rabbits received a total of 21 applications and females 22 applications.
Frequency of treatment:
The test material was applied directly to the gauze 5 days per week.
Remarks:
Doses / Concentrations:
0% (w/v)
Basis:
other: control group
Remarks:
Doses / Concentrations:
1.0% (w/v)
Basis:
analytical per unit area
Remarks:
Doses / Concentrations:
5.0% (w/v)
Basis:
analytical per unit area
No. of animals per sex per dose:
10 males and 10 females per group.
Dose group I = 0%
Dose group II = 1.0%
Dose group III = 5.0%
Control animals:
yes, concurrent vehicle
Details on study design:
Doses determined by preliminary study.

Animals determined to be unsutiable for inclusion on this study because of poor health, outlying body weights or other abnormalities were excluded from selection.
Positive control:
No.
Observations and examinations performed and frequency:
Each animal was observed daily during the 4 week dosing period for dermal and systemic toxicological responses. Clinical laboratory studies were conducted on blood samples collected pretest and at termination.
Sacrifice and pathology:
Gross necropsies were performed and specific organs retained.
Statistics:
The following parameters were statistically analyzed for significant differences.
- mean terminal hematology parameters.
- mean terminal clinical chemistry parameters.
- mean organ weights.
- mean organ to body weight ratio's.
- mean body weights, by weighing period.
- mean food consumption.
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Dermal irritation: The incidence and severity of dermal irritation increased with dose. Mild dermal irritation was observed in many of the low dose group animals. Irritation was more severe in the high dose groups.

Supplemental dermal observations of desquamation, necrosis and eschar were noted in several animals of the high dose group.

In-life observations: Four animals died prior to termination of the study. One Group I male was sacrificed for humane reasons on Day 21, and 1 female of group I was found dead on Day 29. 2 Group III males were found dead on Day 5 and on Day 28 respectively.

Food consumption: There were no treatment related effects on food consumption patterns.

Body weights: Mean body weights for all groups increased over the course of the study.

Hematology parameters: There were statistically significant differences from control in the Group III male MCH, Group II female platelet and Group II female MCHC values. It is unlikely that these differences are biologically significant.

Clinical Chemistry parameters: There were statistically significant differences from control noted in Group II male and female total blirubin, Group III female alkaline phosphatase, Group III male chloride and Group III female calcium values. The decreased calcium mean is attritutable to 1 abnormally low female value; the other mean values fall within the normal biological range for these parameters.

Necropsy Observations: The most common findings observed during gross postmortem examination were renel and pulmonary discolourations. The incidence of these findings was similar in all 3 groups and not considered treatment related.

Organ weights: A statistically elevation in mean adrenal gland weight and mean adrenal to body weight ratio was noted in Group II and III males.





Dose descriptor:
dose level: 5.0% w/v
Effect level:
1 - 5 other: % w/v dose of substance causing dermal irritation.
Sex:
male/female
Basis for effect level:
other: By study termination, 5.0% test substance had elicited moderate to severe irritation in the females but only mild irritation in the majority of males.
Critical effects observed:
not specified
Conclusions:
With the exception of primary dermal irritation, topical adminstration of the test substance at 2 concentrations to male and female rabbits for a period of approximately 4 weeks did not appear to produce toxicological change in the parameters and organs examined, which could unequivocally be related to treatment.
Executive summary:

The objective of this study was to evaluate the dermal irritation potential and systemic toxicity of 2 concentrations of test material MRD-82 -178 following repeated topical application. The material was applied to the dorsal surface of rabbits 5 days per week for at least 4 weeks. 60 New Zealand White rabbits were divided into 3 groups of 10 males and 10 females each. Group I was used as a control. Groups II and III received 2 ml/kg administrations of 1.0 and 5.0% (w/v) test substance. Each animal was observed daily for dermal and systemic toxicological responses. Clinical laboratory studies were conducted on blood samples collected pre-test and at termination. Gross necropsies were performed and specific organs retained.

Four animals died prior to study termination: 1 male and 1 female in the control group and 2 males in the high dose group.

The incidence and severity of dermal irritation increased with dose. By study termination, 5.0% test substance had elicited moderate to severe irritation in the females but only mild irritation in the majority of males.

There was an overall low incidence of in-life observations noted in all 3 groups, with none appearing to be treatment related. There were no treatment related effects on food consumption patterns. Mean body weights for all groups increased over the course of the study.

Statistically significant differences were noted in a small number of mean terminal hematology and clinical chemistry values. It is unlikely that any of these differences are biologically significant.

A review of the in-life, clinical laboratory and gross necropsy findings did not reveal any significant signs of toxicity, other than primary irritation, which could be directly attributed to the administration of MRD-82 -178.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subacute
Species:
rabbit

Additional information

In a study conducted using an equivalent method to OECD 407, the effect of the substance following 30 days of repeated oral exposure to Sprague Dawley rats was evaluated.

There was an overall low incidence of clinical in-life observations noted in the treated and control groups. However, rales and emaciation were noted at a slightly higher incidence for treated group animals than for control group animals.

There were no significant differences noted between male control and treated mean animal weights or mean food consumption during the study. The female treated group animals appeared to gain weight at a lower rate than the controls. The Group III female body weights on Day 7 were significantly less than the control group. The mean food consumption values for the treated females were also less than the control values. This decrease was statistically significant for the Week 1 food consumption interval.

There was no statistically nor biologically significant differences in mean haemotology or serum chemistry values between the treated and control groups. There were no significant differences in male organ weight or relative organ weight mean values between the treated and control groups. The mean femal organ weight values showed no differences between the treated and control groups. However, the Group II and IV female mean relatice adrenal weights were increased when compared to the control value. This response was linearly related to dose, and was statistically significant for Group IV only.

Gross postmortem examination revealed a slightly higher incidence of discolouration of the stomach mucosa and dilate renal pelvis in the high dose animals when compared to controls. Gastro-intestinal tract abnormalities were also limited to animals in the treated groups.

In a study conducted using a method equivalent to OECD 410, the effects of the substance following repeated dermal exposure to New Zealand white rabbits was evaluated. Two concentrations of the substance were applied to the dorsal surface of rabbits 5 days per week for at least 4 weeks. Four animals died prior to study termination: 1 male and 1 female in the control group and 2 males in the high dose group.

There was an overall low incidence of in-life observations noted in all 3 groups, with none appearing to be treatment related. There were no treatment related effects on food consumption patterns. Mean body weights for all groups increased over the course of the study. Statistically significant differences were noted in a small number of mean terminal hematology and clinical chemistry values. It is unlikely that any of these differences are biologically significant. A review of the in-life, clinical laboratory and gross necropsy findings did not reveal any significant signs of toxicity, other than primary irritation, which could be directly attributed to the administration of the substance.

The two studies submitted allowed for a sub-acute oral NOAEL of 60 mg/kg bw/d, and a sub-acute dermal NOAEL of >100 mg/kg bw/d to be determined for use in chemical safety assessment.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study for endpoint.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Key study for endpoint.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Key study for endpoint. Primary dermal irritation noted in study, but no effect level was able to be determined.

Justification for classification or non-classification

The substance does not meet the criteria for classification related to STOT RE.