2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide

Endpoint summary

Description of key information

The key studies for acute oral toxicity endpoints are as follows:

Oral (OECD 401, GLP, RL1), rat LD50 > 5000 mg/kg bw (M-064546-01-1, Johnson, 2002)
Dermal (OECD 402, GLP, RL1), rat LD50 > 5000 mg/kg bw (limit test) (M-064572-01-1, Johnson, 2002)
Inhalation: (OECD 403, GLP, RL1), rat LC50 > 5 mg/L (M-078710-01-1, Pauluhn, 2002)

The following supporting studies are available:

Oral (non-guideline, non-GLP, RL2), rat LD50 > 5000 mg/kg bw (M-087278-01-1, Flucke, 1977)
Oral (non-guideline, non-GLP, RL2), mouse LD50 > 5000 mg/kg bw (M-087278-01-1, Flucke, 1977)
Oral (non-guideline, non-GLP, RL2), dog LD50 > 1000 mg/kg bw (M-087278-01-1, Flucke, 1977)
Dermal (non-guideline, non-GLP, RL2), rat LD50 > 5000 mg/kg bw (M-087278-01-1, Flucke, 1978)
Inhalation: (non-guideline, non-GLP, RL2), rat LC50 > 1.5 mg/L (M-086890-01-1, Sangha, 1981)

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:

18-March-2002 to 03-April-2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were approximately ten weeks of age when treatment was administered. Feed (PMI Certified Rodent Diet 5002) was provided continuously for ad libitum consumption during the acclimation period and throughout the study prior to dosing (with the exception of the overnight fasting period), as was tap water. Feed and water were periodically sampled and analyzed for a variety of potential impurities. Upon receipt, animals were examined and sacrificed if general appearance and/or behavior were considered abnormal. Those animals considered acceptable were individually housed in single cages and acclimated to their ambient laboratory conditions (set for a temperature of 19° to 25°C (66° to 77°F), relative humidity 30-70%, 12-hr light/dark cycles, an average of at least 11 air changes per hour) prior to placement on the study. For the holding period, animal care personnel observed the animals at least once daily for moribundity and mortality. One animal was sacrificed due to moribundity.

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionized water

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

6 animals per sex per dose

Control animals:

yes

Remarks:

vehicle only

Details on study design:

The oral route of exposure was employed in general accordance with the test guidelines for an acute oral toxicity study, based on this being a possible route of human exposure. Doses were prepared by weighing and mixing the appropriate quantity of Triflumuron and vehicle (10 mL/kg deionized water). Control and treated rats were treated in an identical manner, except controls received vehicle only. Each dose group consisted of 6 animals/sex. Dosing preparations (test substance plus vehicle) were stirred continuously during the dosing process and were administered as a single oral dose, utilizing appropriate dosing equipment, after which the animals were returned to their cages. Animals were sacrificed on Day 14. Dose amounts were based on individual body weights determined on Day 0 (day of exposure).

Cage-side observations were conducted at least once daily for mortality or clinical signs of moribundity with the following exception; On Day 12, animals were not observed for mortality, moribundity. No animals were sacrificed due to moribundity. Detailed physical examinations for clinical signs were carried out at least twice daily for three days (Day 0, 1 and 2) and once daily thereafter through Day 14 with the following exceptions; On Day 4, all animals were observed, however, observations for the female 5000 mg/kg level were not recorded, and on Day 12 animals were not observed for clinical signs of toxicity. These examinations were performed at approximately the same time of day. Body weight determinations were performed weekly.

Statistics:

Not required

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

none

Clinical signs:

other: other: There were no mortalities or compound-related clinical signs in the control or 5000 mg/kg dose groups. Clinical signs unrelated to the test compound included rough coat and thinning hair.

Gross pathology:

Gross observational findings consisted of alopecia in one control male.

Interpretation of results:

GHS criteria not met

Conclusions:

As no mortality was observed, an LD50 of greater than 5000 mg/kg was established in male and female rats following acute oral exposure to triflumuron.

Executive summary:

In a study performed to GLP and OECD 401, triflumuron formulated in deionised water (10 mL/kg bw) was administered to groups of fasted male and female rats by single gavage dose. Rats were observed for 14 days. The administration of triflumuron did not elicit any treatment-related findings in mortality, clinical signs, body weight and macroscopic pathology.  The acute oral LD₅₀ of triflumuron was therefore found to be >5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 5 000 mg/kg bw

Quality of whole database:

An acute oral toxicity study in rat is available (GLP, OECD 401, Klimisch 1).

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:

2002-04-22 to 2002-08-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species and species justification: The study was carried out in rats, a rodent species recommended in the test guidelines. Healthy young adult SPF bred Wistar rats, strain Hsd Cpb:WU (SPF), from the experimental animal breeder Harlan-Winkelmann GmbH, Borchen (Germany), were used. Animals of this strain have been used at Bayer AG in toxicological studies for years. Historical data on their physiology, diseases and spontaneous alterations are available. The state of health of the strain is randomly checked regularly at the instance of the Laboratory Animal Services, Bayer AG, for the most important specific infectious pathogens. The results of these examinations are archived.

Acclimatization: The animals were acclimatized to the animal room conditions for at least 5 days before use.

Identification: Animals were identified by both individual color-marking and cage labels. All animals from this study were located on one cage-rack.

Randomization: Before the start of the study the health status of each animal was assessed. Animals were subsequently assigned to exposure groups at random.

Health status: Only healthy rats free of signs were used for this study. The animals were not vaccinated or treated with anti-infective agents either before their arrival or during the acclimatization or study periods. The females were nulliparous and not pregnant.

Age and weight: At the study start the variation of individual weights did not exceed ±10 per cent of the mean for each sex. Animals of the weight class used are approximately 2 months old and hence fulfill the criterion for young adults.

Animal housing: During the acclimatization and study periods the animals were housed singly in conventional Makrolon® Type II cages). Cages were changed twice a week while unconsumed feed and water bottles were changed once per week.

Bedding: Bedding consisted of type BK8/15 low-dust wood granulate The wood granulate was randomly checked for harmful constituents at the request of the Laboratory Animal Services, Bayer AG.

Animal rooms: All animals were housed in a single room. For reasons of space availability rats from other acute toxicity studies were housed in the same room, however mistakes in animal assignments were excluded by adequate spatial separation, clear cage labeling, and appropriate organization of all work procedures.

Room temperature: 22 ± 2 °C
Relative humidity:40 - 60 %
Dark/light cycle: 12 h/12 h; artificial light from 6.00 a.m. to 6.00 p.m.
Light intensity: Central European Time approximately 14 watt/m2 floor area
Ventilation: approximately 10 air changes per hour

The room humidity and temperature were continuously monitored and documented using a calibrated thermohygrograph. Occasional deviations from these conditions occurred, e.g. as a result of animal room cleaning, but these had no detectable influence on the outcome of this study.

Feeding: Ration consisted of a standard fixed-formula diet (KLIBA 3883 = NAFAG 9441 pellets maintenance diet for rats and mice; PROVIMI KLIBA SA, 4303 Kaiseraugst, Switzerland) and tap water (drinking bottles). Both food and water were available ad libitum. The pelletized feed was contained in a rack in the stainless-steel wire cage cover. The nutritive composition and contaminant content of the standard diet was checked regularly by random sampling by the Laboratory Animal Services, Bayer AG.

Water: Drinking quality tap-water (Drinking Water Decree of 05.12.1990, Bundesgesetzblatt [federal law gazette] part I, page 2612) was provided ad libitum in polycarbonate bottles containing approximately 300 ml (based on A. Spiegel and R. Gonnert, Zschr. Versuchstierkunde, 1_, 38 (1961) and G. Meister, Zschr. Versuchstierkunde, 7, 144-153 (1965)). The results of feed and water analyses are retained by Bayer AG.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Mass median aerodynamic diameter (MMAD):

>= 3.7 - <= 6.6 µm

Geometric standard deviation (GSD):

ca. 2

Remark on MMAD/GSD:

With regard to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled at 2.108 mg/L (MMAD 3.7 µm, GSD ~2), but could not be fully achieved at 5.030 mg/L (MMAD 6.6 µm, GSD ~2).

Details on inhalation exposure:

Mode of exposure; Animals were exposed to the aerosolized test substance in Plexiglas exposure tubes applying a directed-flow nose-only exposure principle. Tubes were chosen that accommodated the animals size. These tubes were designed so that the rat's tail remained outside the tube, thus restrained-induced hyperthermia can be avoided. This type of exposure is preferable to whole-body exposure on scientific (Pauluhn, 1984) and technical reasons (rapid attainment of steady-state concentrations, no problems with regard to test atmosphere inhomogeneities, better capabilities to control all inhalation chamber parameters, easier cleaning of exhaust air, and lower consumption of test substance). Moreover, contamination of the fur can largely be avoided. The chambers used are commercially available (TSE, 61348 Bad Homburg) and the performance of this type of chamber has been published (Pauluhn, 1984; Pauluhn, 1988; Pauluhn, 1994).

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

The mean achieved solid aerosol concentrations (dust) were 2108 and 5030 mg/m3 air (2.108 and 5.030 mg/L).

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 2 weeks
- Body weights were measured before exposure, on days 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, rectal temperature

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.03 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Mortality did not occur.

Clinical signs:

other: Group 3 / males: Piloerection Group 3 / females: Nostrils with red encrustations

Body weight:

Comparisons between the control and exposure groups did not reveal an effect on body weight gains which is considered to be of no toxicological relevance. The decrease of mean body weights in group 3 (females only) is causally related to the decreased weight gain of one rat towards the end of the 2- week post exposure period. This rat did not experience any other effect. Therefore, this finding is considered to be incidental.

Gross pathology:

Animals sacrificed at the end of the observation period: In rats exposed to the test compound macroscopic findings were unremarkable, in spite the findings that 2/5 of the males rats of group 3 had lungs displaying isolated dark-red foci.

Other findings:

Rectal temperature: Statistical comparisons between control animals with those in the exposure groups revealed statistically significant decreased body temperatures (females only). Overall, the magnitude of response was too small to be of any toxicological significance.

Interpretation of results:

GHS criteria not met

Conclusions:

Exposure to the maximum technically attainable concentration of 5030 mg/m3 did not result in mortality or any clinical signs of concern. As far as mild and transient signs were observed in one rat only they were nonspecific and appear to be related to the high dust load. Necropsy findings were unremarkable. With regard to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled following exposure to 2108 mg/m3, i.e. the MMAD was < 4 µm (MMAD µm, GSD˜2). In summary, the test substance (solid aerosol) proved to have essentially no acute inhalation toxicity to rats.

Executive summary:

A study on the acute inhalation toxicity of triflumuron (hereafter referred to as test substance) on rats has been conducted in accordance with OECD Guideline No. 403. Test procedures were adapted so as to comply also with the EU Directive 92/69/EEC and OPPTS 870.1300. Two groups of rats were nose-only exposed to a mean solid aerosol concentration (dust) of 2108 and 5030 mg/m3 air. Attempts were made so that aerosol generated was respirable to rats. The results can be summarized as follows:
LC50 inhalation (aerosol, 4 hr) >5030 mg/m3
NO(A)EL = 2108 mg/m3 air
Observations and Measurements: Exposure to the maximum technically attainable concentration of 5030 mg/m3 did not result in mortality or any significant clinical signs. Necropsy findings were unobtrusive. With regard to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled at 2108 mg/m3, i.e. the MMAD was < 4 urn (MMAD 3.7µm, GSD≈2) or could not be fully achieved at 5030 mg/m3, i.e. the MMAD was > 4µm (MMAD 6.6µm, GSD≈2). In summary, the test substance (solid aerosol) proved to have essentially no acute inhalation toxicity to rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 5 mg/L air

Physical form:

inhalation: aerosol

Quality of whole database:

An acute inhalation study in rat is available (GLP, OECD 403, Klimisch 1).

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:

2002-03-27 to 2002-04-23

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:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female (nulliparous and nonpregnant) Wistar Hanover (Crl: WI[Glx/BRL/HAN]GS BR) rats from Charles River Laboratories, Inc., (Raleigh, NC) were used in this study. These animals were approximately 11 weeks of age when treatment was administered.
Feed and Water. Feed (PMI Certified Rodent Diet 5002 in "meal" form, St. Louis, MO) and tap water (Kansas City Missouri municipal water, dispensed by automatic watering system) were provided continuously for ad libitum consumption during the acclimation period and throughout the study. Feed and water were periodically sampled and analyzed for a variety of potential impurities. The results of these analyses were unremarkable. Contaminant concentrations outlined in the Certification Profile for Purina Mills Certified Lab Chows (PMI Nutrition International, 1998) were used as a general standard by which to gauge acceptable levels of contaminants in the feed.

Examination and Acclimation. Upon receipt, animals were examined. No animals were sacrificed due to general appearance and/or abnormal behavior. Those animals considered acceptable were then placed into individual cages and acclimated to their ambient laboratory conditions (set for a temperature of 19-25ºC, relative humidity 30-70%, 12-hr light/dark cycles, 12 air changes /hour) for seven days prior to placement on the study. For the holding period, animal care personnel observed the animals at least once daily for moribundity and mortality.

Care and Housing. While on study, rats were individually housed in suspended stainless steel cages. The cages and cage racks were thoroughly cleaned and disinfected before arrival of the animals. Deotized Animal Cage Board was used in the bedding trays and changed at least two times weekly. The cages, feeders and racks were replaced at least once every two weeks with clean, disinfected equipment. The room was disinfected at least once every two weeks.

Randomization. Randomization by weight stratification utilized software from INSTEM Computer Systems (Stone, Staffordshire, UK). Following seven days of acclimation, animals were weighed. All animals placed on study were within 20% of the mean of all available animals.
These animals were randomly assigned to a control group, or to a single dose group (per sex) in order that, groups had equivalent body weights when treatment was initiated.

Type of coverage:

semiocclusive

Details on dermal exposure:

The dermal route of exposure was employed in general accordance with the test guidelines for an acute limit test dermal toxicity study, based on this being a possible route of human exposure.
The hair from the scapulae (shoulders) to the wing of the ileum (hipbone) and half-way down the flank on each side of the animal was removed using Oster electric clippers equipped with a number 40 blade. Animals were clipped approximately 24 hours before the first dose was administered and as necessary thereafter, depending on hair growth. Care was taken during clipping to avoid abrading the skin. The dose site was distinguished from the surrounding untreated skin by marking with a felt-tip marker. Animals were treated with the test material Triflumuron as received (neat), administered as a single dose for a duration of 24 hours. Dose amounts (mg/kg body weight) were based on individual body weight measurements determined on day 0. The appropriate quantity of dose was moistened with 25ul of deionized water and applied directly onto an area of the back of the animal, representing approximately 10% of it’s total surface areab. A two-ply gauze pad with plastic backing was applied over the treatment site and secured with hypoallergenic tape. The gauze was further secured with Vetrap© (Animal Care Products/3M, St. Paul, MN) bandage, which was also secured with tape.

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw/day

No. of animals per sex per dose:

6

Control animals:

yes, concurrent no treatment

Details on study design:

All animals were fitted with Elizabethan collars (EJAY International, Glendora, CA), which served to reduce animal access to the dose site and thereby reduce ingestion of the test substance, and returned to their cages.
After approximately 24 hours post-dosing (minimum), the bandages and gauze were removed and the dose site was wiped using paper towels dampened with tap water to remove as much of the residual test substance as feasible without damaging the skin. Animals were sacrificed 14 days after dosing. Both controls and treated rats were treated in an identical manner with the exception that the control group did not receive test substance.
Clinical Signs, Body Weights. Cage-side observations were conducted at least once daily for mortality or moribundity. No animals were sacrificed due to moribundity. Detailed physical examinations for clinical signs were carried out twice daily on three days (0, 1 and 2) and once daily for the remaining portion of the in-life phase of the study. These examinations were performed at approximately the same time each day. Body weights were determined on day 0, and on days 7 and 14.
Gross Pathology. Animals were sacrificed by CO2 asphyxiation and subjected to a gross necropsy examination.

Statistics:

Descriptive statistics were generated by Datatox software (Stone, Staffordshire, UK).

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

no mortality occurred.

Clinical signs:

other: other: Lacrimal and nasal staining, in the form of red discharge, in control and the 5000 mg/kg dose groups, were attributed to the animals wearing Elizabethan collars, which interfere with normal rodent preening, and were not considered to be compound-re

Gross pathology:

There were no gross observational findings at necropsy. No evidence of systemic toxicity was found.

Interpretation of results:

GHS criteria not met

Conclusions:

The  acute dermal LD50 of triflumuron was found to be >5000 mg/kg bw under the conditions of this study.

Executive summary:

Triflumuron technical formulated in deionized water was administered to 6 fasted male and female CD-1 rats by single gavage at 5000 mg/kg bw/day. Control animals were treated with deionized water only (10 mL/kg bw). Rats were observed for 14 days. The administration of triflumuron technical did not elicit any mortality or treatment-related findings in clinical signs, body weight and macroscopic pathology. The acute dermal LD₅₀ of triflumuron technical was found to be >5000 mg/kg bw under the conditions of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 5 000 mg/kg bw

Quality of whole database:

An acute dermal study in rat is available (GLP, OECD 402, Klimisch 1).

Justification for classification or non-classification

Based on the acute oral LD50 (>5000 mg/kg bw), acute inhalation LC50 (>5 mg/L) and the acute dermal LD50 (>5000 mg/kg bw) value obtained in GLP- and guideline-compliant studies in the rat, triflumuron does not meet the criteria for classification for acute oral/dermal/inhalation toxicity according to Regulation (EC) No. 1272/2008. Furthermore, there was no clear evidence of specific toxic effects at any target organ or tissue and no signs of respiratory tract irritation or narcotic effects. Therefore, no classification for STOT SE is warranted.