Registration Dossier

Administrative data

Description of key information

The available data suggests that MON 13900 has a moderate potential for acute oral toxicity (LD50 = 869 mg/kg bw) while a low potential for acute inhalation (LC50 >2,300 mg/m3) and dermal toxicity (LD50 > 5,000 mg/kg bw).  

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 23 Feb, 1990 to April 2, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Relative humidity was outside the range specified in the guideline but it did not impact the results outcome.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Male and female young adult Sprague Dawley rats used in this study were obtained from Charles River Laboratories, Inc. (Portage, Michiganand Raleigh, North Carolina). The animals were individually housed in suspended stainless steel cages in an environment-controlled room with a 12-h light/dark cycle. Agway Prolab rodent feed and water were provided to each animal ad libitum. The rats were individually identified using metal ear tags and cage cards. All animals were allowed to acclimate to the laboratory environment for a minimum of 5 d prior to dosing.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test substance was ground and passed through a 40 mesh sieve prior to mixing with Mazola Corn Oil at a 25% w/v concentration. The dose volume administered was varied to achieve the designated mg/kg treatment levels.
Doses:
100, 500, 1000 and 1500 mg/kg bw
No. of animals per sex per dose:
5/dose (males) for 100 and 1500 mg/kg/ bw and 5/sex/dose for 500 and 1000 mg/kg/ bw
Control animals:
no
Details on study design:
All animals were fasted overnight prior to dose administration. The animals were observed frequently on the day of dosing and once daily thereafter for the duration of the study (Day 15). Mortality checks were performed twice daily. Individual body weights were determined and recorded on Days -1, 1, 8 and 15, or at death. All animals were subjected to a gross necropsy examination at the time of sacrifice (CO2, asphyxiation) or death.
Statistics:
LD50 values and 95% confidence intervals were calculated using the method of Litchfield and Wilcoxon.
Sex:
female
Dose descriptor:
LD50
Effect level:
1 250 mg/kg bw
Based on:
test mat.
95% CL:
>= 1.13 - <= 1.21
Remarks on result:
other: Slope was 1.17
Sex:
male
Dose descriptor:
LD50
Effect level:
521 mg/kg bw
Based on:
test mat.
95% CL:
>= 1.02 - <= 2.4
Remarks on result:
other: Slope was 1.57
Sex:
male/female
Dose descriptor:
LD50
Effect level:
869 mg/kg bw
Based on:
test mat.
95% CL:
>= 1.51 - <= 3.1
Remarks on result:
other: Slope was 2.17
Mortality:
All deaths in the LD50 animals occurred by study Day 5.
Clinical signs:
A variety of adverse clinical signs was observed in the LD50 study animals. The majority of the clinical signs occurred during study Days 1-5. The most notable clinical signs included decreased fecal output, reddish colored urine and urine stains. Additional indications of toxicity included decreased activity, tremors, breathing abnormalities, piloerection and apparent hypothermia.
Body weight:
Body weight gains were noted in all surviving animals during the test period.
Gross pathology:
No remarkable gross internal findings were noted in animals which survived. In animals which died, the most notable findings consisted of colored mucoid/fluid contents in the digestive tract, reddened stomach mucosa, black/red foci on the stomach and dark red foci on thymus.

Results:

Sex

Calculated LD50 value (mg/kg)

95% confidence interval (mg/kg)

Slope

95% confidence interval

Males

521

428-634

1.17

1.13-1.21

Females

1250

840-1858

1.57

1.02-2.43

Combined

869

566-1333

2.17

1.51-3.12

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the test conditions, the acute oral LD50 of MON 13900 for male and females rats was calculated to be 521 and 1,250 mg/kg bw respectively. The combined LD50 for both the sexes was calculated to be 869 mg/kg bw.
Executive summary:

A study was performed to assess theacute oral toxicityof MON 13900 in SD rat according to the EPA OPP 81-1 Guideline in compliance with GLP. Group of rats (5/dose for lowest and the highest dose and 5/sex/dose for the middle doses) were administered the test substance at 100, 500, 1,000 and 1,500 mg/kg bw.

A variety of adverse clinical signs were noted, including decreased fecal output, reddish coloured urine, urine stains, decreased activity, tremors, breathing abnormalities, piloerection and apparent hypothermia. The majority of these signs occurred during Days 1-5. All surviving animals exhibited body weight gains during the test period. The most notable necropsy observations occurred in the animals which died and consisted of abnormalities of the digestive tract and thymus.

Under the test conditions, the acute oral LD50 of the test substance for male and females rats was calculated to be 521 and 1,250 mg/kg bw respectively. The combined LD50 for both the sexes was calculated to be 869 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
869 mg/kg bw
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
yes
Remarks:
The relative humidity was not maintained between 40% and 60%, however no explanation for this marked deviation was provided.
GLP compliance:
yes
Test type:
other: Limit test
Limit test:
yes
Species:
rat
Strain:
other: Sprague Dawley Albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Portage, MI
- Age at study initiation: Six weeks
- Weight at study initiation: Males (204±5 g), females (153±2 g)
- Housing: Individual
- Diet (e.g. ad libitum): Feed (Purina Mills Rodent Chow #5002)
- Water: Ad libitum)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2 ± 0.8 ⁰C
- Humidity (%): 20.9 ± 0.7%
- Air changes (per hr): 87.6 ± 3 L/min
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
The exposure chamber was a 2,500 L New York University-style stainless steel chamber with a pyramidal top and bottom. During exposure, animals were placed in individual stainless steel wire mesh cages, positioned in one tier in the chamber. The test substance was introduced using a jet mill which milled and fed the test material into an aerosol neutralizer. The aerosol passed through the neutralizer prior to entering the exposure chamber. The chamber concentration of test substance was controlled by regulating the speed at which the twin screw feed mechanism fed test substance into
the jet mill. Chamber airflow, temperature, and percent relative humidity was monitored and recorded approximately every 30 min. Mean airflow was determined to be 87.6±3.0 L/min. Mean temperature and relative humidity were 20.2±0.8⁰C and 20.9±0.7%, respectively. Oxygen level (21%) was determined once during the exposure using an electronic sensor. The equilibration period (T99) was determined to be 13.1 min.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
2.3 mg/L
No. of animals per sex per dose:
5/sex
Control animals:
no
Details on study design:
Animals were observed hourly during exposure; however, the placement of cages allowed only limited observation of the animals. Mortality and moribundity were checked twice daily. Animals were observed for signs of toxicity immediately following exposure and once daily during the 14-d observation period after cessation of exposure. Body weights were determined on the exposure day (prior to exposure) and 2, 7, and 14 d following exposure. All animals were sacrificed 14 d after exposure and subjected to gross pathological examinations.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.3 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: 2.3 mg/L was the highest attainable concentration.
Mortality:
No
Clinical signs:
other: Immediately after exposure (Day 0), clear nasal discharge was noted in one male and perioral wetness was noted in two males and four females. On post-exposure Day 1, red/brown perinasal encrustation was noted in two males and three females. All animals ap
Body weight:
All animals lost weight from Day 0 to Day 2. By post-exposure Day 14, all animals exceeded their pre-exposure weights.
Gross pathology:
No gross abnormalities were observed at final necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the acute inhalation LC50 of MON 13900 was >2.3 mg/L in rats.
Executive summary:

A study was conducted to assess the acute inhalation toxicity of MON 13900 according to the EPA OPP 81-3 Guideline in compliance with GLP.

 

Five male and five female rats were exposed (whole body) for a single continuous 4 h period to an atmosphere of aerosolized test substance dust at the highest attainable mean analytical exposure concentration of 2.3 mg/L in air.

 

No deaths occurred, therefore, the LC50 was greater than 2.3 mg/L.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

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 Feb 28, 1990 to March 14, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
yes (Relative humidity was outside the range specified in the guideline but it did not impact the results outcome.)
GLP compliance:
yes (incl. certificate)
Test type:
other: Limit test
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Males and female young adult Sprague Dawley rats, obtained from Charles Rivers Laboratories, Inc., Raleigh, North Carolina, were used for the study. The animals were individually housed in suspended stainless steel cages in an environment-controlled room with a 12-h light/dark cycle. Agway Prolab rodent feed arid water was provided to each animal ad libitum. The rats were individually identified using metal ear tags and cage cards. All animals were allowed to acclimate to the laboratory environment for a minimum of 5 d prior to initiation of the study.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The test substance was administered to one group of five male and five female rats by a single dermal dose at a level of 5000 mg/kg bw. On the day prior to dosing, the fur was clipped from the dorsal area of the trunk of each animal using small animal clippers. The clipped area measured
approx 10% of the animal’s total body surface. Care was taken during clipping to avoid accidental abrasion to the skin. On the following day, 5 male and 5 female rats were weighed and the test substance was applied uniformly over the clipped area at the appropriate dose. Each animal’s dose was contained at the area of application using an 8 ply gauze dressing covered with plastic wrap. A stockinette sleeve was positioned around the trunk of each animal and secured in place using tape. After an exposure period of 24 h, the stockinette sleeve, plastic wrap and gauze dressing were removed. The exposure site on each animal was rinsed with distilled water to remove residual test substance. No attempt was made to quantitate the amount of nonabsorbed test substance. Following dosing, the animals were observed frequently for clinical signs on the day of dosing and once daily thereafter for the duration of the study. Mortality checks were performed twice daily, in the morning and afternoon. Individual body weights were determined and recorded on Days 1, 8 and 15. All animals were subjected to a gross necropsy examination at the time of sacrifice (CO2 asphyxiation).
Duration of exposure:
24 h
Doses:
5000 mg/kg/ bw
No. of animals per sex per dose:
5/sex
Control animals:
not required
Details on study design:
Following dosing, the animals were observed frequently for clinical signs on the day of dosing and once daily thereafter for the duration of the
study. Mortality checks were performed twice daily, in the morning and afternoon. Individual body weights were determined and recorded on Days 1, 8 and 15. All animals were subjected to a gross necropsy examination at the time of sacrifice (CO2 asphyxiation).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality observed.
Clinical signs:
No apparent test substance related clinical signs were observed.
Body weight:
Mean body weight maintenance was acceptable for the test period.
Gross pathology:
No remarkable gross internal findings were observed in the animals at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the acute dermal LD50 of MON 13900 for rats was estimated to be greater than 5,000 mg/kg bw.
Executive summary:

A study was conducted to evaluate the acute dermal toxicity of MON 13900 in rats according to the EPA OPP 81-2 Guideline in compliance with GLP.

A group of male and female rats received a topical application of the test substance at 5,000 mg/kg bw. Following dosing, the rats were observed daily and weighed weekly. No mortality or apparent test substance related clinical signs were observed. Mean bodyweight gain was acceptable. No remarkable gross internal findings were observed in the animals at necropsy.

Under the test conditions, the acute dermal LD50 of the test substance for male and female rats was estimated to be greater than 5,000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

Additional information

A study was performed to assess the acute oral toxicity of MON 13900 in SD rat according to the EPA OPP 81-1 Guideline in compliance with GLP. Group of rats (5/dose for lowest and the highest dose and 5/sex/dose for the middle doses) were administered the test substance at 100, 500, 1,000 and 1,500 mg/kg bw. A variety of adverse clinical signs were noted, including decreased fecal output, reddish coloured urine, urine stains, decreased activity, tremors, breathing abnormalities, piloerection and apparent hypothermia. The majority of these signs occurred during Days 1-5. All surviving animals exhibited body weight gains during the test period. The most notable necropsy observations occurred in the animals which died and consisted of abnormalities of the digestive tract and thymus. Under the test conditions, the acute oral LD50 of the test substance for male and females rats was calculated to be 521 and 1,250 mg/kg bw, respectively. The combined LD50 for both the sexes was 869 mg/kg bw.

A study was conducted to assess the acute inhalation toxicity of MON 13900 according to the EPA OPP 81-3 Guideline in compliance with GLP. Five male and five female rats were exposed (whole body) for a single continuous 4 h period to an atmosphere of aerosolized test substance dust at the highest attainable mean analytical exposure concentration of 2.3 mg/L in air. No deaths occurred, therefore the LC50 was greater than 2.3 mg/L (i.e. 2,300 mg/m3).

Finally, the acute dermal toxicity of MON 13900 in rats was evaluated according to the EPA OPP 81-2 Guideline in compliance with GLP. A group of male and female rats received a topical application of the test substance at 5,000 mg/kg bw. Following dosing, the rats were observed daily and weighed weekly. No mortality or apparent test substance related clinical signs were observed. Mean bodyweight gain was acceptable. No remarkable gross internal findings were seen in the animals at necropsy. Under the test conditions, the acute dermal LD50 of the test substance for male and female rats was estimated to be greater than 5,000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint

Only one guideline compliant study was available.

Justification for selection of acute toxicity – inhalation endpoint

Only one guideline compliant study was available.

Justification for selection of acute toxicity – dermal endpoint

Only one guideline compliant study was available.

Justification for classification or non-classification

Based on an acute oral LD50 of 869 mg/kg bw, MON 13900 qualifies for classification as Acute Tox. 4 (H302 - Harmful if swallowed) according to Regulation (EC) 1272/2008. However, the available data indicates a low potential for acute inhalation (LC50 > 2,300 mg/m3) and dermal (LD50 > 5,000 mg/kg bw) toxicity. Classification for these endpoints is therefore not warranted.