Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 946-945-0 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Oct 2011 - Jan 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP / guideline study without deficiencies
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- d-Phenothrin
- IUPAC Name:
- d-Phenothrin
- Reference substance name:
- Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methyl-1-propenyl)-, (3-phenoxyphenyl) methyl ester, (1R)
- IUPAC Name:
- Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methyl-1-propenyl)-, (3-phenoxyphenyl) methyl ester, (1R)
- Reference substance name:
- 188023-86-1
- Cas Number:
- 188023-86-1
- IUPAC Name:
- 188023-86-1
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): d-Phenothrin
- Physical state: yellow to brown transparent viscous liquid
- Purity test date: 20 January 1011
- Lot/batch No.: R1101004
- Expiration date of the lot/batch: January 2014
- Stability under test conditions: test material stability in feed was verified
- Storage condition of test material: room temperature
Constituent 1
Constituent 2
Constituent 3
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Crl:WI rats
- Source: Charles River Laboratories, 97633 Sulzfeld, Germany
- Age at study initiation: ca. 6 weeks
- Weight at study initiation: males 201 - 221 g, females: 150 - 181 g
- Housing: Type II and/or III polycarbonate
- Diet (e.g. ad libitum): rabbit pellet feed ad libitum
- Water (e.g. ad libitum): charcoal filtered and UV sterilised tap water ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 65 - 66
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-LIFE DATES: From: 2006-04-20 To: 2006-04-25
Administration / exposure
- Route of administration:
- oral: feed
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): once
- Mixing appropriate amounts with (Type of food): ssniff® SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” by ssniff Spezialdiäten GmbH, D-59494 Soest Germany
- Storage temperature of food: room temperature - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test item concentration and/or homogeneity in feed were determined on 3 analytical occasions, twice at receipt of the diets (concentration and homogeneity), and once towards completion of the treatment (concentration of remaining diet and stability from the animal room).
The samples were extracted and analysed by HPLC using UV detection based on a validated analytical method (CiToxLAB Hungary Ltd. study 11/089-316AN).
d-Phenothrin proved to be stable in diet under ambient storage conditions in the animal room (approximately 22 ±3 °C) for at least 14 days
and in the diet storage room (approximately 15 - 21 °C) for at least 8 weeks. - Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- via diet, ad libitum
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 ppm
- Remarks:
- nominal in diet
equivalent to 67 and 84 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 3 000 ppm
- Remarks:
- nominal in diet
equivalent to 202 and 252 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 10 000 ppm
- Remarks:
- nominal in diet
equivalent to 685 and 1030 mg/kg bw/d in males and females, respectively
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: DRF study (Kuszky, 2012a)
- Rationale for selecting satellite groups: no satellite groups were maintained
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day). General clinical observations were made at least once a day at approximately the same time, with minor variations as practical.
- Cage side observations checked in table 1 were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were made on all animals outside the home cage at randomisation (Day -7), on the first day of treatment (Day 0) and at least once a week afterwards.
BODY WEIGHT: Yes
- Time schedule for examinations: Day -7, Day 0, then at least weekly, including on Day 89, and prior to scheduled necropsy (fasted, on Day 90)
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Ophthalmoscopy was conducted in all animals before treatment (Day -8), and in the Control Group 1 and High dose Group 4 animals, during Week 13 (Day 88).
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes (pentobarbital)
- Animals fasted: Yes, overnight
- How many animals: all survivors
- Parameters checked in table 2 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: Yes
- How many animals: all survivors
- Parameters checked in table 3 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: Day 90, prior to necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 4 were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Day 84
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / landing foot splay - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 5)
HISTOPATHOLOGY: Yes (see table 6) - Statistics:
- Evaluation was made by comparing the data for each of the Groups 2 to 4, respectively, against the Control Group 1. The heterogeneity of variance between groups was checked by Bartlett's homogeneity of variance test. Where no significant heterogeneity was detected, a oneway analysis of variance was carried out. If the obtained result was positive, Duncan's Multiple Range test was used to assess the significance of inter-group differences.
Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorov-Smirnov test. In case of abnormal distribution, the nonparametric method of Kruskal-Wallis One-Way analysis of variance was applied. If there was a positive result, the inter-group comparisons were performed using MannWhitney U-test. The mean and standard deviations values, the frequency of clinical observations, macroscopic and microscopic findings were calculated as applicable.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced BW gain at high dose
- 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):
- WBC was increased in the Mid and High dose males. Decreased neutrophils in High dose females.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased phosporus in High dose animals.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased liver, kidney and thyroid weights in High dose animals.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Bilateral enlargement of the thyroids in High dose males
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- High dose animals: Hypertrophy of the follicular cells in the thyroids, hepatocellular centrilobular hypertrophy in the liver and cortical tubular proteinaceous casts in the kidney.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- BODY WEIGHT AND WEIGHT GAIN
Lower than control body weight gain was noted for the 90 day period of treatment in the High dose group, with a weight gain suppression of approximately 8.5% in the males and 16.2% in the females. Body weights of the High dose group of both sexes consistently remained below control, approximately after Week 6 (males) or Week 2 (females), to termination. None of these changes were statistically significant.
HAEMATOLOGY
White blood cell count (WBC) was 76% and 91% higher than control in the Mid and High dose males, with increases of 18% in the High dose females only, without attaining statistical significance. In the females, decreases in the neutrophils of approximately 36%, p<0.01 and increases in the lymphocytes (18%, p<0.01) were observed at 10'000 ppm. In the males, the APTT was approximately 7% lower than control at 10'000 ppm. At 3000 and 10'000 ppm, the PT was 6% and 10% lower than control, changes considered to reflect a possible effect of the test item at these dose levels. There were no similar effects in the females, which showed minor variations only, up to 3%.
CLINICAL CHEMISTRY
Phosphorus was approximately 22% higher than control in the High dose males and 33% in the High dose females. At 3000 ppm, the mean value was 23% higher than control in the males with no effect in the females. A 12% increase occurred in the Low dose males only, however, the mean and individual values remained within the normal ranges, not considered toxicologically significant or to reflect an adverse effect. Bile acids were higher than control at 3000 and 10'000 ppm in both males and females, although without a clear dose response, up to 51% in the males and up to 45% in the females, with statistical significance in the Mid dose females only. Total protein, albumin and A/G ratio were marginally lower in the High dose females only, 7%, 11% and 9% lower than the control values, respectively. No statistically or toxicologically significant changes were recorded in these parameters in the males. Calcium mean concentration Ca++ was 5% and 7% higher than control in the High dose males and females, respectively.
ORGAN WEIGHTS
Possible treatment-related increases were noted in the liver, kidney and thyroid weights in the males and/or females mostly in the High dose group and on occasion in the Mid dose group. The mean absolute kidney weight was 17% higher than control in the High dose males and 14% higher than control when adjusted for the brain weight, with no changes in the females. When adjusted for the terminal body weight, the relative kidney weight was up to 21% higher than control in both male and female High dose animals. Statistically higher than control liver weights were noted at 10'000 ppm, 23% higher in the females only, when evaluated as absolute values, and in males and/or females when adjusted for the body or brain weights (up to 33% and 20% higher, respectively).
Absolute thyroid weights were 26% and 23% higher than control in the High dose males and females, respectively and 21% higher in the Mid dose females. When
adjusted for the brain weight, the mean relative thyroid weights were 24% (High dose males), 19% (High dose females) and 20% (Mid dose females) higher than control.
When adjusted for the terminal body weight, the mean value in the 10'000 ppm males was 31% higher than control, without attaining statistical significance. In the females, statistically higher values were noted at 3000 and 10'000 ppm, up to approximately 26% and 32% higher, p<0.05, respectively.
GROSS PATHOLOGY
Bilateral enlargement of the thyroids was observed in 2/10 High dose males.
HISTOPATHOLOGY: NON-NEOPLASTIC
Minimal to mild microscopic findings were observed in three tissues. These were hypertrophy of the follicular cells in the thyroids, hepatocellular centrilobular hypertrophy in the liver and cortical tubular proteinaceous casts in the kidney predominantly in the High dose group.
In the thyroid gland, minimal hypertrophy of the follicular cells was seen in 4/10 males and 3/10 females from the High dose group and in 1/10 Mid dose female. No hypertrophy was observed in Mid dose males. These findings correlated with the organ weight data. Based on the isolated occurrence in 1/10 Mid dose females only and in the absence of any indication of thyroid weight changes in Low dose females, histopathological examination was not considered necessary at the Low dose. In the liver, minimal hepatocellular centrilobular hypertrophy affected 4/10 High dose females but not males. No hypertrophy was noted in Mid dose females duringadditional microscopic evaluation.
In the kidney, minimal to mild bilateral cortical tubular proteinaceous casts were observed in 8/10 High dose males. Minimal bilateral/left casts in 2/10 Mid dose males were noted during additional examination. In the males, casts were not seen in controls; however one control female had also bilateral minimal casts.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 202 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: gross pathology; organ weights; histopathology
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 67 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: gross pathology; organ weights; histopathology
- Dose descriptor:
- LOAEL
- Effect level:
- 252 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: gross pathology; organ weights; histopathology
- Dose descriptor:
- NOAEL
- Effect level:
- 84 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: gross pathology; organ weights; histopathology
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 7: Haematology changes in males |
|||||
DOSE GROUP n=10 |
|
APTT sec. |
PT sec. |
WBC 109/L |
LUC % |
Control |
MEAN |
18.96 |
24.40 |
3.67 |
0.23 |
1000 ppm |
MEAN |
18.69 |
23.51 |
3.99 |
0.41 |
±% |
-1.4 |
-3.6* |
8.7 |
2.9 |
|
3000 ppm |
MEAN |
18.98 |
22.94 |
6.48 |
0.41 |
±% |
0.1 |
-6** |
76* |
78** |
|
10’000 ppm |
MEAN |
17.71 |
21.87 |
7.01 |
0.42 |
±% |
-7** |
-10** |
91* |
83** |
Table 8: Haematology changes in females |
|||
DOSE GROUP n=10 |
|
NE % |
LY % |
Control |
MEAN |
32.19 |
62.80 |
1000 ppm |
MEAN |
26.56 |
68.65 |
±% |
-17 |
9.3 |
|
3000 ppm |
MEAN |
27.76 |
67.64 |
±% |
-14 |
7.7 |
|
10’000 ppm |
MEAN |
20.63 |
74.03 |
±% |
-36** |
18** |
Table 9: Clinical-chemical changes in males |
||||||||
DOSE GROUP n=10 |
CL- mmol/L |
Ca++ mmol/L |
Phos. mmol/L |
Tot. prot g/L |
Alb. g/L |
A/G |
Bile acids µmol/L |
|
Control |
MEAN |
105.98 |
2.50 |
2.05 |
55.40 |
28.42 |
1.05 |
11.68 |
1000 ppm |
MEAN |
105.25 |
2.56 |
2.30 |
55.64 |
28.75 |
1.07 |
11.87 |
±% |
-0.7 |
2.2* |
12** |
0.4 |
1.2 |
1.9 |
1.6 |
|
3000 ppm |
MEAN |
103.92 |
2.57 |
2.53 |
56.24 |
29.59 |
1.11 |
17.66 |
±% |
-1.9** |
2.6* |
23** |
1.5 |
4.1 |
5.7 |
51** |
|
10’000 ppm |
MEAN |
103.34 |
2.64 |
2.49 |
53.81 |
28.10 |
1.10 |
15.29 |
±% |
-2.5** |
5.3** |
22** |
-2.9 |
-1.1 |
4.8 |
31** |
Table 10: Clinical-chemical changes in females |
||||||||
DOSE
GROUP n=10 |
CL- mmol/L |
Ca++ mmol/L |
Phos. mmol/L |
Tot. prot g/L |
Alb. g/L |
A/G |
Bile acids µmol/L |
|
Control |
MEAN |
103.74 |
2.48 |
1.71 |
60.52 |
33.77 |
1.26 |
9.91 |
1000 ppm |
MEAN |
103.31 |
2.56 |
1.82 |
59.56 |
33.68 |
1.30 |
11.42 |
±% |
-0.4 |
3.3 |
6.4 |
-1.6 |
-0.3 |
3.2 |
15 |
|
3000 ppm |
MEAN |
102.86 |
2.54 |
1.69 |
58.29 |
32.86 |
1.29 |
14.41 |
±% |
-0.8 |
2.5 |
-1.3 |
-3.7 |
-2.7 |
2.4 |
45** |
|
10’000 ppm |
MEAN |
104.66 |
2.65 |
2.28 |
56.37 |
30.18 |
1.15 |
12.90 |
±% |
0.9 |
6.7** |
33** |
-6.9* |
-11* |
-8.7* |
30 |
Table 11: Effects on absolute organ weights (g) |
|||||||||
DOSE GROUP n=10 |
Terminal bw |
Kidney |
Liver |
Thyroid w/ parathyroids |
|||||
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
||
Control |
MEAN |
544.2 |
291.9 |
3.212 |
1.946 |
14.470 |
8.114 |
0.0232 |
0.0168 |
1000 ppm |
MEAN |
526.9 |
301.9 |
3.088 |
1.990 |
14.496 |
8.572 |
0.0250 |
0.0193 |
±% |
-3.2 |
3.4 |
-3.9 |
2.3 |
0.2 |
5.6 |
7.8 |
15 |
|
3000 ppm |
MEAN |
520.8 |
283.2 |
3.259 |
1.905 |
14.220 |
7.898 |
0.0242 |
0.0203* |
±% |
-4.3 |
-3.0 |
1.5 |
-2.1 |
-1.7 |
-2.7 |
4.3 |
21 |
|
10’000 ppm |
MEAN |
519.9 |
272.6 |
3.751* |
1.974 |
15.703 |
9.985** |
0.0292** |
0.0206* |
±% |
-4.5 |
-6.6 |
17 |
1.4 |
8.5 |
23 |
26 |
23 |
Table 12: Effects on relative organ weight changes (% BW) |
|||||||||
DOSE GROUP n=10
|
Brain |
Kidney |
Liver |
Thyroid w/ parathyroids |
|||||
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
||
Control |
MEAN |
0.41430 |
0.69864 |
0.59328 |
0.66376 |
2.66125 |
2.76754 |
0.00427 |
0.00573 |
1000 ppm |
MEAN |
0.42344 |
0.70934 |
0.58769 |
0.66901 |
2.75474 |
2.86573 |
0.00477 |
0.00646 |
±% |
2.2 |
1.5 |
-0.9 |
0.8 |
3.5 |
3.5 |
12 |
13 |
|
3000 ppm |
MEAN |
0.42794 |
0.73030 |
0.62285 |
0.67411 |
2.71609 |
2.80329 |
0.00467 |
0.00720* |
±% |
3.3 |
4.5 |
5.0 |
1.6 |
2.1 |
1.3 |
9 |
26 |
|
10’000 ppm |
MEAN |
0.43889 |
0.77274** |
0.72189** |
0.72501* |
3.01784** |
3.66899** |
0.00561 |
0.00757 * |
±% |
5.9 |
11 |
22 |
9.2 |
13 |
33 |
31 |
32 |
Applicant's summary and conclusion
- Conclusions:
- In conclusion, under the conditions of this study based on the potentially treatment related findings noted at 3000 and 10'000 ppm, the NOAEL of d-Phenothrin administered in the diet to Wistar rats for 90 consecutive days is considered to be 1000 ppm, equivalent to approximately 67 and 84 mg/kg bw/day achieved dose levels in males and females, respectively.
- Executive summary:
The objective of this study was to obtain information on the toxicity of d-Phenothrin administered in diet, pelleted by simple compression, daily for 90 days according to the following experimental design:
Control group: basal diet (0 mg d-Phenothrin/kg bw/d) 10 males/10 females
Low dose group: 1000 ppm in diet (~75 mg d-Phenothrin/kg bw/d) 10 males/10 females
Mid dose group: 3000 ppm in diet (~227 mg d-Phenothrin/kg bw/d) 10 males/10 females
High dose group: 10000 ppm in diet (~857 mg d-Phenothrin/kg bw/d) 10 males/10 females
Parameters monitored during this study were mortality and clinical observations, including neurological assessment and ophthalmoscopy, towards the end of the treatment period and examination of the vaginal smears prior to necropsy for evaluation of the oestrus cycle phase. Body weights and food consumption were measured weekly and food conversion efficiency and test item intake were calculated.
Clinical pathology (haematology, clinical chemistry and urinalysis) was conducted prior to necropsy on Day 90, followed by necropsy with macroscopic examination and selected organ weight measurements. Full histopathology was performed for Groups 1 (Control) and 4 (High dose) and any organs showing macroscopic findings. Following initial examination, additional slide preparation and examination was conducted for Group 3 Mid dose animals, on the liver from females, thyroids from males and females and kidneys from males only.
Test item content and/or homogeneity in the diet were determined by HPLC using UV detection based on a validated analytical method, twice at receipt of the diet and once towards completion of the treatment period, within the stability interval The samples were extracted and analysed by d-Phenothrin proved to be stable in ssniff® SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” under ambient storage conditions in the diet storage room at approximately 15 - 21 °C for at least 8 weeks and in the animal room at approximately 22 ±3 °C for at least 14 days. No d-Phenothrin was detected in the control samples. Test item-diets were homogeneous and had measured concentrations within 95 - 102% of the nominal concentrations, within the intended range of ±10% nominal.
No unscheduled mortality, clinical signs, or toxicologically significant changes were noted in the animal behaviour, general physical condition, in the reactions to different type of stimuli, landing foot splay or grip strength or motor activity.
There were no test item related changes at ophthalmoscopy or in the oestrus cycle phases evaluated prior to necropsy.
Lower than control body weight gain was noted for the 90-day period of treatment in the High dose group, with a weight gain suppression of approximately 8.5% in the males and 16.2% in the females. Body weights of the High dose group of both sexes consistently remained below control, approximately after week 6 (males) or week 2 (females), to termination. None of these changes were statistically significant. There were no test item related adverse effects on the animal mean daily food consumption or food conversion efficiency.
The test item intake calculated between Days 0 and 89 was approximately 67, 202 and 685 mg/kg bw/day in the Low, Mid and High dose groups males and 84, 252 and 1030 mg/kg bw/day in the females, with mean group values of 75, 227 and 857 mg/kg bw/day achieved dose levels at 1000, 3000 and 10000 ppm.
In the haematology, the white blood cell count (WBC) was 76% and 91% higher than control in the Mid and High dose males, with increases of 18% in the High dose females only, without attaining statistical significance. In the females, decreases in the neutrophils of approximately 36%, p<0.01 and increases in the lymphocytes (18%, p<0.01) were observed at 10000 ppm. In the males, the APTT was approximately 7% lower than control at 10000 ppm. At 3000 and 10000 ppm, the PT was 6% and 10% lower than control, changes considered to reflect a possible effect of the test item at these dose levels. There were no similar effects in the females, which showed minor variations only, up to 3%.
Clinical chemistry evaluation did not reveal any obvious toxicity for d-Phenothrin. Phosphorus was approximately 22% higher than control in the High dose males and 33% in the High dose females. At 3000 ppm, the mean value was 23% higher than control in the males with no effect in the females. A 12% increase occurred in the Low dose males only, however, the mean and individual values remained within the normal ranges, not considered toxicologically significant or to reflect an adverse effect. Bile acids were higher than control at 3000 and 10000 ppm in both males and females, although without a clear dose response, up to 51% in the males and up to 45% in the females, with statistical significance in the Mid dose females only. Total protein, albumin and A/G ratio were marginally lower in the 10000 ppm High dose females only, 7%, 11% and 9% lower than the control values, respectively. No statistically or toxicologically significant changes were recorded in these parameters in the males. Calcium mean concentration Ca++ was 5% and 7% higher than control in the High dose males and females, respectively.
There were no adverse effects in the haematology or clinical chemistry parameters evaluated in the 1000 ppm Low dose group. There were no d-Phenothrin-related, or adverse effects at urinalysis performed prior to necropsy at any of the dose levels tested.
Possible treatment-related increases were noted in the liver, kidney and thyroid weights in the males and/or females mostly in the 10000 ppm High dose group and on occasion in the 3000 ppm Mid dose group and these correlated with the macroscopic and/or microscopic findings.
The mean absolute kidney weight was 17% higher than control in the High dose males and 14% higher than control when adjusted for the brain weight, with no changes in the females. When adjusted for the terminal body weight, the relative kidney weight was up to 21% higher than control in both male and female High dose animals.
Statistically higher than control liver weights were noted at 10000 ppm, 23% higher in the females only, when evaluated as absolute values, and in males and/or females when adjusted for the body or brain weights (up to 33% and 20% higher, respectively).
Absolute thyroid weights were 26% and 23% higher than control in the High dose males and females, respectively and 21% higher in the Mid dose females. When adjusted for the brain weight, the mean relative thyroid weights were 24% (High dose males), 19% (High dose females) and 20% (Mid dose females) higher than control. When adjusted for the terminal body weight, the mean value in the 10000 ppm males was 31% higher than control, without attaining statistical significance. In the females, statistically higher values were noted at 3000 and 10000 ppm, up to approximately 26% and 32% higher, p<0.05, respectively.
At macroscopic evaluation performed during necropsy on Day 90, bilateral enlargement of the thyroids was observed in 2/10 High dose males. This was subsequently found to be correlated with microscopic changes. There were no other macroscopic findings which appeared to be treatment related.
At histopathological evaluation, minimal to mild microscopic findings were observed in three tissues. These were hypertrophy of the follicular cells in the thyroids, hepatocellular centrilobular hypertrophy in the liver and cortical tubular proteinaceous casts in the kidney predominantly in the High dose group.
In the thyroid gland, minimal hypertrophy of the follicular cells was seen in 4/10 males and 3/10 females from the High dose group and in 1/10 Mid dose female. No hypertrophy was observed in Mid dose males. These findings correlated with the organ weight data. Based on the isolated occurrence in 1/10 Mid dose females only and in the absence of any indication of thyroid weight changes in Low dose females, histopathological examination was not considered necessary at the Low dose. In the liver, minimal hepatocellular centrilobular hypertrophy affected 4/10 High dose females but not males. No hypertrophy was noted in Mid dose females during additional microscopic evaluation.
In the kidney, minimal to mild bilateral cortical tubular proteinaceous casts were observed in 8/10 High dose males. Minimal bilateral/left casts in 2/10 Mid dose males were noted during additional examination. In the males, casts were not seen in controls; however, one control female had also bilateral minimal casts.
Examination of the organ weight data, clinical chemistry and urine analysis together with the histopathology observations indicate that there was no adverse effect on the male kidney in the Mid dose group. Similarly, the data on the Low dose males suggest that there were no effects therefore no additional histopathological evaluation was performed. The 1000 ppm Low dose level was considered to be a no-observed-adverse-effect–level for d-Phenothrin in terms of the histopathology.
In conclusion, under the conditions of this study based on the potentially treatment-related findings noted at 3000 and 10000 ppm, the NOAEL of d-Phenothrin administered in the diet to Wistar rats for 90 consecutive days is considered to be 1000 ppm, equivalent to approximately 67 and 84 mg/kg bw/day achieved dose levels in males and females, respectively, with a mean achieved dose for males and females combined of approximately 75 mg/kg bw/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.