Desmedipham

Endpoint summary

Description of key information

Acute oral toxicity

The key rat study reports an acute oral LD₅₀ for desmedipham of >2000 mg/kg bw.  A supporting mouse study reports an acute oral LD₅₀ for desmedipham of >3500 mg/kg bw.  A supporting rat study reports an acute oral LD₅₀ for desmedipham of >5000 mg/kg bw.  The studies show that desmedipham is not classified for acute oral toxicity in any category according to CLP.

Test method/  species	Result	Assessment	Reference
Not stated (pre-guideline); comparable to OECD 401 -	No mortality or clinical signs reported in this mouse study at 5000 mg/kg bw	The study is inadequately reported.  The test procedures, stability of the test material, raw data on body weights, clinical signs and necropsy findings were not included in the report.	Schöbel and Siegmund (1975)
OECD 401 (Limit Test) - Mouse study	One mortality (0/5M, 1/5F) reported in this mouse study at 3500 mg/kg bw; clinical signs limited to the decedent mouse	Supporting study	Davies (1990)
OECD 401 (Limit Test) - Rat study	No mortality but some clinical signs reported in this rat study at 5000 mg/kg bw	Supporting study	Ullmann and Sacher (1984)
OECD 401 (Limit Test) - Rat study	No mortality or clinical signs reported in this rat study at 2000 mg/kg bw	Key study	Cuthbert and Jackson (1990)

Acute inhalation toxicity

The key rat study reports an acute (4-hour, nose-only) inhalation LC₅₀ for desmedipham of >7.4 mg/L.  The study shows that desmedipham is not classified for acute inhalation toxicity in any category according to CLP.

Test method/  species	Result	Assessment	Reference
Not specified.	No animals were exposed due to technical difficulties in generating a test atmosphere	The study is invalid due to technical difficulties in generating a suitable test atmosphere.  Consequently, no animals were exposed.	McDonald (1991)
OECD 403 - Rat study	No deaths or clinical signs reported in rats exposed nose-only for four hours to atmospheres containing desmedipham at 5.7 or 7.4 mg/L (measured concentrations).	Key study	Thévenaz (1990)

Acute dermal toxicity

The key rat study reports an acute dermal LD₅₀ for desmedipham of >2000 mg/kg bw.  The supporting rabbit study reports an acute dermal LD₅₀ for desmedipham of >4000 mg/kg bw.  The studies show that desmedipham is not classified for acute dermal toxicity in any category according to CLP.

Test method/  species	Result	Assessment	Reference
Not stated (pre-guideline); comparable to OECD 402 - Rabbit study: limited reliability (only 3/sex)	No mortality or clinical signs reported in this rabbit study at 4000 mg/kg bw	Supporting study	Ullmann and Suter (1984)
OECD 402 - Rat study	No mortality or clinical signs reported in this rat study at 2000 mg/kg bw	Key study	Cuthbert and Jackson (1991)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1990-03-06 to 1990-09-26

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Study in the mouse

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

the test animals were not fasted prior to dosing

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 36-day old male and 43-day old female
- Weight at study initiation: body weights ranged from 26.9 g to 33.1 g for males and 22.4 g to 26.9 g for females.
- Fasting period before study: Not done.
- Housing: Mice were housed by sex and dose level in polycarbonate cages with quality controlled wood shavings as bedding
- Diet: Modified Expanded Rat and Mouse Diet No. 1, free access
- Water: tap water, free access
- Acclimation period: 1 day before randomisation and 13 days after.
- Method of randomisation in assigning animals to test and control groups: Following 1 day of acclimatisation, mice were weighed and allocated into 2 groups of 5 males and 2 groups of 5 females, (a total of 20 animals) on the basis of body weight so that each group had similar initial mean body weights and weight distributions. Each animal was then individually identified by ear marks.

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C to 22°C
- Humidity: 48% to 62%.
- Air changes (per hr): 15
- Photoperiod: 12-hour photo-period from 0730h to 1930h

Route of administration:

oral: gavage

Vehicle:

other: methyl cellulose in distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.25% (w/v) methyl cellulose in distilled water
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

0 (control) and 3500 mg/kg/bw

No. of animals per sex per dose:

5/sex/group

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs and mortality:
Animals were observed frequently on the day of treatment, at least once each morning and afternoon on working days thereafter, and at least once each other day for 14 days. Behaviour (including aggression, excitability and response to sound), coordination and reflexes, were assessed daily by observing interaction of the mice with the observer and with each other. The times of onset and recovery of all clinical signs were recorded wherever possible.

Body weights were recorded at receipt, randomisation, immediately prior to treatment and on 7 and 14 days after dosing.

- Necropsy of survivors performed: yes
Surviving animals were killed by carbon dioxide asphyxiation, 14 days after treatment. Animals killed in extremis and those surviving to termination were subjected to gross post-mortem examination for external abnormalities and for abnormalities of the thoracic and abdominal viscera.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: One mortality at 3500 mg/kg bw

Mortality:

One female mouse was killed in extremis 5 days after being dosed with 3500 mg/kg/bw. The decedent female mouse had laboured respiration and was comatose and cool to touch on the day the animal was killed.

Clinical signs:

other: other: No effects

Body weight:

other body weight observations

Gross pathology:

No abnormalities were detected at terminal necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of desmedipham in male and female mice was >3500 mg/kg/bw under the conditions of this study.

Executive summary:

The purpose of this study was to determine the acute oral toxicity of desmedipham to the mouse.  Groups of five male and five female mice received a single oral dose by gavage of either 0 or 3500 mg/kg bw suspended in 0.25% w/v methyl cellulose in distilled water. Animals were observed for 14 days after treatment and then examined post-mortem. There was one mortality and no significant clinical signs were observed. Body weight was unaffected. At terminal necropsy no abnormalities were detected. The acute oral LD₅₀ of desmedipham in male and female CD-1 mouse was therefore >3500 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1984-03-12 to 1984-05-21

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Remarks:

Older study, predates mandatory GLP

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Han, outbred, SPF-quality

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: males: 220 - 236 g, females: 176 - 186 g
- Fasting period before study: 12 to 18 hours
- Housing: Groups of five in Makrolon type-3 cages with standard softwood bedding
- Diet: Pelleted standard rat maintenance diet available ad libitum.
- Water: Community tap water from, available ad libitum.
- Acclimation period: One week
- Method of randomisation in assigning animals to test and control groups: Computer-generated random algorithm.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): 10-15
- Photoperiod: 12 hours artificial fluorescent light/12 hours dark, at least 8 hours music/light period.

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 400

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 20 mL/kg bw

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 22 days
- Frequency of observations and weighing:
Mortality / Viability: Four times during test day 1, and daily during days 2-22.
Body Weights: Test days 1 (pre-administration), 8, 15 and 22.
Symptoms: Each animal was examined for changes in appearance and behavior four times during day 1, and daily during days 2-22.
All abnormalities were recorded.
- Necropsy of survivors performed: yes
Necropsies were performed by experienced prosectors supervised by a pathologist.
All animals were anesthetized by intraperitoneal injection of sodium pentobarbital and killed by exsanguination.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality at 5000 mg/kg bw

Mortality:

There were no deaths

Clinical signs:

other: other:

Gross pathology:

At terminal necropsy no macroscopic abnormalities were detected.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of desmedipham in male and female rats was found to be >5000 mg/kg/bw under the conditions of this study. Desmedipham does not therefore require classification for acute oral toxicity in any category according to CLP.

Executive summary:

The test article DESMEDIPHAM, was administered to rats of both sexes by oral gavage, at a dose of 5000 mg/kg. The following death rate was observed: 0% at 5000 mg/kg.  The acute oral LD₅₀ of DESMEDIPHAM in rats of both sexes, observed over a period of 22 days, was estimated to be greater than 5000 mg/kg bw.  Desmedipham does not therefore require classification for acute oral toxicity in any category according to CLP.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990 -11-08 to 1991-03-18

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

The test material, a white powder, was stored in the dark under ambient conditions.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adults, 6-8 weeks.
- Weight at study initiation: 149-171 g.
- Fasting period before study: 18 h before dosing
- Housing: The rats were housed by sex in polypropylene cages with mesh floors suspended over absorbent paper lined trays with a maximum of 5 animals per cage.
- Diet: Rat and Mouse No. 1 Diet.
- Water: ad libitum.
- Acclimation period: 7 days.
The diet and water are analysed on a regular basis.

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 21°C
- Humidity: 50%
- Photoperiod: 12 h light/dark (light hours 0700-1900 h)

The rats were uniquely identified within the study using an ear punch system.

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5% aqueous CMC

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION:
On the day of dosing, Desmedipham was freshly prepared in 0.5% CMC at a concentration of 200 mg/mL

Doses:

Single dose of 2000 mg/kg bw

No. of animals per sex per dose:

5/sex

Control animals:

no

Remarks:

Not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed frequently on the day of dosing and once daily for 14 days following dosing. They were weighed immediately prior to dosing, 7 days after dosing and at sacrifice at the end of the 14 day observation period.
- Necropsy of survivors performed: yes, at the end of the observation period and sacrifice by carbon dioxide asphyxiation, each animal was subjected to necropsy.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths at the limit dose

Mortality:

No mortality was observed

Clinical signs:

other: other:

Body weight:

other body weight observations

Gross pathology:

No abnormalities detected

Table 1: Desmedipham: Acute Oral Toxicity (Limit) Test in Rats Test Results 2000 mg/kg bw

Sex	Animal	Mortality	Clinical signs	Necropsy Findings
Males	1 2 3 4 5	0/5	NAD NAD NAD NAD NAD	NAD NAD NAD NAD NAD
Females	6 7 8 9 10	0/5	NAD NAD NAD NAD NAD	NAD NAD NAD NAD NAD

NAD = No abnormalities detected

 

Table 2: Desmedipham: Acute Oral Toxicity (Limit) Test in Rats Body Weights 2000 mg/kg bw

Sex	Animal	Body weight (g)
		At Dosing	After 7 days	After 14 days	Gain (Loss)
Males	1 2 3 4 5	159 171 163 163 156	220 239 231 240 213	265 275 280 270 245	106 104 117 107 89
	Mean ± S.D.	162 6	229 12	267 14	105 10
Females	6 7 8 9 10	151 149 158 152 156	195 194 205 190 199	209 211 215 201 217	58 62 57 49 61
	Mean ± S.D.	153 4	197 6	211 6	57 5

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of desmedipham was >2000 mg/kg/bw in male and female rats under the conditions of this study. Desmedipham does not require classification for oral acute toxicity in any category according to the CLP criteria.

Executive summary:

The acute oral toxicity potential of Desmedipham, was investigated in rats. The vehicle for the dosing solution was 0.5% carboxymethylcellulose (CMC).  There were no deaths following a single orally administered dose of Desmedipham at the limit dose level of 2000 mg/kg bw to a group of 5 male and 5 female rats. No clinical signs or necropsy findings were noted.  The Median Oral Lethal Dose (LD₅₀) of Desmedipham in male and female rats is greater than 2000 mg/kg bw.  Desmedipham does not require classification for oral acute toxicity in any category according to the CLP criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The key rat study (K1) was performed to GLP and OECD 401. A supporting mouse study (K2) was performed to GLP and OECD 401. A supporting rat study (K2) was performed to OECD 401 but not GLP.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-04-18 to 1990-08-01

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

Deviations:

yes

Remarks:

The number of exposure concentrations was insuffient with only two dose levels being applied instead of three, and there was no control group.

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

yes

Remarks:

The number of exposure concentrations was insuffient with only two dose levels being applied instead of three, and there was no control group.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Version / remarks:

November 1982; Revised Edition, November 1984.

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

other: Agricultural Chemicals Laws and Regulations, Japan 1984

Version / remarks:

Society of Agricultural Chemical Industry. Plant Protection Division, Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries: "Guidance on Toxicology Study Data for Application of Agricultural Chemical Registration", January 28, 1985.

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

no

Specific details on test material used for the study:

White to light beige powder

Species:

rat

Strain:

Wistar

Remarks:

Albino Wistar rat, Han, (outbred), SPF quality.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Males : 8-10 weeks, Females : 10 - 12 weeks.
- Weight at delivery: Males : 181 - 199 g, Females : 181 - 200 g.
- Housing: Animals were housed in groups of five in Makrolon type-4 cages with standard softwood bedding.
- Diet: Pelleted standard rat maintenance diet ad libitum.
- Water: Community tap water, ad libitum.
- Acclimation period: 9 days (group 1) and 14 days (group 2) under laboratory conditions after clinical health examination.
- Method of randomisation in assigning animals to test and control groups: Randomly selected at time of delivery in groups of five, by computer-generated random algorithm.
- Identification: By unique cage number and individual markings with picric acid.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 30-70%
- Air changes: 10-15 air changes per hour.
- Photoperiod: 12 hours artificial fluorescent light and 12 hours dark period. Music was broadcasted during the major part of the light period.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

<= 3 µm

Remark on MMAD/GSD:

GSD not reported; MMAD adequately small with particle size analysis reporting ~50% in the respirable range.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: This system is constructed of anodized aluminium and readily accepts a variety of different sized Makrolon animal restraint tubes which have been designed in consideration of the anatomy and physiology of the rodent. The test article stream reaches the animal's nose through ports situated at different levels around the axis of the exposure chamber. Each level has 8 ports and can be rotated, allowing close observation of all the animals without interruption of exposure.
- Exposure chamber volume: 1 Liter
- Method of holding animals in test chamber: The animals were confined separately in tubes which are positioned radially around the exposure chamber.
- Source and rate of air (airflow): 1.7 L air/animal/minute.
- System of generating particulates/aerosols: piston/brush-feed aerosol generator feeding a micronizing jet mill.
- Method of particle size determination: Mercer 7 stage cascade impactor.
- Temperature and humidity in air chamber: The relative humidity and temperature were determined every thirty minutes during each exposure using a HMI 12.
Temperature: Group 1: 18.8-20.1, Group 2: 19.6-21.5; Humidity: Group1: 13.1-18.5, Group 2: 14.9-17.6.


TEST ATMOSPHERE
- Brief description of analytical method and equipment used (Gravimetric Determination of Concentration): The test article, sampled from the exposure unit was collected on 47 mm diameter glass fiber filters using a stainless steel filter sampling device. The relative aerosol concentration was monitored using a RAM-1 light scattering type aerosol monitor. Four gravimetric determinations were performed at each concentration.
- Samples taken from breathing zone: yes
- Particle size distribution: The particle size of the test atmosphere was determined using a Mercer 7 stage cascade impactor.
The test atmosphere was impacted at each stage onto stainless steel slips which were weighed before and after sampling. The airflow rate through the impactor was 1.0 L/min. Two determinations of particle size distribution were performed during each exposure.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Concentrations (mg/L air) in Gravimetric (means):
Group 1: 5.7, Group 2: 7.4

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Clinical observations:
Mortality : Once per hour during exposure, once after exposure on test day 1, and twice daily thereafter.
Body Weights : On days 1 (before exposure), 8 and 15 of test.
Clinical Signs : Once per hour during exposure (only grossly abnormal signs, due to the animals being in restraint tubes), once after exposure and at least once daily thereafter.
- Other examinations performed:
PATHOLOGY:
Necropsy:
Necropsies were performed by experienced prosectors under the management of a pathologist. All animals were anesthetized with an intraperitoneal injection of sodium pentobarbital and sacrificed by exsanguination. All macroscopic changes or abnormalities were described and recorded. The lungs, trachea and larynx were collected from all animals and fixed in a neutral phosphate buffered 4% formaldehyde solution.

Statistics:

The LOGIT-Model could not be applied since no deaths occurred. The toxicity was estimated without the use of a statistical model.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

>= 7.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No deaths occurred at the tested concentrations of 5.7 and 7.4 mg/L air.

Clinical signs:

other: No clinical signs were observed.

Body weight:

The mean body weight values recorded in animals of both sexes were unremarkable. No treatment-related effects on body weight were observed. The slight weight decrease observed in one female from group 1 (5.7 mg/L) during the first observation week was considered to be incidental, since no similar change occurred at the highest concentration level, and since otherwise no adverse effects were seen in any animal.

Gross pathology:

No gross macroscopical changes were found at terminal necropsy.

Table 1: EXPOSURE CONDITIONS

Group	Mean Gravimetric Concentration (mg/L air)		Mean % of Particles <3 µm*	Temperature (°C)	Relative Humidity (rh %)	Oxygen Concentration (vol %)
	Administered	Respirable**
1 2	5.7 7.4	3.1 4.4	55.0 59.4	18.8-20.1 19.6-21.5	13.1-18.5 14.9-17.6	20.9 20.9

* Mean percentage of particles collected on 3 μm (mass median aerodynamic diameter) or less, stage of the impactor.
** Particles with an aerodynamic diameter of 3 μm or less are considered to be respirable by rodents, i.e. to reach the lung terminal airways and alveoles.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation LC50 of desmedipham in male and female rats was found to be >7.4 mg/L under the conditions of this study. Desmedipham does not require classification for acute inhalation toxicity in any category according to CLP.

Executive summary:

The purpose of this study was to evaluate the acute toxicity of DESMEDIPHAM when administered to rats by inhalation. The protocol for this study was based on recommendations by the OECD, US-EPA and Japanese-MAFF test guidelines and performed according to GLP. Wistar rats (5 males and 5 females) per group were exposed to DESMEDIPHAM during a single four-hour period via the inhalation route at measured (gravimetric) concentrations of 5.7 and 7.4 mg/L. Clinical signs and mortality were noted during and following each exposure over a 15-day observation period. Body weights were recorded prior to each exposure and weekly thereafter. All animals were necropsied and all gross macroscopical changes were recorded.  No deaths occurred at the tested concentrations of 5.7 and 7.4 mg/L.  Desmedipham had no treatment-related effects on body weight were observed. In addition, no clinical signs were observed and no gross macroscopical changes were found at terminal necropsy.  The acute inhalation LC₅₀ of desmedipham in male and female rats was found to be >7.4 mg/L under the conditions of this study. Desmedipham does not require classification for acute inhalation toxicity in any category according to CLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 7.4 mg/L air

Physical form:

inhalation: dust

Quality of whole database:

The key rat study (K2) was performed to GLP and OECD 403 with acceptable deviations.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-10-25 to 1991-03-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Five male and 5 female nulliparous and non-pregnant young adult rats of the Sprague-Dawley strain were used. They were 8-10 weeks old and weighed 215-273 g at dosing. The rats were housed by sex in polypropylene cages with mesh floors suspended over absorbent paper lined trays with a maximum of 5 animals per cage. The rats were fed Rat and Mouse No. 1 Diet. Food and tap water were available ad libitum throughout the study. The diet and water are analysed on a regular basis and meet the laboratory's criteria. Mean environmental maximum and minimum temperatures were 21°C and 19°C and mean relative humidity was 50%. A 12 h light/dark cycle was in operation (light hours 0700-1900 h). The rats were allowed an acclimatisation period of 7 days before test commencement.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

A group of 5 male and 5 female rats was prepared by clipping the backs free of hair, approximately 24 hours before application of the test material. Care was taken to avoid abrading the skin. Desmedipham was administered dermally in a single application under occlusion at a dose level of 2000 mg/kg bw. The test material was applied evenly onto a gauze dressing which was applied to the shaved back of each rat. At least 10% of the body surface was in contact with the test material. The trunk of the rat was then encircled with a strip of non-irritating tape. After a contact period of 24 hours following dosing the dressing was removed and the skin wiped with a water dampened tissue to remove excess test material.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Remarks:

Not required for this study type

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Observed daily. Weighed 3 times: prior to dosing, 7 days after dosing and 14 days after dosing.
- Necropsy of survivors performed: yes

Statistics:

Not specified.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortality observed at the limit dose of 2000 mg/kg bw

Mortality:

None

Clinical signs:

other: other:

Body weight:

other body weight observations

Gross pathology:

There were no effects of treatment

Table 1: Desmedipham: Acute Dermal Toxicity (Limit) Test in Rats, Test Results: Mortality

Animal/Sex	Mortality	Clinical signs	Necropsy findings
11 (M)	0/5	NAD	NAD
12		NAD	NAD
13		NAD	NAD
14		NAD	NAD
15		NAD	NAD
16 (F)	0/5	NAD	NAD
17		NAD	NAD
18		NAD	NAD
19		NAD	NAD
20		NAD	NAD

 

Table 2: Desmedipham: Acute Dermal Toxicity (Limit) Test in Rats, Test Results: Body weight

Animal/Sex	Body Weight (g)
	At Dosing	After 7 Days	After 14 Days	Gain (Loss)
11 (M)	266	305	328	62
12	272	304	337	65
13	264	301	329	65
14	273	305	332	59
15	272	320	351	79
Mean	269	307	335	66
± S.D.	4	7	9	8
16 (F)	215	229	229	14
17	236	252	276	40
18	253	260	290	37
19	238	260	280	42
20	224	241	249	25
Mean	233	248	265	32
± S.D.	14	13	25	12

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 of desmedipham in the rat was found to be >2000 mg/kg bw under the conditions of this study. Desmedipham does not therefore require classification for acute dermal toxicity in any category according to the CLP criteria.

Executive summary:

The acute dermal toxicity potential of Desmedipham, was investigated in rats.  No deaths occurred and no clinical signs were noted after a 24 hour dermal administration, under occlusion, of Desmedipham at a dose level of 2000 mg/kg bw.  No abnormalities were detected at necropsy.  The acute dermal LD₅₀ of desmedipham in the rat was found to be >2000 mg/kg bw under the conditions of this study. Desmedipham does not therefore require classification for acute dermal toxicity in any category according to the CLP criteria.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1984-03-26 to 1984-06-15

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Limitations: there were less than the required 5 animals/sex. The study is relevant for the hazard assessment

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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:

Total number of animals: 3 males and 3 females
Age: 15 - 16 weeks
Body weight at start of treatment: males (2.3 - 2.6 kg); females (2.8 - 2.9 kg)
Identification: By unique cage number and individual ear tags.
Randomization: Due to the small number of animals, no randomization was performed.
Acclimation: One week under laboratory conditions after veterinary examination.

Standard Laboratory Conditions:
air-conditioned with 10-15 air changes per hour, and hourly monitored environment with temperature 22±2 degrees centigrade, relative humidity 55±10%, 12 hours artificial fluorescent light/12 hours dark, at least 8 hours music/light period.
Accommodation: Individually in stainless steel cages equipped with an automatic cleaning and drinking system.
Diet: Pelleted standard was available ad libitum.
Water: Community tap water was available ad libitum.

Type of coverage:

occlusive

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2%

Details on dermal exposure:

Desmedipham technical was applied at a dose of 4000 mg/kg bw on the skin of 3 male and 3 female New Zealand White rabbits. A weight by weight dilution of test substance and 2% carboxymethyl cellulose in distilled water was prepared and applied in a volume giving a dose of 8 g/kg/bw. The test substance was evenly dispersed on the back (area of 40 cm2) of test animals and covered with an occlusive dressing. After 24 hours the dressing was removed and the skin was cleaned with lukewarm water. The animals were then observed for 15 days. Food and tap water were available ad libitum throughout the study. The skin reactions were assessed using Noaks and Sanderson method (1969).

Duration of exposure:

24 hours

Doses:

4000 mg/kg bw

No. of animals per sex per dose:

One group: 3/sex/dose

Control animals:

no

Details on study design:

Test Article Preparation:
The test article was placed into a glass beaker on a tared balance and the vehicle (carboxymethyl cellulose 2 %., CMC) in distilled water was added. A weight/weight dilution was prepared using a homogenizer. Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer. The preparations were made immediately prior to each dosing.

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Mortality/ Viability: Four times during test day 1, and daily during days 2 - 15; Body weight: days 1, 8, 15.
- Necropsy of survivors performed: yes
- Clinical signs including body weight
GENERAL BEHAVIOR: aggressiveness, crying, restlessness/ excitement, nervousness, fear, sedation somnolence, sleep and coma.
RESPIRATION: apnea and dyspnea.
EYE: chromodacryorrhea, exophthalmos, miosis, mydriasis, whitish discharge and lid adhesion.
NOSE: rhinorrhea and epistaxis.
MOTILITY: akinesia, ataxia, dropped head, hyperkinesia, hypokinesia, paralysis flaccid, paralysis spastic, paddling movements, stiff movements, rolling movements, and hunched posture.
BODY POSITION: ventral body position, latero-abdominal position, and curved body position.
MOTOR SUSCEPTIBILITY: spasms, tonic muscle spasms, clonic muscle spasms, opisthotonus, saltatory spasms, trismus, retching, "Straub" phenomenon, tremor, muscle-twitching and muscle-twitching generalized.
SKIN: erythema, edema and necrosis.
VARIOUS: loss of weight, emaciation, negative corneal reflex, diarrhea, ruffled fur, necrosis of tissue of application area, salivation, pallor and cyanosis.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 4 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortalities

Mortality:

No deaths or clinical signs of toxicity were observed during the study.

Clinical signs:

other: other:

Gross pathology:

At terminal necropsy congested lungs with dark red discoloration were noted in 3/6 test animals, two males and one female. According to the investigators this necropsy finding was not considered to be caused by treatment with the test substance. The acute dermal LD50 of desmedipham to the rabbit was estimated to be greater than 4000 mg/kg/bw.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 was estimated to be higher than 4000 mg/kg/bw in the rabbit. No classification is warranted according to Regulation 1272/2008.

Executive summary:

The test article Desmedipham was administered to the skin of rabbits of both sexes at a dose of 4000 mg/kg bw. The following death rate was observed: 0% at 4000 mg/kg Based on these observations, the LOGIT model could not be applied to the observed rate of death. Therefore, the LD₅₀ of Desmedipham was estimated to be greater than 4000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The key rat study (K1) was performed to GLP and OECD 402. The supporting rabbit study (K2) was not performed to GLP or a recognised guideline, but was broadly comparable to OECD 402 with the exception of group size.

Justification for classification or non-classification

Desmedipham does not require classification for acute oral toxicity in any category, based on acute oral LD₅₀ values of >2000 mg/kg bw in the rat (Key study), >5000 mg/kg bw in the rat (supporting study) and >3500 mg/kg bw in the mouse (supporting study).

Desmedipham does not require classification for acute inhalation toxicity in any category, based on an acute inhalation (4-hour, nose-only) LC₅₀ value of >7.4 mg/L in the rat (Key study).

Desmedipham does not require classification for acute dermal toxicity in any category, based on acute dermal LD₅₀ values of >2000 mg/kg bw in the rat (Key study) and >4000 mg/kg bw in the rabbit (supporting study).