Fenamiphos

Endpoint summary

Description of key information

Endpoints for repeated dose toxicity are covered by available animal studies.

 

The test substance was shown to result in adverse effects in repeated dose toxicity studies: erythrocyte ChE inhibition.

 

The NOAEL for repeated dose toxicity was 0.083 mg/kg bw/day in a 1-year feeding study in dogs and 0.06 mg/kg bw/d in a 2-year feeding study in dogs.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991-10-29 to 1992-04-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

dog

Strain:

Beagle

Details on species / strain selection:

The Beagle dog was selected as the test animal due to its suitability and acceptance as a non-rodent species for toxicological testing as well as the availability of a large historical database on the strain.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: White Eagle Laboratories, Doylestown, Pennsylvania
- Females nulliparous and nonpregnant: yes
- Age at study initiation: not be greater than nine months of age
- Weight at study initiation: 7.62 - 9.11kg
- Housing: stainless steel cages
- Diet (ad libitum): Purina Mills Lab Canine Diet 5006-3
- Water (ad libitum): tap water via automatic waterers
- Acclimation period: at least seven days

DETAILS OF FOOD AND WATER QUALITY:
A sample from each batch of feed and corn oil used in this study was analyzed for selected contaminants by Hazleton Laboratories America, Inc., Madison, Wisconsin. Tap water (Kansas City Municipal Water) was analyzed for impurities quarterly by NUS Laboratories in Houston, Texas. Contaminant concentrations specified in the Certification Profile for Purina Mills Certified Lab Chows (see Appendix VI, page 640) were used as the standard by which to gauge acceptable levels of contaminants in feed, corn oil and water.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 25
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

corn oil

Details on oral exposure:

DIET PREPARATION
Corn oil will be used as a vehicle for the test article at one percent by weight of the diet; acetone will serve as a solvent In the diet preparation process. The control diet will be prepared the same way except without the test article. Administration of treated and control feed to all test groups will be Initiated on the same day and continued on a dally basis thereafter. The feed with designated amounts of the test article for four test groups (three treated and one control) will be mixed weekly and stored In the freezer at -23 °C until used (refer to Diet Prep Protocol concerning the mixing procedures for this study). Moreover, a sample of each batch of control and treated feed will be stored in the freezer for archiving.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of active ingredient will be verified prior to study initiation and at approximately six-month intervals. The homogeneity and stability (following both room temperature and freezer exposure) of the test substance in the feed also will be determined prior to study initiation on both the low (1 ppm) and high (12 ppm) dietary levels. During the in-life phase of the study, the stability of the test article in the ration will be determined quarterly, utilizing uneaten feed left at room temperature over a normal feeding period.

Duration of treatment / exposure:

12 months

Frequency of treatment:

not applicable, diet ad libitum

Dose / conc.:

0 mg/kg diet

Dose / conc.:

1 mg/kg diet

Remarks:

equivalent to 0.03 mg/kg bw/day in males and females

Dose / conc.:

3 mg/kg diet

Remarks:

equivalent to 0.089 mg/kg bw/day in males and 0.083 mg/kg bw/day in females

Dose / conc.:

12 mg/kg diet

Remarks:

equivalent to 0.308 mg/kg bw/day in males and 0.349 mg/kg bw/day in females

No. of animals per sex per dose:

2 animals per sex and dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses for this study were chosen based principally on the results of a 2-year study and a 90-day study of the test item in dogs. The 2-year study utilized dose levesls of 0.5, 1, 2, 5 and 10 ppm, while the 90-day study utilized levels of 0, 0.6, 1.0 and 1.7 ppm in the diet. With the exception of a reduction of cholinesterase activity, the animals appeared

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, twice daily

BODY WEIGHT: Yes, weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes, daily
The amount of fenamiphos administered to the test was calculated on a mg/kg/day basis from these data.

OPHTHALMOSCOPIC EXAMINATION: Yes, on all animals prior to administration of the test substance and on all survivors at termination of the study. The pupil reflex, conjunctiva, cornea and iris were initially examined prior to dilation with a mydriatic (Tropicacyl 1%); following mydriasis, the lens, vitreous humor and retina were examined. An ophthalmoscope will be used in the examination which will include retinal photographs of both eyes taken with a fundus camera.

HAEMATOLOGY: Yes, at three months, six months, nine months and at termination

CLINICAL CHEMISTRY: Yes
Cholinesterase activity (plasma and erythrocyte), clinical chemistry and complete blood counts including differentials will be determined three separate times prior to administration of the test article.

HORMONES: Yes, thyroid hormone will be assessed in control animals only, as they are serving as a common control for a concurrent dog study

URINALYSIS: Yes, at three months, six months, nine months and at termination. In addition, a single urinalysis will be done prior to initiation of dosing.

OTHER: Yes, palpation for abnormal growths or masses and visual observations
for pharmacotoxic effects will be assessed on a weekly basis

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
A complete gross examination will be conducted on all animals that are found dead during the study or that are sacrificed (by IV injection of euthanasia solution) due to moribundity or study termination. In addition, the following tissues will be examined and preserved in ten percent buffered formalin with the exception of the eyes, optic nerves and lacrimal gland of the third eyelid which will be collected in Bouin's:

All gross lesions with a border
of normal tissues
Adrenals
Bone
Femur
Ribs, costochondral junction
Sternum
Bone marrow
Brain (The left half of the brain will be taken for determination of cholinesterase activity)
Cerebral cortex
Cerebellar cortex
Medulla/pons
Cecum
Cervix
Colon
Dorsal aorta
Epididymis (longitudial section)
Esophagus
Eyes
Gall bladder
Heart
Joint, femorotibial
Kidneys
Lacrimal gland, 3rd eyelid
Larynx
Liver
Lungs
Lymph node
Cervical
Meserteric
Mammary gland
Muscle, gastrocnemius
Optic nerves
Ovaries
Pancreas
Parathyroids
Peripheral nerve, Sciatic
Pituitary
Prostrate gland
Rectum
Salivary glands
Skin, inguinal
Skull (examined only - not collected)
Small intestine
Duodenum
Jejunum
Ileum
Spinal Cord
Cervical
Thoracic
Lumbar
Spleen
Stomach
Testes
Thymus
Thyroid
Trachea
Urinary bladder
Uterus

Weights on the following organs will be recorded:
Heart
Lung
Liver
Spleen
Adrenals
Kidneys
Gonads
Thyroid
Pituitary
Brain, including brainstem

HISTOPATHOLOGY: Yes
All of the above mentioned tissues will be trimmed, processed, embedded in paraffin, sectioned and mounted, stained with H & E (Hematoxylin and Eosin) and examined microscopically for all animals, including those found dead or sacrificed in extremis.

Statistics:

Continuous data examined statistically were analyzed by Analysis of Variance (ANOVA) followed by a Student's t-test for between-group comparisons if a significant F value was obtained in the ANOVA.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

12 mg/kg feed: mild anemia characterized by lower erythrocyte counts and lower haemoglobin and haematocrit values was observed in males (refer to Table 1 in "Any other information on results incl. tables").

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

> 1 mg/kg feed: There was a dose-dependent inhibition of plasma ChE activity in both sexes. Toxicologically relevant inhibition of erythrocyte ChE activity was established for male and female dogs at 12 mg/kg feed. At this dose level also brain ChE activity was slightly lower in treated dogs in comparison to the control animals.

Endocrine findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Key result

Dose descriptor:

LOAEL

Effect level:

0.35 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

Key result

Dose descriptor:

NOAEL

Effect level:

0.083 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.35 mg/kg bw/day (actual dose received)

System:

nervous system

Organ:

other: no target organ

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Table 1: Chronic study on dogs – hematology

Dose level	Hgb [g/dl]	HCt [%]	RBC [10*6/mm³]		Dose level	Hgb [g/dl]	HCt [%]	RBC [10*6/mm³]
males					females
day -3					day -3
0 ppm	13.5	40.1	6.05		0 ppm	14.6	42.7	6.35
1 ppm	15.1	44.1	6.58		1 ppm	15.3	44.9	6.80
3 ppm	14.1	41.1	6.25		3 ppm	15.6	45.2	6.73
12 ppm	13.6	40.1	5.78		12 ppm	15.4	44.3	6.83
day 98					day 98
0 ppm	16.5	47.4	7.13		0 ppm	15.9	45.7	6.80
1 ppm	15.7	45.3	6.63		1 ppm	16.5	47.3	7.13
3 ppm	15.7	45.2	6.78		3 ppm	17.1	48.9	7.25
12 ppm	14.1+	40.7	5.80+		12 ppm	15.0	43.0	6.30
day 189					day 189
0 ppm	17.0	49.7	7.35		0 ppm	17.2	50.5	7.35
1 ppm	16.3	47.4	6.90+		1 ppm	16.2	47.2	7.03
3 ppm	15.9	46.0	6.85		3 ppm	15.9	46.2	6.80
12 ppm	14.5	42.0+	5.98+		12 ppm	15.0	43.9	6.38

day 280					day 280
0 ppm	16.2	45.5	6.90		0 ppm	15.0	42.3	6.38
1 ppm	16.4	45.7	6.83		1 ppm	15.6	43.6	6.62
3 ppm	15.8	44.4	6.68		3 ppm	16.2	45.3	6.81
12 ppm	14.8	41.9	6.09+		12 ppm	16.6	46.6	6.79
day 361					day 361
0 ppm	16.7	48.4	7.28		0 ppm	16.7	47.7	7.13
1 ppm	16.7	47.2	7.00		1 ppm	16.1	45.9	7.03
3 ppm	16.5	47.0	7.08		3 ppm	16.8	47.9	7.15
12 ppm	15.6	44.9	6.45+		12 ppm	16.8	48.2	7.05

Conclusions:

The NOAEL was concluded to be 3 mg/kg feed, equivalent to 0.083 mg/kg bw/day, based on lower brain and erythrocyte ChE activities and on haematological findings at 12 mg/kg feed.

Executive summary:

The test substance was administered to groups of 4 male and 4 female Beagle dogs in the diet. 

Dose levels: 0, 1, 3 and 12 mg/kg feed (equivalent to 0.03, 0.089, 0.308 mg/kg bw/day in males and 0.03, 0.083, 0.349 mg/kg bw/day in females). Study duration: 12 months.

General observations: No treatment related effects on feed consumption or body weight gain were observed. All animals survived until the scheduled end of the study. Clinical observations and ophthalmic examinations provided no indication for any treatment-related effects.

Hematology, clinical chemistry, urinalysis: Mild anemia characterized by lower erythrocyte counts and lower haemoglobin and haematocrit values was observed in males at 12 mg/kg feed.

The measurements of ChE activities provided the following findings: There was a dose-dependent inhibition of plasma ChE activity in both sexes at > 1 ppm. Toxicologically relevant inhibition of ery ChE activity was established for male and female dogs at 12 mg/kg feed. At this dose level also brain ChE activity was slightly lower in treated dogs in comparison to the control animals.

Gross pathology, organ weights, histopathology: Absolute and relative organ weights were unaffected in all dose group animals. No treatment- related gross- or histopathological changes were observed.

In summary, brain ChE activity significantly reduced (<20%) in females at 0.35 mg/kg bw/day. Mild, transient anaemia in males at 0.35 mg/kg bw/day (decreased erythrocyte counts: 11-19%, haemoglobin: 7-15%, haematocrit: 7-15%, increased MCV: 4-5%) Inhibition erythrocyte ChE activity (>20%) at males 0.35 mg/kg bw/day. Erythrocyte ChE activity compared to pre-treatment values: significant decrease males and females (>20%) at ≥ 0.083 mg/kg bw/day.

A LOAEL and NOAEL based on brain cholinesterase inhibition of 0.35 and 0.083 mg/kg bw/day were derived.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.083 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Klimisch 1

System:

nervous system

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

3.5 mg/m³

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

2.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

The information provided below was taken from the original plant protection dossier on the active substance submitted in 2017 for inclusion of the test substance to Annex I of Directive 91/414/EEC and has been previously evaluated in the Draft Assessment Report (DAR) according to the Commission Regulation (EU) No 1107/2009 (2003) (revisioned in the Renewal Assesment Report (December 2018)) and subject to peer review by EFSA and Member States (2006).

 

Subacute and subchronic repeated dose toxicity

Watanabe & Iyatomi (1985): The test item was administered to groups of six male and six female rats for 4 weeks in the diet at concentrations of 0, 1, 3, 10, 30 and 100 ppm. Animals of the main group were sacrificed after 4weeks of treatment. A recovery group was kept for 4 further weeks without treatment. Slight tremor of limbs, exophthalmos and lower body weight gain and food consumption were found in males and females at 100 ppm. In females, the activity of plasma ChE was lower at > 3 ppm. At >30 ppm the activity of ery ChE was reduced and only at 100 ppm brain ChE was affected. In male animals only ery ChE activity was lower at > 30 ppm; no effects on plasma and brain ChE were seen. After the 4-week recovery period the levels of ChE acitivities were back to normal ranges. Slight lower level of glucose was found in males at 100 ppm, which was considered to be a secondary change due to the low growth rate relatively to control group. No other treatment-related effects were found. No compound-related changes were determined in the gross pathology. The NOAEL was 10 ppm (equivalent to 0.5 mg/kg bw/day) based on lower ery ChE activity at 30 ppm.

 

Kroetlinger & Geiss (2000): In a dermal 28-day study according to OECD 410, the test item was formulated in polyethylene glycol 400 and applied to the dorsal skin of groups of five male and five female rats at concentrations of 0, 2.5, 10 and 40 mg/kg bw for 6 hour/day. On the first three weeks of the study, the formulations were applied on 5 days per week, and in the fourth week also on Saturday and Sunday. No treatment-related systemic clinical signs were observed in males and females. No animal died throughout the entire treatment period. No effects on food intake and body weight development were noted at 40 mg/kg bw. No local skin reddening and skinfold thickness was observed in the dose groups at 40 mg/kg bw. No treatment related changes in haematology and clinical chemistry were observed at 40 mg/kg bw/day in males and females. The determination of cholinesterase in blood plasma showed a decrease of the activity at 40 mg/kg bw/day (approx. 30 % in males and approx. 20 % in females. The decrease of activity was statistically significant in males. Gross necropsy did not reveal compound-related changes. A NOAEL of 40 mg/kg bw/day based on the absence of erythrocyte and brain ChE inhibition  at this dose level (highest dose tested) was determined.

 

Mihail & Schilde (1980): In a 28-day study in the rabbit, the test item was formulated with Cremophor EL in water and applied to the dorsal skin of groups of six male and six female rabbits at concentrations of 0, 2.5, and 10 mg/kg bw for 6 hour/day, 5 days/week for 3 weeks. In a supplementary experiment additional doses of 0 and 0.5 mg/kg bw were tested. In half of the animals the skin of the treatment site was abraded. No signs of toxicity and no mortality were observed. Slight erythema and edema of the treatment sites were observed in animals with abraded skin during the first week only; this effect cleared by day 7. There were no apparent differences between test and control group animals for hematology, urinalysis and clinical chemistry. Plasma ChE activity was lower at > 2.5 mg/kg bw/day in females and at 10 mg/kg bw/day in males. In both sexes ery ChE was lower at 10 mg/kg bw/day. No clear result was obtained regarding brain ChE: While in males no inhibition was seen at 10 mg/kg bw/day, there was a tendency for lower values at > 2.5 mg/kg bw/day in females. As, however, erythrocythe ChE was not reduced in females at 2.5 mg/kg bw/day, it has to be doubted that there really was a treatment-related reduction of brain ChE activity at this dose level. No effects on any ChE compartment was found in animals treated with 0.5 mg/kg bw/day. Gross necropsy did not reveal compound-related changes. The NOAEL was 2.5 mg/kg bw/day based on inhibition of erythrocyte ChE at 10 mg/kg bw/day.

 

Thyssen (1979): For subacute inhalation exposure in the rat, the test item was dissolved in a mixture of ethanol and Lutrol and the solution was aerosolized into dynamic flow inhalation cambers. Groups of 10 male and 10 female rats were exposed to concentations of 0, 0.03, 0.25 and 3.5 mg active ingredient/m³ for 6 hours per day on five days per week over a period of 3 weeks; 98 % of the particles were < 3 µm.b No mortality occurred. Male and female rats tolerated concentrations up to 3.5 mg/m³ without clinical symptoms. No signs of intoxication and no significant differences in body weight gains were noticed. The haematology, clinical chemistry and urinalyses did not reveal any indication of exposure-related changes. Moderate inhibition of plasma ChE activity in male rats and severe depression in female rats was observed at 3.5 mg/m³ dose. In females slight reduction of ery ChE activity was found at the highest concentration tested. Brain ChE was not affected in both sexes. Gross necropsy did not reveal compound-related changes. The NOAEC was 0.25 mg/m³ (equivalent to ~ 0.07 mg/kg bw/day ) based on lower activity of erythrocyte ChE at 3.5 mg/m³.

 

Loeser (1968): In an oral 90-day study in the rat, the test subtance was administered in the diet to groups of 15 male and 15 female rats at concentrations of 0, 4, 8, 16 and 32 ppm. The body weights and food intakes were determined at weekly intervals. Cholinesterase activities in the whole blood, plasma and erys were assayed prior to study initiation and after one, four, eight and 12 weeks. Cholinergic signs were observed in males and females at 32 ppm. No dose-related effects on body weight, body weight gain and food intakes were noted in both sexes. Dose-related inhibition of plasma and ery ChE activities were observed at > 8 ppm. No toxicologically relevant differences between controls and treated animals were observed in haematology, clinical chemistry and urinalysis. No compound-related changes were determined. A NOAEL of 4 ppm (equivalent to ~ 0.2 mg/kg bw/day) based on lower ery ChE activity at > 8 ppm was derived.

 

Hayes (1986): In a 90-day cholinesterase study on rats, the test item was given to 20 male and 20 female Fischer 344 rats in the diet at concentrations of 0, 0.36, 0.6 or 1.0 ppm for 14 weeks. The concen-trations were equivalent to doses of 0, 0.03, 0.045 and 0.072 mg/kg bw/day in males and 0, 0.035, 0.053 and 0.084 mg/kg bw/day in females, respectively. There was no evidence for severe toxicological effects, moribundity or deaths. Slight differences of the feed consumption and body weight gain during the study period did not reveal a dose- related effect. At 1 ppm plasma ChE activity was slightly inhibited in females only; ery and brain ChE were not influenced in both sexes up to 1 ppm. No compound-related changes were determined in gross pathology. The NOAEL was 1 ppm, equivalent to 0.072 mg/kg bw/day in males and 0.084 mg/kg bw/day in females, based on the absence of ery and brain ChE inhibition at this dose level (highest dose tested).

 

Hayes (1983): In a ninety-day cholinesterase study on dogs, the test substance was given to groups of 4 male and 4 female Beagle dogs over a period of 100 days in the diet at dose levels of 0, 0.6, 1.0 or 1.7 ppm. The animals were observed for clinical signs twice daily; body weight and food consumption were measured. Haematology, clinical chemistry and urinalysis were not performed and tissues and organs were not investigated histopathologically. No treatment-related changes in behavior or physical condition were observed. Body weight and food consumption of the treated dogs did not differ from those of the control animals. Only plasma ChE activity was depressed in male dogs at 1.7 ppm. No signi-ficant plasma ChE inhibition was found in female dogs. Ery and brain ChE were not inhibited in both sexes at 1.7 ppm. Organs/tissues were not subjected to examination. A NOAEL of 1.7 ppm (equivalent to ~ 0.04 mg/kg bw/day) based on the absence of ery and brain ChE inhibition at this dose level (highest dose tested) was derived.

 

A summary of the results of subacute and subchronic studies is presented in Table 1.

 

Table 1: Summary of subacute and subchronic studies

Test / Reference	Route of administation	Key data
Short-term repeated dose toxicity (28 days) / Watanabe & Iyatomi (1985)	Oral	28-day oral NOAEL rat = 10 mg/kg food (0.9 mg/kg bw/day)
Short-term repeated dose toxicity (28 days) according to OECD 410 / Kroetlinger & Geiss (2000)	Dermal	28-day dermal NOAEL rat = 40 mg/kg bw/day
Short-term repeated dose toxicity (28 days) / Mihail & Schilde (1980)	Dermal	21-day dermal NOAEL rabbit = 2.5 mg/kg bw/day
Short-term repeated dose toxicity (28 days) / Thyssen (1979)	Inhalation	28-day inhalation NOAEL rat = 3.5 µg/L
Sub-chronic toxicity (90-day), one species, rodent, male and female, most appropriate route of administration / Loeser (1968)	Oral	90-day NOAEL rat = 8 mg/kg food (0.4 mg/kg bw/day)
Sub-chronic toxicity (90-day), one species, rodent, male and female, most appropriate route of administration / Hayes (1986)	Oral	90-day NOAEL rat = 0.91 mg/kg food (0.07 mg/kg bw/day)
Sub-chronic toxicity (90-day), one species, rodent, male and female, most appropriate route of administration / Hayes (1983)	Oral	90-day NOAEL dog = 1.7 mg/kg food (0.042 mg/kg bw/day)

 

Chronic repeated dose toxicity

Riethe (1991): In a chronic study according to OECD 452, the test substance was administered to groups of 4 male and 4 female Beagle dogs in the diet with dose levels of 0, 1, 3 and 12 mg/kg feed (equivalent to 0.03, 0.089, 0.308 mg/kg bw/day in males and 0.03, 0.083, 0.349 mg/kg bw/day in females) and a study duration of 12 months. No treatment related effects on feed consumption or body weight gain were observed. All animals survived until the scheduled end of the study. Clinical observations and ophthalmic examinations provided no indication for any treatment-related effects. Mild anemia characterized by lower erythrocyte counts and lower haemoglobin and haematocrit values was observed in males at 12 mg/kg feed. The measurements of ChE activities provided the following findings: There was a dose-dependent inhibition of plasma ChE activity in both sexes at > 1 ppm. Toxicologically relevant inhibition of ery ChE activity was established for male and female dogs at 12 mg/kg feed. At this dose level also brain ChE activity was slightly lower in treated dogs in comparison to the control animals. Absolute and relative organ weights were unaffected in all dose group animals. No treatment- related gross- or histopathological changes were observed. In summary, brain ChE activity significantly reduced (<20%) in females at 0.35 mg/kg bw/day. Mild, transient anaemia in males at 0.35 mg/kg bw/day (decreased erythrocyte counts: 11-19%, haemoglobin: 7-15%, haematocrit: 7-15%, increased MCV: 4-5%) Inhibition erythrocyte ChE activity (>20%) at males 0.35 mg/kg bw/day. Erythrocyte ChE activity compared to pre-treatment values: significant decrease males and females (>20%) at ≥ 0.083 mg/kg bw/day. A LOAEL and NOAEL based on brain cholinesterase inhibition of 0.35 and 0.083 mg/kg bw/day were derived.

 

Loeser (1972): In a chronic study, the test substance was administered to groups of four male and four female Beagle dogs in the diet at concentrations of 0, 0.5, 1, 2, 5, and 10 mg/kg feed (equivalent to 0.015, 0.029, 0.06, 0.15 and 0.31 mg/kg bw/day in males and 0.014, 0.036, 0.063, 0.17 and 0.34 mg/kg bw/day in females) for 24 months. There were no treatment-related effects on mortality, body weights, body weight gain and food consumption. Behaviour and appearance of the treated animals did not differ from the control animals. No ophtalmoscopically hanges were observed in either sex. No treatment-related effects on hematology, clinical chemistry and urinalysis were observed in male and female dogs at 10 mg/kg feed. Plasma ChE activity was lower at doses of > 2 mg/kg feed and ery ChE activity at > 5 mg/kg feed. Brain ChE activity was not measured in this study. Gross and histopathological examination showed no treatment-related changes of all tissues and organs in males and females at 10 mg/kg feed. No changes in organ weights were observed at 10 mg/kg feed in either sex. Based on the inhibition of erythrocyte ChE activity (> 20%) at 5 mg/kg feed and above, the NOAEL in this study is 2 mg/kg feed, equal to 0.06 mg/kg bw/day.

 

A summary of the results of chronic studies is presented in Table 2.

 

Table 2: Summary of chronic studies

Test / Reference	Route of administation	Key data
chronic repeated dose toxicity (1 year) / Riethe (1991)	Oral	1-year NOAEL dog = 0.083 mg/kg bw/day
chronic repeated dose toxicity (2 year) / Loeser (1972)	Oral	2-year NOAEL dog = 0.06 mg/kg bw/day

 

Conclusion

The summary on this toxicological endpoint as given in the final RAR (2018) is shown in the following.

The main effect following repeated oral, dermal and inhalation administration of the test item to rats and dogs is the inhibition of cholinesterase activity, which at higher dose levels may lead to endogenous cholinergic overstimulation resulting in typical cholinergic symptoms. Plasma ChE was found to be the most sensitive parameter which, however, is regarded to have no toxicological relevance if erythrocyte and brain acetylcholinesterase activities have been adequately measured and are not affected. Erythrocyte ChE inhibition was in all studies the toxicologically most relevant effect. This is probably because of the limited ability of fenamiphos to cross the blood-brain-barrier, resulting in brain ChE being inhibited to a lesser extent. The dog seemed to be the most sensitive species. The LOAEL for erythrocyte ChE inhibition in the one-year dog study was 0.31 mg/kg bw/day and the NOAEL 0.083 mg/kg bw/day. In the two-year dog study the LOAEL was 0.15 mg/kg bw/d and the NOAEL 0.06 mg/kg
bw/day.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available studies are considered reliable for this assessment.

 

Repeated dose toxicity: oral, dermal, inhalation:

Based on the above stated assessment of the specific target organ toxicity potential after repeated oral, dermal and inhalation exposure, the test compound does not need to be classified according to Regulation (EC) No 1272/2008 of the European Parliament and of the Council No 1272/2008 (CLP), , as amended for the eighteenth time in Regulation (EU) 2022/692.