Registration Dossier

Administrative data

Description of key information

An oral diet repeated dose toxicity study (combined with a reproduction/developmental toxicity screening test) was conducted with NERYL ACETATE according to guideline OECD 422 and in compliance with GLP. The NOAEL for systemic  toxicity was 7500 ppm, the highest dose tested, corresponding to 440 mg/kg bw/day for males, 465 mg/kg bw/day for toxicity phase females and 484 mg/kg/day for reproductive phase females during pre-mating period.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
30 April to 10 October 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Related information:
Composition 1
Reason / purpose:
reference to other study
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
November 2015
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River (UK) Limited
- Age of F0 animals at study initiation: Approximately 10 weeks
- Weight at study initiation: Males: 338-383 g; Females: 207-259 g
- Housing: No. of animals per cage - Males: pre pairing and post pairing - up to 5 animals; Females: pre
pairing - up to 5 animals; During pairing - one male and one female;
Toxicity phase and recovery phase - up to five animals of one sex. Cages comprised
of a polycarbonate body with a stainless steel mesh lid. Solid (polycarbonate) bottom cages were use
d during the acclimatisation and treatment period with the exception of pairing periods. Grid bottomed
cages comprising of polypropylene body were used during pairing.
- Diet: SDS VRF1 Certified powdered diet, ad libitum
- Water: Potable water from the public supply via polycarbonate bottles with sipper tubes, ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature: 19-23 °C
- Humidity: 40-70 %
- Air changes: Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod: 12 h dark / 12 h light
Route of administration:
oral: feed
Vehicle:
other: carrier diet, including corn oil
Details on oral exposure:
- Carrier diet: SDS VRF1 certified diet.
- Stabiliser: Corn oil (test material to corn oil ratio 5:1)
- Method of preparation: On each occasion of the preparation of the premix the required amount of test
substance and corn oil were mixed together and stirred. The mixture was added to an equal amount of
plain diet and stirred until visibly homogenous. This doubling up process was repeated until half of the
final weight of premix was achieved or the mixture appeared dry. This mixture was then ground using
a mechanical grinder after which it was made up to the final weight of the premix with plain diet. This
premix was mixed in a Turbula mixer for 100 cycles to ensure the test substance was dispersed in the
diet. Aliquots of the premix were then diluted with further quantities of plain diet to produce the required
dietary concentrations. Each batch of treated diet was mixed for a further 100 cycles in a Turbula mixer.
For Control diet the corn oil was added directly to the diet and then prepared as indicated for the premix.
- Frequency of preparation: Weekly, however, preparations on some occasions were made in advance a
nd stored frozen, but were used within the frozen stability period (22 days when stored frozen nominally
-20 °C).
- Storage of preparation: Frozen (nominally -20 °C).
GROUPS
Groups 1, 2, 3 and 4: 0, 1000, 2500 and 7500 ppm, respectively
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and homogeneity: Before commencement of treatment, the suitability of the proposed mixing procedures was determined and specimen formulations at 100 and 20000 ppm were analysed to assess the stability and homogeneity of the test substance in the diet matrix. Stability was confirmed as eight days at ambient temperature and 22 days when stored frozen. However, only one day ambient stability was used.
Achieved concentration: Samples of each formulation prepared for administration in Weeks 1 and 5 of treatment were analysed for achieved concentration of the test substance.
Duration of treatment / exposure:
Toxicity phase males were treated daily for three weeks before pairing, throughout pairing and up to necropsy after a minimum of five consecutive weeks.
Toxicity phase females were treated daily for a minimum of five consecutive weeks up to necropsy in Week 6.
High dose Recovery phase male and female rats were treated daily for a minimum of six consecutive weeks, followed by a 14 day period without treatment.
Frequency of treatment:
Continuously (fresh diet given daily). During the recovery period, all animals were given untreated diet (without corn oil).
Dose / conc.:
1 000 ppm
Remarks:
nominal in diet
Dose / conc.:
2 500 ppm
Remarks:
nominal in diet
Dose / conc.:
7 500 ppm
Remarks:
nominal in diet
No. of animals per sex per dose:
Toxicity phase : 5 animals/sex/dose for vehicle and high dose groups; 10 males/dose for 1000 and 2500 ppm dose groups; 5 females/dose for 1000 and 2500 ppm dose groups
Recovery phase: 5 animals/sex/dose for vehicle and high dose groups
Control animals:
other: control group was provided with the carrier diet, including corn oil
Details on study design:
- Dose selection rationale: Dose levels were selected in conjunction with the Sponsor following the
completion of the dose range finder study (Study number OAD0022). In the dose range finding study
the doses of 1500, 7500 or 15000 ppm were well tolerated (no mortality), no adverse clinical signs or macroscopic changes in organ appearance were detected at any dose level. Effects of treatment at 15000 ppm included initial body weight loss for the first few days of treatment in males and females, associated with lower food consumption, probably due to low palatability of the treated diet. In males, no effects on body weight and body weight gain were observed up to 7500 ppm but the overall bodyweight change in the high dose group was 23% lower compared to Control group. In females, body weight gain was lower than Control group at 7500 and 15000 ppm, especially during Days 1-7 and 15-22, leading to overall body weight gains 64% and 46% lower than Control group, respectively. The lower bodyweight gain observed in the mid dose group was mainly due to one female showing overall bodyweight loss during the treatment period (-3 g). However, even without this animal, the body weight gain in this group was only 50% of the Control group. Therefore, the high dose to be tested in the main study was considered to be 7500 ppm due to the toxicity observed in females. Then, the lower doses were spaced approximately by a 2.5 to 3-fold factor, i.e. 2500 and 1000 ppm.
Rationale for animal assignment: Randomly allocated on arrival. Using the sequence of cages in the battery, one animal at a time was placed in each cage with the procedure being repeated until each cage held the appropriate number of animals. Each sex was allocated separately.
Positive control:
Not applicable
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). During the acclimatisation and recovery periods, observations of the animals and their cages were recorded at least once per day.

NEUROBEHAVIOURAL EXAMINATION: Yes
Detailed physical examination and arena observations: Before treatment commenced and during each week of treatment and recovery, detailed physical examination and arena observations were performed on each adult animal.
Time schedule:
- Sensory reactivity and grip strength: Sensory reactivity and grip strength assessments were performed on all recovery animals in Groups 1 and 4 and the five lowest numbered surviving toxicity phase males and females in Groups 2 and 3, during Week 6 of treatment.
- Motor activity:
During Week 6 of treatment, the motor activity of all recovery animals in Groups 1 and 4 and the five lowest numbered surviving toxicity phase males and females in Groups 2 and 3 was measured.

BODY WEIGHT: Yes
- Time schedule for examinations:
Toxicity and Recovery phase animals: Before feeding on the day that treatment commenced (Day 1), weekly thereafter and before necropsy.

FOOD CONSUMPTION: Yes
- Time schedule for examinations:
Toxicity and recovery phase males and females: Daily. From these records the mean daily consumption per animal (g/rat/day) was calculated for each cage. Food consumption was not recorded for males during the period when paired for mating (Day 22 to 28). Food consumption recordings recommenced on
Day 29.

HAEMATOLOGY AND CLINICAL CHEMISTRY: Yes
Haematology: Week 6 - Five lowest numbered toxicity phase males and females per group; Recovery Week 2 - All recovery phase animals
Clinical chemistry: Week 6 - Five lowest numbered toxicity phase males and females per group; Recovery Week 2 - All recovery phase males
- Animals fasted: Yes, Blood samples were collected after overnight withdrawal of food.
- Animals were held under light general anaesthesia induced by isoflurane. Blood samples were withdrawn from the sublingual vein.
- Haematology parameters: Haematocrit, Haemoglobin concentration, Erythrocyte count (RBC), Absolute reticulocyte count, Percentage reticulocyte count, Mean cell haemoglobin, Mean cell haemoglobin concentration, Mean cell volume, Red cell distribution width, Total leucocyte count, Differential leucocyte count: Neutrophils, Lymphocytes, Eosinophils, Basophils, Monocytes, Large unstained cells, Platelet count,
Morphology: Anisocytosis, Macrocytosis, Microcytosis, Hypochromasia, Hyperchromasia, Prothrombin time and Activated partial thromboplastin time.
- Blood Chemistry parameters: Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transpeptidase (gGT), Total bilirubin, Bile acids, Urea, Creatinine, Glucose, Total cholesterol, Triglycerides, Sodium (Na), Potassium (K), Chloride (Cl), Calcium (Ca), Inorganic phosphorus, Total protein, Albumin and Albumin/globulin ratio (A/G Ratio).

Sacrifice and pathology:
SACRIFICE
- Toxicity phase animals: Following completion of Week 6 investigations
after mating.
- Recovery phase animals: After at least 14 days without treatment.
- Method of sacrifice: F0 animals were killed by Carbon dioxide asphyxiation with subsequent exsanguination
Other examinations:
GROSS NECROPSY
- All adult animals were subject to a detailed necropsy. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
HISTOPATHOLOGY / ORGAN WEIGHTS
For bilateral organs, left and right organs were weighed together.
Histology
Fixation: Tissues were routinely preserved in 10 % Neutral Buffered Formalin with the exception of Testes in modified Davidson’s fluid; Eyes In Davidson’s fluid.
Processing: Tissue samples were dehydrated, embedded in paraffin wax and sectioned at a nominal four to five micron thickness. For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required. The five lowest numbered males and females in Groups 1 and 4 at scheduled termination.
Abnormalities only: All animals
- Routine staining: Sections were stained with haematoxylin and eosin; in addition samples of the testes were stained using a standard periodic acid Schiff (PAS) method.
Statistics:
See section "Any other information on materials and methods incl. tables”.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain during Week 1 of treatment was reduced in males and female receiving 7500 ppm with statistical significance.
Overall body weight gain in males was similar to Controls up to 2500 ppm and was lower but not statistically significantly at 7500 ppm.
Overall bodyweight gains in females were statistically significantly lower than Controls in all treated groups, but a dose response was not apparent.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Overall food consumption for males and toxicity phase females receiving Neryl Acetate up to 7500 ppm was unaffected by treatment.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly lower group mean erythrocyte counts in males receiving 7500 ppm, and a slight but not statistically significant lower level for males receiving 2500 or 1000 ppm when compared with Controls was revealed.
Statistically significantly higher mean cell haemoglobin levels for males receiving 7500 ppm and slightly but statistically significant higher mean cell volume levels for males receiving 1000 ppm or above were observed.
Mean cell haemoglobin concentration was slightly but statistically significantly higher for females receiving 1000 ppm or above.
After 2 weeks of recovery haematological examinations were similar to that of the Controls. As a consequence these findings were considered to be of no toxicological significance.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Organ weights for males and toxicity phase females killed after 6 weeks of treatment indicated that the adjusted group mean kidney weights for animals that received 7500 ppm and the adjusted group mean liver weights for females that received 7500 ppm were slightly but statistically significantly higher than that of the Controls.
Organ weights taken following the two-week recovery period for animals that received 7500 ppm, were similar to Controls indicating no persistent affects.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
All histological changes were considered to be unrelated to treatment.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY:
There were no decedents in the study. Routine physical examination and arena observations did not reveal any abnormalities that were considered related to treatment with test item.

BODY WEIGHT:
Group mean bodyweight gain during Week 1 of treatment was reduced in males receiving 7500 ppm and females receiving 1000, 2500 and 7500 ppm when compared with Controls, with statistical significance being attained at 7500 ppm for both males and females. Bodyweight gain was slightly, but not statistically significantly lower during Weeks 4-5 for males receiving 2500 ppm and almost throughout treatment period for males receiving 7500 ppm when compared with Controls. Overall bodyweight gain in males was similar to Controls up to 2500 ppm and was lower but not statistically significantly at 7500 ppm (87% of Controls). Bodyweight gain was slightly, but not statistically significantly lower during Weeks 1-2, 3-4 and 4-5 for toxicity phase females receiving Neryl Acetate when compared with Controls, and overall bodyweight gains were statistically significantly lower than Controls in all treated groups, but a dose res
ponse was not apparent.
- Overall bodyweight change during the recovery period was slightly but not statistically significantly lower than Controls for males, and was higher for females (200% of Controls) that had received 7500 ppm, but no statistical significance was attained.

FOOD CONSUMPTION:
Overall food consumption for males and toxicity phase females receiving Neryl Acetate up to 7500 ppm was unaffected by treatment. Food intake was slightly lower on Day 1 of treatment for females receiving 7500 ppm when compared with Controls.

GROSS PATHOLOGY:
- The macroscopic examination performed after the six weeks scheduled treatment period revealed no test substance related lesions.
The macroscopic examination performed after 2 weeks of recovery revealed no test substance related lesions. All findings were similar to the background of changes commonly seen in Sprague Dawley rats seen at these laboratories.

HISTOPATHOLOGY:
No treatment related changes were observed in rats up to 7500 ppm by dietary administration for five weeks.
- Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of various cell types present within the different stages. No cell or stage specific abnormalities were noted.
- Minimal cortical tubular hypertrophy of kidney was observed in one male (4M No. 13) at 7500 ppm. This finding correlated with slight increase in the weight of kidneys. However, considering the single incidence in only one sex, its relationship to treatment is uncertain.
- An increase in the minimal multifocal aggregates of alveolar macrophages in the lung was observed in 4/5 females at 7500 ppm. One of the control females also had this finding. The aggregates of alveolar macrophages were mainly observed in the sub pleural locations or in the parenchyma away from terminal bronchioles, which are considered as common background finding in rats. The increase in the incidence in treated females alone is considered as incidental.

OTHER FINDINGS:
- Sensory reactivity and grip strength: There was no effect of test item on sensory reactivity or grip strength.
- Motor activity: Motor activity was unaffected for females up to 7500 ppm, when compared to Controls and there were no clear effects on either rearing (high beam) or ambulatory (low beam) motor activity for males.
- Haematology: Haematological examination during Week 6 of treatment revealed statistically significantly lower group mean erythrocyte counts in males receiving 7500 ppm, and a slight but not statistically significant lower level for males receiving 2500 or 1000 ppm when compared with Controls. Statistically significantly higher mean cell haemoglobin levels for males receiving 7500 ppm and slightly but statistically significant higher mean cell volume levels for males receiving 1000 ppm or above were observed. Mean cell haemoglobin concentration was slightly but statistically significantly higher for females receiving 1000 ppm or above. - Other inter-group differences from Controls were minor; neutrophil counts were higher for females receiving 7500 ppm when compared to Controls, but lacked a dose-relationship and was confined to one sex and was therefore considered due to normal biological variation.
- In Week 2 of recovery, haematological examinations of erythrocyte counts, mean cell haemoglobin and mean cell volume in males that received 7500 ppm and mean cell haemoglobin concentration,
total leucocyte count and differential leucocyte count (neutrophils, lymphocytes, eosinophils, basophils, monocytes and large unstained cells) in females that received 7500 ppm were similar to that of the
Controls
- Clinical chemistry: The biochemical examination of the blood plasma in Week 6 of treatment did not indicate any clear effects of treatment. When compared with the Controls, plasma levels of bile acids for males receiving 1000 ppm or above were slightly, but statistically significantly decreased, but no dose trend was apparent.
- All other inter-group differences from Controls were minor, were confined to one sex or lacked a dose-relationship. Such differences included minor, transient variations of some plasma electrolyte
concentrations such as sodium levels in males and potassium levels in females receiving 7500 ppm; these values were considered fortuitous and were therefore considered of no toxicological importance.
- Review of bile acid levels in Week 2 of recovery revealed levels similar to Controls for males that received 7500 ppm. Group mean sodium levels in Week 2 of recovery were the same as Controls.
Key result
Dose descriptor:
NOAEL
Effect level:
7 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect observed at the highest concentration tested, corresponding to 440 mg/kg bw/day for males, 465 mg/kg bw/day for toxicity phase females and 484 mg/kg/day for reproductive phase females during pre-mating period.
Critical effects observed:
no

Formulation analysis:

The mean concentrations were within applied limits of +10%/-15%, confirming the accuracy of formulation. The difference from mean values was <3 %, confirming precise analysis. Procedural recovery values remained within 94.2 and 100.8 %, confirming the continued accuracy of the method.

Achieved dose

Achieved intake of animals measured during the toxicity phase generally maintained the intended intervals between treatment groups. As anticipated, achieved intake was higher at the start of the treatment period and declined progressively as the animals matured.

Table 7.8.1/4: Achieved dosage for Toxicity and Recovery phase males:

Level (ppm)

Achieved dosage (mg/kg bw/day)

Mean

Range

1000

61

51-72

2500

150

129-175

7500

440

366-518

Table 7.8.1/5: Achieved dosage for Toxicity and Recovery phase females

Level (ppm)

Achieved dosage (mg/kg bw/day)

Mean

Range

1000

65

55-71

2500

150

127-169

7500

465

436-495

Achieved intake of females measured throughout the treatment period, generally maintained the intended intervals between treatment groups. Achieved intake was relatively stable during gestation, but increased significantly during lactation, reflecting increasing food intake during this period of high physiological demand on the parent female.

 

Table 7.8.1/6: Achieved dosage for Reproductive phase females

Level (ppm)

Achieved dosage (mg/kg bw/day)

Pre-pairing phase

Gestation

Lactation

Average

Range

Range

Range

1000

67

63-70

65-80

98-151

2500

172

161-182

168-189

266-390

7500

484

483-484

471-547

624-1080

Conclusions:
The NOAEL for systemic toxicity was 7500 ppm, the highest dose tested, corresponding to 440 mg/kg bw/day for males, 465 mg/kg bw/day for toxicity phase females and 484 mg/kg/day for reproductive phase females during pre-mating period.
Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted according to guideline OECD 422 and in compliance with GLP, groups of Crl:CD(SD) rats received NERYL ACETATE orally, via the diet, at concentrations of 1000, 2500 or 7500 ppm. Toxicity phase males were treated daily for three weeks before pairing, throughout pairing and up to necropsy after a minimum of five consecutive weeks. Toxicity phase females were treated daily for a minimum of five consecutive weeks up to necropsy in Week 6. Five high dose Recovery phase male and female rats were treated daily for a minimum of five consecutive weeks, followed by a 14 day period without treatment. Recovery phase males were used for pairing with reproductive phase females, but recovery females were not paired. A similarly constituted Control group was assigned to each phase, and received the vehicle in untreated diet, throughout the same relative treatment period.

During the study, clinical condition, detailed physical and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology, blood chemistry, oestrous cycles, organ weight and macroscopic investigations were undertaken for adult animals.

Microscopic pathology investigations were undertaken for the first five Toxicity phase males and Reproductive and Toxicity phase females in Group 1 (Control) and Group 4 (7500 ppm).

The mean concentrations of the test item in formulations were within applied limits of +10%/-15%, confirming the accuracy of formulation.

Administration of the test item at dose levels of 1000, 2500 and 7500 ppm was well tolerated with no mortalities or effects that could be attributed to treatment on clinical condition, sensory reaction, grip strength, motor activity, oestrous cycles, macroscopic or microscopic pathology among the adult animals.

Mean achieved dosages during the pre-pairing phase were 61, 150 and 440 mg/kg bw/day for males and 65, 150 and 465 mg/kg bw/day for toxicity phase females and 67, 172 and 484 mg/kg/day for reproductive phase females receiving 1000, 2500 and 7500 ppm, respectively.

Group mean bodyweight gain (Week 1 of treatment) was reduced in males receiving 7500 ppm and females receiving 1000, 2500 and 7500 ppm when compared with Controls; and overall bodyweight gain was statistically significantly lower than Controls in females, but a dose response was not apparent. Overall bodyweight change during the recovery period was slightly but not statistically significantly lower for males, but was significantly higher for females that had received 7500 ppm.

Overall food consumption for males and toxicity phase females receiving Neryl Acetate up to 7500 ppm was unaffected by treatment. Food intake was slightly lower on Day 1 of treatment for toxicity when compared with Controls.

Haematological examination during Week 6 of treatment revealed statistically significantly lower group mean erythrocyte counts in males receiving 7500 ppm, and a slight but not statistically significant lower level for males receiving 2500 or 1000 ppm when compared with Controls.

Statistically significantly higher mean cell haemoglobin levels for males receiving 7500 ppm and slightly but statistically significant higher mean cell volume levels for males receiving 1000 ppm or above. Mean cell haemoglobin concentration was slightly but statistically significant higher for females receiving 1000 ppm or above.

Haematological parameters examined in Week 2 of recovery were similar to that of the Controls.

The biochemical examination of the blood plasma in Week 6 of treatment did not indicate any clear effects of treatment. When compared with the Controls, plasma levels of bile acids for males receiving 1000 ppm or above were slightly, but statistically significantly decreased, but no dose trend was apparent.

Review of bile acids levels in Week 2 of recovery revealed similar levels to Controls for males that received 7500 ppm.

Organ weights for males and toxicity phase females killed after 6 weeks of treatment indicated that the adjusted group mean kidney weights for animals that received 7500 ppm and the adjusted group mean liver weights for females that received 7500 ppm were slightly but statistically significantly higher than that of the Controls.

Organ weights taken following the two week recovery period for animals that received 7500 ppm, were similar to Controls indicating no persistent effects.

All histological changes were considered to be unrelated to treatment.

Therefore, the NOAEL for systemic toxicity was 7500 ppm, the highest dose tested, corresponding to 440 mg/kg bw/day for males, 465 mg/kg bw/day for toxicity phase females and 484 mg/kg/day for reproductive phase females during pre-mating period.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
440 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Recent GLP study conducted according to OECD Guideline No 422 without any deviation (Klimisch score = 1).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted according to guideline OECD 422 and in compliance with GLP, groups of Crl:CD(SD) rats received NERYL ACETATE orally, via the diet, at concentrations of 1000, 2500 or 7500 ppm. Toxicity phase males were treated daily for three weeks before pairing, throughout pairing and up to necropsy after a minimum of five consecutive weeks. Toxicity phase females were treated daily for a minimum of five consecutive weeks up to necropsy in Week 6. Five high dose Recovery phase male and female rats were treated daily for a minimum of five consecutive weeks, followed by a 14 day period without treatment. Recovery phase males were used for pairing with reproductive phase females, but recovery females were not paired. A similarly constituted Control group was assigned to each phase, and received the vehicle in untreated diet, throughout the same relative treatment period.

During the study, clinical condition, detailed physical and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology, blood chemistry, oestrous cycles, organ weight and macroscopic investigations were undertaken for adult animals.

Administration of the test item at dose levels of 1000, 2500 and 7500 ppm was well tolerated with no mortalities or effects that could be attributed to treatment on clinical condition, sensory reaction, grip strength, motor activity, oestrous cycles, macroscopic or microscopic pathology among the adult animals.

All histological changes were considered to be unrelated to treatment.

Justification for classification or non-classification

No toxic effects were observed in a repeated dose toxicity study until the highest dose tested, corresponding to 440 mg/kg bw/day for males, 465 mg/kg bw/day for toxicity phase females and 484 mg/kg/day for reproductive phase females during pre-mating period.

Therefore NERYL ACETATE is not classified for repeated dose toxicity according to CLP Regulation (EC) No 1272 /2008.