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EC number: 415-490-5 | CAS number: 141773-73-1 HELVETOLIDE
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 2001-11-23 to 2002-03-30
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study performed according to OECD test guideline No. 415 and in compliance with GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Version / remarks:
- 1983
- Deviations:
- no
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- UK GLP Compliance Program (inspected on: 2000-02-28 / signed on 2000-04-26)
- Limit test:
- no
Test material
- Reference substance name:
- 2-{(1RS)-1-[(1SR)-3,3-DIMETHYLCYCLOHEXYL]ETHOXY}-2-METHYLPROPYL PROPIONATE
- Molecular formula:
- C17 H32 O3
- IUPAC Name:
- 2-{(1RS)-1-[(1SR)-3,3-DIMETHYLCYCLOHEXYL]ETHOXY}-2-METHYLPROPYL PROPIONATE
- Reference substance name:
- 2-{(1RS)-1-[(1RS)-3,3-DIMETHYLCYCLOHEXYL]ETHOXY}-2-METHYLPROPYL PROPIONATE
- Molecular formula:
- C17 H32 O3
- IUPAC Name:
- 2-{(1RS)-1-[(1RS)-3,3-DIMETHYLCYCLOHEXYL]ETHOXY}-2-METHYLPROPYL PROPIONATE
- Reference substance name:
- 2-METHYL-2-{[(1RS,2RS)-2,6,6-TRIMETHYLCYCLOHEPTYL]OXY}PROPYL PROPIONATE
- Molecular formula:
- C17H32O3
- IUPAC Name:
- 2-METHYL-2-{[(1RS,2RS)-2,6,6-TRIMETHYLCYCLOHEPTYL]OXY}PROPYL PROPIONATE
- Test material form:
- liquid
- Details on test material:
- - Physical state: clear colourless liquid
- Storage condition of test material: room temperature, in the dark until 2001-10-18 and thereafter approximately 4°C in the dark under nitrogen
Constituent 1
Constituent 2
Constituent 3
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Remarks:
- Crl: CD (SD) IGS BR
- Details on species / strain selection:
- The rat was selected as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS: Crl: CD (SD) IGS BR strain
- Source: Charles River (UK) Limited, Manston Road, Margate, Kent- UK
- Age at study initiation: no data
- Weight at study initiation: Males: 185 to 259 g; Females: 187 to 277g
- Fasting period before study: none
- Housing: Upon arrival, the animals were housed in groups of four in polypropylene cages with stainless steel grid floors and tops, suspended over paper-lined polypropylene trays. During the mating period animals were transferred to a similar type cage on a one male to one female per cage basis. Following evidence of successful mating, the males were returned to their original cages and transferred to a separate animal room of comparable conditions. The females were housed, individually, in polypropylene cages with solid floors and stainless steel tops. Mated females were given softwood chips, as bedding throughout gestation and lactation.
- Diet (e.g. ad libitum): ad libitum (pelleted Rat and Mouse VRF1C Diet (Charles River UK Limited, Margate, Kent))
- Water (e.g. ad libitum): ad libitum
- Acclimation period: seventeen days for males and thirty one days for females
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 15
(On isolated occasions the room temperature and/or humidity fell outside the protocol target limits but this was considered not to have affected the purpose or integrity of the study)
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2001-11-06 To: 2002-03-30
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5 %
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test material was prepared at the appropriate concentration as a solution in 0.5 % carboxymethyl cellulose (vehicle). For each dose level a separate aliquot of test material was weighed into the appropriate container. The vehicle was added and mixed using a Silverson homogeniser to ensure a homogeneous suspension was formed.
VEHICLE
- Justification for use and choice of vehicle (if other than water): not soluble in water
- Concentration in vehicle: 0, 5, 25 and 100 mg/L
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no. (if required): no data
- Purity: no data - Details on mating procedure:
- - M/F ratio per cage: 1 (1 female + 1 male per cage)
- Length of cohabitation: until evidence of successful mating (up to three weeks)
- Proof of pregnancy: The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating
- After successful mating each pregnant female was caged (how): Following evidence of successful mating, mated females were separated from male and housed individually during the period of gestation and lactation. The males were returned to their original cages and transferred to a separate animal room of comparable conditions.
- Any other deviations from standard protocol: none - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of each formulation were taken once per week during the first four weeks and approximately once every month until study completion and analysed by gas chromatography (GC) using an external standard technique. The results indicate that the prepared formulations were within acceptable limits of the nominal concentration. The analytical method used has been satisfactorily validated in terms of linearity, specificity and accuracy for the purposes of the study.
- Duration of treatment / exposure:
- (P) Females: 17 days prior to pairing, then throughout mating, gestation and lactation.
(P) Males: 73 days before mating, then like females - Frequency of treatment:
- Once daily
- Details on study schedule:
- Male animals were dosed for 73 days and female animals were dosed for 17 days, at their appointed dose levels, prior to pairing.
Parental males and females were paired within their respective dose groups for up to twenty one days.
Following evidence of mating, the animals were separated and males returned to their holding cages.
The pregnant females were allowed to deliver their offspring. The offspring were observed for growth and development during lactation.
At weaning on Day 21 (or as near to this date as possible) post partum the surviving offspring were killed and examined macroscopically post mortem.
The surviving adult Parental animals were killed and examined macroscopically post mortem.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 28 animals/sex/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The concentrations tested in this study were determined from a previous 28-d toxicity study (OECD 407 Guideline) performed with the same test material on the same rat strain and for which a NOEL of 250 mg/kg bw was determined.
- Rationale for animal assignment (if not random): random - Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during the normal week and once daily during the week-end and public holidays
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily, immediately before, immediately after and one hour after dosing for clinical signs of toxicity
BODY WEIGHT: Yes
- Time schedule for examinations: weekly during maturation and mating period. Following mating the parental males were weighed weekly until termination. Parental generation females showing evidence of mating were weighed on days 1, 4, 7, 14 and 21 post coitum. Parental generation females with a live litter were weighed on Days 1, 4, 7, 14 and 21 post partum.
FOOD CONSUMPTION:
During the maturation periods food consumption was recorded for each cage of parental generation adults. For parental generation females showing evidence of mating, food consumption was recorded for the periods covering days 1 to 7, 7 to 14 and 14 to 21 post coitum. For parental generation females with live litters, food consumption was recorded for the periods covering Days 1 to 7 and 7 to 14 postpartum. - Oestrous cyclicity (parental animals):
- A vaginal smear was prepared for each female and the stage of the oestrous cycle or the presence of sperm was recorded.
- Sperm parameters (parental animals):
- Not Applicable/Not required in OECD 415 Guideline
Parameters examined in male parental animals: testis weight, epididymis weight, seminal vesicles (with coagulating gland) weight, spermatozal content - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in offspring:
- Number (daily)
- Sex (PND 1 and 21)
- Bodyweight (PND 1, 4, 7, 14 and 21)
- Clinical signs (Daily)
- Physical development including detachment of pinna, tooth eruption, eye opening
- Reflexological assessment including surface righting reflex (PND 1), mid-air righting reflex (PND 17), startle reflex (PND 21) and pupil reflex (PND21).
GROSS EXAMINATION OF DEAD PUPS:
yes, all offspring that died, or were killed in extremis during the lactation period were examined macroscopically and externally. - Postmortem examinations (parental animals):
- All adult animals, killed in extremis or found dead during the course of the study, were examined macroscopically for internal and external abnormalities. All significant abnormalities were retained in fixative for possible further study.
SACRIFICE
Following successful weaning of offspring, all the surviving adults, including non-fertile animals, were killed by carbon dioxide asphyxiation, followed by cervical dislocation.
GROSS NECROPSY
All animals were examined macroscopically for both internal and external abnormalities. Selected organs and tissues were retained in fixative.
HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights were determined for: Epididymides, Kidneys, Liver, Ovaries, Pituitary gland, Prostate, Seminal vesicles (with coagulating gland), Testes, Uterus with cervix.
Histopathology was performed on: Cervix, Coagulation gland, Epididymides, Kidneys, Liver, Pituitary gland, Prostate, Seminal vesicles, Significant abnormalities, Testes, Uterus, Vagina, Ovaries. Initially the tissues from high dose and control animals were processed and embedded in paraffin wax BP (mp 56 °C). Sections of the tissues were taken at 5 µm thickness, mounted on glass slides and stained with haematoxylin and eosin. In addition, following the results of the initial examination, the target organs from the low and intermediate dose groups were similarly processed.
The sections of reproductive and target organs from control and high dose animals were examined microscopically by a pathologist. Examination of the target organs was extended to the low and intermediate dose groups. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem macroscopic examinations for internal and external abnormalities. - Statistics:
- The following parameters were analysed statistically, where appropriate using the test methods outlined as follows:
Adult male and female bodyweight during the maturation, gestation and lactation periods, adult male food consumption, female food consumption during maturation, gestation and lactation, litter size, litter weight, individual offspring bodyweight, offspring landmarks of physical development.
Adult precoital intervals, female gestation lengths, offspring reflexological responses and litter sex ratios: Individual values were compared using the Kruskal-Wallis non-parametric rank sum test. Where significant differences were seen, multiple comparisons of control values against treated group values was performed using Mann-Whitney "U" test.
Histopathology: Chi-squared analysis for differences in the incidence of lesions occurring with an overall frequency of 1 or greater. Kruskal-Wallis one-way non-parametric analysis of variance for the comparison of severity grades for the more frequently observed conditions. - Reproductive indices:
- For each group the following were calculated.
Pre-coital interval: calculated as the time elapsing between initial pairing and the observation of positive mating
Mating Index % = number of animals mated/number of animals paired * 100
Pregnancy index % = Number of pregnant females / Number of animals mated * 100
Gestation length: calculated as the number of days of gestation including the days for observation of mating at the start of parturition. When the start of parturition occurred overnight, the total was adjusted by substracting half a day.
Parturition index % = Number of females delivering live pups / Number of pregnant females * 100 - Offspring viability indices:
- The following indices were calculated for each group from individual data.
Live birth index = Number of pups alive on Day 1 / Number of pups born * 100
Viability Index 1 (%) = Number of pups alive on Day 4/Number of pups alive on Day 1 * 100
Viability Index 2 (%) = Number of pups alive on Day 7/Number of pups alive on Day 4 * 100
Viability Index 3 (%) = Number of pups alive on Day 14/Number of pups alive on Day 7 * 100
Viability Index 4 (%) = Number of pups alive on Day 21/Number of pups alive on Day 14 * 100
Viability Index 5 (%) = Number of viable pups at weaning/Number of pups alive on Day 1 * 100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/d there was evidence of increased salivation, predominantly post dosing for males and females. For males only, there was increased salivation pre-dosing which was at a lower incidence and frequency compared to post-dosing salivation. All other clinical findings were those commonly observed on this type of study.
At 250 mg/kg bw/d the majority of males showed evidence of increased salivation immediately post dosing. The incidence and frequency were lower than was seen at the highest dose level. Only one female showed similar findings. There were no other significant clinical findings.
At 50 mg/kg bw/d one male only showed evidence of increased salivation immediately post dosing. There were no other significant clinical findings for this group. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- At 1000 and 250 mg/kg bw/d there were no mortalities during the course of the study.
At 50 mg/kg bw/d one female was found dead during the gestation phase of the study. There was no previous clinical history. Post mortem macroscopic findings showed significant changes within the gastro-intestinal tract including gaseous distension of the small intestine and discolouration of the contents of the intestines.
At 0 mg/kg bw/d there were no mortalities. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effect
- Food consumption and compound intake (if feeding study):
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- 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
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- See table 7.8.1/2
At 1000 mg/kg bw/d there were no treatment-related histopathological changes associated with reproductive organs. Treatment-related changes were present in the kidney of males and liver of both sexes. A statistically significant increase in the incidence and severity of globular accumulations of eosinophilic material in the renal tubular epithelium (p<0.001) and a greater severity and prevalence of groups of basophilic renal tubules (p<0.001) were observed when compared to control values. Generalised hepatocyte enlargement was observed for males and females at a statistically significant incidence (p<0.01 and p<0.001 respectively). In addition, associated low severity grades of glycogen type hepatocyte vacuolation were observed for males and females (p<0.01 and p<0.05 respectively).
At 250 mg/kg bw/d, a statistically significant incidence and severity of globular accumulations of eosinophilic material was observed in the renal tubular epithelium of males only (p<0.001) together with higher severity grades and prevalence of groups of basophilic tubules. Generalised heptatocyte enlargement was observed for males only at an incidence that was statistically significant (p<0.05) with low severities of glycogen type hepatocyte vacuolation (p<0.01).
At 50 mg/kg bw/d a statistically significant increase in incidence and severity of globular accumulations of eosinophilic material was observed in the kidneys for males only (p<0.001). - Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no significant treatment-related effects upon mating performance or fertility. The intergroup distribution of precoital intervals showed that the majority of pairings resulted in positive evidence of mating within four days after pairing.
There were no significant treatment-related effects upon pregnancy or parturition.
At 50 mg/kg bw/d one female was found dead during parturition but this was not attributed to a test material effect upon pregnancy.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect observed
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no significant treatment-related effects upon offspring clinical condition throughout lactation; as indicated by comparable incidence and severity ofclinical findings observed.
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- There were no significant treatment-related effects upon litter size at birth and subsequent offspring viability during lactation.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no significant treatment-related effects upon individual offspring weight gain during lactation.
The onset of tooth eruption of group 3 offspring (250 mg/kg bw/d) was significantly different (p<0.05) from the control: 10.6 days compared to 11.4 days. However at completion this difference was no longer significant: 14.4 compared to 14.8 days. This isolated statistically significant differences in onset of landmarks of development was considered to be incidental events that were unrelated to treatment. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no significant. treatment-related .differences in the type and incidence of macroscopic post mortem findings for offspring that died during the course of lactation or for offspring at terminal necropsy.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no significant treatment-related effects upon offspring reflexological responses.
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect observed
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Table 7.8.1/1: Kidneys and Liver weight of parental males
Dose level (mg/kg bw/d) |
Kidneys |
Liver |
||||
Weight (g) |
% of bodyweight |
Weight (g) |
% of bodyweight |
|||
Males |
0 |
Mean SD N |
3.872 0.5117 28 |
0.637 0.0624 28 |
20.414 0.3163 28 |
3.337 0.3161 28 |
50 |
Mean SD N |
4.031 0.2891 28 |
0.667 0.0563 28 |
20.802 2.3768 28 |
3.426 0.2510 28 |
|
250 |
Mean SD N |
4.227** 0.5127 28 |
0.674 0.0610 28 |
22.213 3.3218 28 |
3.518 0.2809 28 |
|
1000 |
Mean SD N |
4.389*** 0.3850 28 |
0.737*** 0.0466 28 |
23.271** 2.4034 28 |
3.901*** 0.2629 28 |
*= significantly different from control value (p<0.05)
** = significantly different from control value (p<0.01)
*** = significantly different from control value (p<0.001)
Table 7.8.1/2 : Histopathological findings in parental animals
Histopathological Finding |
Dose Level (mg/kg bw/d) |
|||||||
Males (28 animals/dose) |
Females (28 animals/dose) |
|||||||
0 |
50 |
250 |
1000 |
0 |
50 |
250 |
1000 |
|
Kidney |
||||||||
Groups of basophilic tubules |
|
|
+ |
+++ |
|
|
|
|
- Absent |
13 |
13 |
8 |
3 |
26 |
26 |
25 |
28 |
- Minimal |
15 |
13 |
14 |
13 |
2 |
2 |
3 |
0 |
- Slight |
0 |
1 |
4 |
12 |
0 |
0 |
0 |
0 |
- Moderate |
0 |
1 |
2 |
0 |
0 |
0 |
0 |
0 |
Globular accumulations of eosinophilic material |
|
+++ |
+++ |
+++ |
|
|
|
|
- Absent |
17 |
3 |
2 |
2 |
|
|
|
|
- Minimal |
6 |
18 |
18 |
10 |
|
|
|
|
- Slight |
5 |
5 |
8 |
12 |
|
|
|
|
- Moderate |
0 |
2 |
0 |
4 |
|
|
|
|
|
Liver |
|||||||
Hepatocyte vacuolation |
|
|
-- |
-- |
|
|
|
- |
- Absent |
2 |
2 |
3 |
13 |
9 |
9 |
9 |
18 |
- Minimal |
15 |
16 |
23 |
10 |
18 |
18 |
17 |
10 |
- Slight |
11 |
10 |
2 |
5 |
1 |
1 |
2 |
0 |
Hepatocyte enlargement |
|
|
+ |
++ |
|
|
|
+++ |
- Absent |
28 |
26 |
22 |
19 |
25 |
20 |
22 |
12 |
- Minimal |
0 |
2 |
6 |
8 |
3 |
7 |
3 |
13 |
- Slight |
0 |
0 |
0 |
1 |
0 |
1 |
3 |
3 |
+/- = significantly greater/lower from control value (p<0.05)
++/-- = significantly greater/lower from control value (p<0.01)
+++/--- = significantly greater/lower from control value (p<0.001)
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study, the No Effect Level (NOAEL) for parental toxicity, reproduction and offspring development is therefore 1000 mg/kg bw/d. Under the test conditions, the test material is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and to to the GHS.
- Executive summary:
In a one-generation reproduction toxicity study performed in accordance with OECD test guideline No. 415 and in compliance with GLP, the test material diluted in carboxymethylcellulose (CMC) was administered orally, by gavage, to groups of twenty-eight Sprague-Dawley Crl: CD (SD) IGS BR rats per sex throughout maturation, mating, gestation and lactation. The dose levels were 50, 250 and 1000 mg/kg bw/day with a similar sized control group receiving vehicle alone. Following at least ten and two weeks of dosing respectively, male and female rats were paired within their dose groups to produce litters. At weaning of the offspring, all surviving animals were killed and examined macroscopically.
Parental animals were observed daily for clinical signs. Bodyweights and food consumption were recorded weekly during the maturation phase which was continued for males after the mating phase. Mated females were weighed and food consumption recorded on specific days post coitum and post partum. The offspring were observed daily for clinical signs. The litter size and individual pup bodyweights were recorded on specific days post partum. During the lactation period, the offspring were observed for intra-litter onset and duration of landmarks or physical development. On specific days of lactation, reflexological assessment of offspring was performed.
Post mortem macroscopic examinations were performed on all adults and offspring, including decedents. Reproductive and potential target organs were weighed from all parental animals and were then preserved in fixative. Histopathology was carried out on reproductive and target organs from control and high dose groups parental animals. The target organs were examined from the low and intermediate groups.
For all dose levels, particularly 250 mg/kg bw/day and above there was evidence of increased salivation, predominantly post dosing. The incidence and frequency were dosage-related. The finding was considered to be an adaptation to administration of an unpleasant-tasting material. There were no other significant effects upon adults during the in-life phase of the study.
There were no treatment-related effects upon reproductive performance or fertility and upon offspring viability, growth or development.
Post mortem findings showed no treatment-related effects upon the reproductive organs.
Significant liver weight increases were observed in males dosed at 1000 mg/kg bw/day. Histopathology showed higher incidence of hepatocyte enlargement associated with lower severity grades of glycogen type hepatocyte vacuolation at 1000 mg/kg bw/day for both males and females, and at 250 mg/kg bw/day for males only. It is assumed that the observed hepatocyte enlargement occurs as an induction of the microsomal drug metabolizing enzyme systems caused by the treatment and is considered as cellular adaptation phenomena in the absence of associated inflammatory or degenerative changes.
Significant kidney weight increases were also observed in males dosed at both highest doses. These increases were accompanied by eosinophilic accumulations together with an increased prevalence of basophilic tubules in the kidney of males only. In the case of the renal tubular accumulations of eosinophilic material (considered by the study author to be alpha-2 microglobin), this change is exclusive to male rats. Tubular basophilia is known to be an early stage of chronic progressive nephrosis which is frequently seen in Sprague-Dawley rat.
Under the test conditions, the No Effect Level (NOAEL) for parental toxicity, reproduction and offspring development is therefore 1000 mg/kg bw/day.
The one-generation reproduction toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a one-generation reproduction toxicity study (OECD 415) in rats.
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