cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine

Endpoint summary

Description of key information

Fenpropimorph is harmful after oral administration, but will not be absorbed through the skin in toxic doses after a single exposure (LD 50 > 5000 mg/kg bw). LC 50 values after acute inhalation exposure range between 2.9 and 9.1 mg/L.

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:

09. - 12.2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

December 17, 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

certified by Umweltministerium Baden-Württemberg

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: young adult animals (approx. 10 weeks)
- Weight at study initiation: 168.0 g mean bw of test group 2000 mg/kg; 188.3 g mean bw of test group 500 mg/kg (1); 182.7 g mean bw of test group 500 mg/kg (2)
- Fasting period before study: at least 16 hours
- Housing: Animals were single housed
- Diet: VRF1 (P), ad libitum except for the day of administration
- Water: Tap water, ad libitum
- Acclimation period: at least 5 days
- Method of randomisation in assigning animals to test and control groups : not applicable

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): not specified
- Photoperiod (12h dark /12h light): 6.00 a.m. - 6.00 p.m. / 6.00 p.m. - 6.00 a.m.

IN-LIFE DATES
- From: 2010-09-22
- To: 2010-10-19

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25 g /100 mL
- Amount of vehicle (if gavage): 500 mg/kg bw (0.5% solution of CMC in deionized water)
- Justification for choice of vehicle: good homgeneity in water could not be guaranteed
- Purity: not specified

MAXIMUM DOSE VOLUME APPLIED: 2.12 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: By the request of the sponsor a starting dose of 500 mg/kg bw was chosen in the first step with 3 female animals.

Doses:

2000 mg/kg bw (undiluted); 500 mg/kg bw (emulsion)

No. of animals per sex per dose:

3 female animals per 2000 mg/kg; 6 female animals per 500 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of clinical observations: Recording of clinical signs several times on the day of administration and at least once daily thereafter each workday.
- Frequency of weighing: On day 0 shortly before administration, thereafter weekly and on the last day of observation. Additionally, at day of death in animals that diet starting with study day 6.
- Necropsy of survivors performed: yes
- Clinical signs including body weight : yes
- Other examinations performed: check for mortality once each workday

Statistics:

No statistical analysis was conducted.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 500 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

- 500 mg/kg bw test group: No mortality occured in the six females
- 2000 mg/kg bw test group: A delayed mortality was observed in two out of three animals at study day 6 after the administration

Clinical signs:

other: - 500 mg/kg bw test group: Impaired general state, dyspnoea and piloerection from hour 3 to hour 5 after administration in four out of six animals. Two out of six animals did not show any clinical signs. - 2000 mg/kg bw test group: Impaired general state,

Gross pathology:

There were no macroscopic pathological findings in the animals which died or were sacrified at the end of the observation period.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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:

03. - 05.2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

07 Sep 2009

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

certified by Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht Rheinland-Pfalz

Test type:

traditional method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

RccHan:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst, Netherlands
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals (male animals approx. 8 weeks, female animals approx. 10 weeks)
- Weight at study initiation: Group 1 (2.036mg/L): 265.66 g mean bw of males and 210.70 g mean bw of females. Group 2 (5.036 mg/L): 271.88 g mean bw of males and 214.52 g mean bw of females.
- Fasting period before study: not specified
- Housing: Single housing or up to 5 animals
- Diet: Kliba-Labordiät, ad libitum
- Water: Tap water. ad libitum
- Acclimation period: at least 5 days before exposure
- Method of randomisation in assigning animals to test and control groups : Animals were randomly selected from a pool of animals. Five male and five female rats were used for each test group.

ENVIRONMENTAL CONDITIONS
- Temperature: 20 – 24°C
- Humidity: 30 – 70%
- Air changes:1 5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 h / 12 h (6.00 a.m. – 6.00 p.m. / 6.00 p.m. – 6.00 a.m.)

IN-LIFE DATES:
- From: 2011-03-17
- To: 2011-04-13

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 1 - <= 1.7 µm

Geometric standard deviation (GSD):

>= 3 - <= 5.3

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction)
- Exposure chamber volume: approx. 55 L
- Method of holding animals in test chamber: the animals were restrained in glass tubes and their snouts projected into the inhalation system
- Source and rate of air (airflow): Compressed air was produced by an oil-free compressor. Conditioned air was provided from a central air-conditioning system (1.5 m³/h).
- Method of conditioning air: Cold air passed through an activated charcoal filter, was adjusted to room temperature of 20 to 24°C and passed through a second particle filter.
- System of generating particulates/aerosols: Diaphragm metering pump (KNF, Switzerland), Two-component atomizer Mod. 970 (stainless steel, Schlick)
- Method of particle size determination: Cascade impactor measurement
- Treatment of exhaust air: The exhaust air was filtered and conducted into the exhaust air of the building (airflow: 1.35 m³/h).
- Temperature: The temperatures in the inhalation system were measured continuously with a digital thermometer.
- Humidity: The humidities in the inhalation system were measured with a dielectric probe (Testo).
- Pressure in air chamber: not specified

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: For the quantitative determination of the aerosol an air sampler GS 312 (DESAGA) and high-performance-liquid chromatographic method was used.
- Samples taken from breathing zone: yes
- Time needed for equilibrium of exposure concentration before animal exposure : approx. 10 min.

CLASS METHOD
- Rationale for the selection of the starting concentration: The selection of the concentration of test group 1 was based on available information about the toxicity of the test substance.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

ca. 4 h

Concentrations:

Mean concentration of 2.036 mg/L (analytical concentration) for test group 1 and 5.036 mg/L (analytical concentration, limit concentration) for test group 2

No. of animals per sex per dose:

Five male and five female rats were used for each test group.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of clinical observations: Detailed clinical observations were recorded for each animal separately several times during exposure and at least once daily on the pre-exposure day and during the observation period.
- Frequency of weighing: Individual body weights once during the acclimatization period, shortly before exposure (day 0) and at least on days 1, 3 and 7, and before the sacrifice of the animals at the end of the observation period.
- Necropsy of survivors performed: yes
- Clinical signs including body weight: yes
- Other examinations performed: check for mortality twice each work day and once on saturdays, sundays and on public holidays

Statistics:

Binomial test

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.036 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Test group 1 and 2:
- No lethality was observed in male and female animals during the study period of 14 days. Therefore, the study satisfies the criteria of a limit test.

Clinical signs:

other:

Remarks:

see "Any other information on results incl. tables"

Body weight:

Test group 1 and 2:
- lower than 10% body weight loss
- other body weight observations: The mean body weights of the male animals decreased during the first post exposure observations day and increased from study day 3 onward. The mean body weights of the female animals decreased during the first few post exposure observations days and increased from study day 7 onward.

Gross pathology:

Test group 1 and 2:
- No gross pathological abnormalities were detected during the necropsy in the animals at the termination of the post exposure periods.

Clinical observations:

- Test group 1 (2.036 mg/L): Substance contamined fur, abdominal and accelerated respiration with sounds, piloerection from day 0 to day 3, but no clinical signs and findings were observed from study day 4 onwards.

- Test group 2 (5.036 mg/L): Colorless eye and nose discharge, substance contamined fur, red encrusted nose, accelerated respiration with sounds, piloerection from day 0 to day 4, but no clinical signs and findings were observed from study day 5 onwards.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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:

09. - 12.2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

February 24, 1987

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

certified by Umweltministerium Baden-Württemberg

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han) SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 12 weeks
- Weight at study initiation: 248.2 g (mean bw of males); 198.6 (mean bw of females)
- Housing: Single housing
- Diet: VRF 1(P), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: At least 5 days
- Method of randomisation in assigning animals to test and control groups: not applicable

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70 %
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 h / 12 h (6.00 a.m. - 6.00 p.m. / 6.00 p.m. - 6.00 a.m.)

IN-LIFE DATES:
- From: 2010-09-14
- To: 2010-09-28

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal and dorsolateral parts of the trunk
- % coverage: 40 cm² (corresponding to at least 10 %)
- Type of wrap if used: semiocclusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing: rinsing with warm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 1 application of 5.29 mL/kg bw (5000 mg/kg bw)
- Constant volume or concentration used: yes

Duration of exposure:

24 h

Doses:

- other: 5000 mg/kg bw

No. of animals per sex per dose:

5m / 5f

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of clinical observations: several times on the day of administration, at least once therafter each workday.
- Frequency of weighing: shortly befor administration (day 0), weekly thereafter and on the last day of observation.
- Necropsy of survivors performed: yes
- Clinical signs including body weight : yes
- Other examinations performed: Mortality at least once each workday; Scoring of skin findings 30-60 minutes after removal of the dressing (day 1) and at least weekly and on the last day of observation

Statistics:

No statistical analysis was conducted.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured.

Clinical signs:

other: Male animals systemic effects: - impaired general state and piloerection from study day 6 until day 10 at the latest (all males) - one animal additionally showed dyspnoea from day 8 until day 8 Male animals local effects: - slight to severe erythema (gra

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals examined on the last day of observation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

Fenpropimorph is classified for acute oral toxicity Cat.4 (H302) according to EC/1272/2008 Annex VI. Despite the fact that one acute inhalation study showed an LC50 of 2.9 mg/l, Fenpropimorph is not classified for acute inhalation toxicity which is in line with the fact that the study has been available at the time the decision on legal classification has been made (study dates 1979, ECB decision has been adopted with the 24th ATP, 1998). In addition to that, there is a newer, GLP conform study available based upon which no classification is needed (key study, BASF 2011).