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EC number: 801-093-8 | CAS number: 1315251-11-6
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 Nov 2015 to 14 Mar 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guidelines for Testing of Chemicals No. 421 “Reproduction/Developmental Toxicity Screening Test
- Version / remarks:
- 27 July 1995
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (8S)-7,7,8,9,9-pentamethyl-5H,6H,7H,8H,9H-cyclopenta[h]quinazoline
- EC Number:
- 801-093-8
- Cas Number:
- 1315251-11-6
- Molecular formula:
- C16H22N2
- IUPAC Name:
- (8S)-7,7,8,9,9-pentamethyl-5H,6H,7H,8H,9H-cyclopenta[h]quinazoline
- Test material form:
- solid
1
Test animals
- Species:
- rat
- Strain:
- other: Wistar Han™:RccHan™:WIST
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Blackthorn, Bicester, Oxon, UK
- Age at study initiation: Approximately twelve weeks old.
- Weight at study initiation: The females weighed 183 to 213g
- Housing: All animals were housed in groups of four in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding, except during mating. Mated females were housed individually during gestation and lactation in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 11 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: 21 Dec 2015 to 4 Feb 2016
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
A known amount of test item was mixed with a small amount of basal laboratory diet in a Robot Coupe Blixer 4 mixer until homogeneous. This pre-mix was then added to a larger amount of basal laboratory diet and mixed for a further sixty minutes at a constant speed, setting 1 in a Hobart U200/H800 mixer.
DIET PREPARATION
- Storage temperature of food: at -18 °C
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity of the dietary admixtures was determined. The concentration of the substance in the the final solution was quantified by HPLC using UV detection. The peak area response for the substance in each calibration standard chromatogram was measured. Calibration curves were constructed by linear regression of calibration standard response versus calibration standard concentration. The area response of the peak observed at the characteristic retention time for the substance in sample and procedural recovery chromatogram, was measured.
- Details on mating procedure:
- - M/F ratio per cage: Animals were paired on a 1 male: 1 female basis within each dose group
- Length of cohabitation: 14 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: Mated females were housed individually during the period of gestation and lactation - Duration of treatment / exposure:
- Up to seven weeks including a two week pre-pairing phase, pairing, gestation and early lactation for females
- Frequency of treatment:
- Continuously
- Duration of test:
- On day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days. Pregnant females were allowed to give birth and maintain their offspring until day 5 post partum, at which all females and surviving offspring were killed and examined macroscopically. The male dose groups were killed and examined macroscopically on day 43.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 ppm
- Remarks:
- Equivalent to 3.0 and 3.4 mg/kg bw/day for males and females, respectively
- Dose / conc.:
- 150 ppm
- Remarks:
- Equivalent to 9.1 and 10.5 mg/kg bw/day for males and females, respectively
- Dose / conc.:
- 500 ppm
- Remarks:
- Equivalent to 31.0 and 34.0 mg/kg bw/day for males and females, respectively
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, plain diet
Examinations
- Maternal examinations:
- CLINICAL OBSERVATIONS:
- Time schedule for examinations: All animals were examined for overt signs of toxicity, ill-health or behavioral change daily from the start of treatment. All observations were recorded
- Each pregnant female was observed at least three times a day (early morning, mid-day and as late a s possible during the normal working day) around the period of expected parturition. Observations were carried out at approximately 08:30 and as late as possible at weekends and public holidays. The following was recorded for each female:
i. Date of pairing
ii. Date of mating
iii. Date and time of observed start of parturition
iv. Date and time of observed completion of parturition
BODY WEIGHT:
- Time schedule for examinations: Days 0, 7, 14 and 20 post coitum, and on days 1 and 4 post partum.
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, during the pre-pairing period, weekly food consumption was recorded for each cage of adults until pairing. This was continued for males after the mating phase. For females showing evidence of mating, food consumption was recorded for the periods covering post coitum Days 0-7, 7-14 and 14-20. For females with live litters, food consumption was recorded during the lactation period (days 1-4).
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes, weekly food efficiency (body weight gain/food intake) was calculated retrospectively for males and for females during the pre-pairing phase. Due to offspring growth and milk production for lactation, food efficiency for females could not be accurately calculated during gestation and lactation.
WATER CONSUMPTION:
- Time schedule for examinations: Water intake was observed daily by visual inspection of water bottles for any overt changes.
GROSS NECROPSY
- All adult animals and offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
HISTOPATHOLOGY
- Samples of the following tissues were preserved from all animals from each dose group, in buffered 10% formalin: Coagulating gland, liver, ovaries, mammary gland, pituitary, prostate, seminal vesicles, stomach, thyroids/parathyroids, uterus/cervix and vagina
SACRIFICE
- Adult males were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination on day 43. Adult females were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination on day 5 post partum. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes - Fetal examinations:
- - External examinations: Yes, all animals
- Internal examinations: Yes, all animals
- Macroscopic abnormalities: Yes, all animals - Statistics:
- Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05
- Indices:
- Live Birth Index = Number of offspring alive on Day 1 / Number of offspring born x 100%
Viability Index = Number of offspring alive on Day 4 / Number of offspring alive on Day 1 x 100%
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- See section 6.2.1 and Table 3 of the report, attached in the repeated dose toxicity section
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- See section 6.1.2 of the report, attached in the repeated dose section.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Females treated with 500 ppm showed a reduction in body weight gain during maturation. Although statistical significance was not achieved and a true dose related response was not evident, body weight gain during the first two weeks of gestation and during lactation was reduced when compared to controls. Reductions were evident for cumulative body weight gains between days 0 and 14 and days 0 and 20 of gestation and for body weight on day 4 of lactation and for body weight gain during lactation. Statistical significance was achieved for cumulative body weight gain between days 0 and 14 of gestation, body weight gain during lactation and body weight on day 4 of lactation.
See section 6.2.2 and Table 5 of the report, attached in the repeated dose section. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Females treated with 500 ppm showed a slight reduction in food consumption during the first week of treatment. Recovery was evident thereafter. No such effects were detected in females treated with 150 or 50 ppm,
See section 6.2.3 and Table 7 of the report, attached in the repeated dose section. - Food efficiency:
- no effects observed
- Description (incidence and severity):
- Females treated with 500 ppm showed a slight reduction in food conversion efficiency during the first week of treatment. Recovery was evident th ereafter. No such effects were detected in females treated with 150 or 50 ppm.
See section 6.2.3 and Table 7 of the report, attached in the repeated dose section. - Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- See section 6.2.4 of the report, attached in the repeated dose toxicity section
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine 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
- Description (incidence and severity):
- Animals of either sex treated with 500 ppm and females treated with 150 ppm showed a statistically significant increase in liver weight both absolute and relative to terminal body weight. Females treated with 500 ppm also showed a statistically significant increase in thyroid/parathyroid weight and reduced pituitary weight both absolute and relative to terminal body weight. No such effects were detected in males treated with 150 ppm or in animals of either sex treated with 50 ppm.
See section 6.5.1.1 and Table 16 of the report, attached in the repeated dose section. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No macroscopic abnormalities were detected.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related microscopic abnormalities were detected
See section 6.5.2 and Annex 1 of the report, attached in the repeated dose section. - Histopathological findings: neoplastic:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences.
See section 6.4.1 and Table 9-11 of the report, attached in the repeated dose toxicity section. - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences.
See section 6.4.1 and Table 9-11 of the report, attached in the repeated dose toxicity section. - Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences in fertility.
See section 6.4.1 and Table 9-11 of the report, attached in the repeated dose toxicity section. - Dead fetuses:
- not examined
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Gestation lengths were between 22 and 23½ days and the distribution of gestation lengths for treated females was essentially similar to control.
See section 6.3.3 of the report, attached in the repeated dose toxicity section. - Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 500 ppm
- Based on:
- test mat.
- Remarks:
- Equivalent to 31.0 and 34.0 mg/kg bw/day for males and females, respectively
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 ppm
- Based on:
- test mat.
- Remarks:
- Equivalent to 9.1 and 10.5 mg/kg bw/day for males and females, respectively
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no toxicologically significant effects detected.
See section 6.4.2 and Tables 9, 12 and 13 of the report, attached in the repeated dose toxicity section - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- See section 6.4.1 and tables 9 to 11 of the report, attached in the repeated dose toxicity section
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratio was comparable to controls.
See section 6.4.1 and tables 9 to 11 of the report, attached in the repeated dose toxicity section - Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Of the litters born, litter size at birth and subsequently on days 1 and 4 post partum were comparable to controls.
See section 6.4.1 and tables 9 to 11 of the report, attached in the repeated dose toxicity section - Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The clinical signs and necropsy findings apparent for offspring on the study were typical for the age observed. Neither the incidence nor distribution of these observations indicated any adverse effect of maternal treatment on offspring development at 50, 150 and 500 ppm.
See section 6.4.1 and tables 9 to 11 of the report, attached in the repeated dose toxicity section.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 500 ppm
- Based on:
- test mat.
- Remarks:
- Equivalent to 31.0 and 34.0 mg/kg bw/day for males and females, respectively
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Verification of test diets:
3.1 Method validation:
The analytical procedure was successfully validated for the substance in diet with respect to the specificity of chromatographic analysis, the linearity of detector response, method accuracy and precision.
The specificity of the analytical method was demonstrated by the absence of a peak at the characteristic retention time for the substance in the control sample chromatogram.
The data was found to have a linear correlation within the calibration range of 2.108 to 10.540 ppm The R2 fit of the calibration curve to the ck ta was 0.9999 and was considered to be acceptable.
A mean recovery value of 104% (CV= 1.91%, n=5) was obtained for 5 ppm and 114% (CV= 10.3%, n=5) was obtained for 500 ppm.
The limit of quantification (LOQ) was determined as the lowest standard concentration used during the study which was 2.108 ppm.
3.2 Homogeneity and stability of dose admixtures
The homogeneity and stability of the substance in dietary admixtures was assessed with respect to the level of concentration at nominal concentration of 50 ppm and 500 ppm.
Homogeneity was confirmed at the initial stability time point. The mean analysed concentration for the nine samples remained within 20% of the initial time zero value and the variation was less than 20%.
3.3 Concentration of dose formulations
The mean concentrations were within applied limits +/- 20% confirming accurate preparation.
Table 1. Results of admixture analysis
Analysis Number |
Nominal Concentration [ppm] |
Mean Concentration f ound |
|
[ppm] |
[expressed as % of nominal] |
||
1 |
0 |
ND |
|
50 |
46.5 |
93 |
|
150 |
146 |
98 |
|
500 |
503 |
101 |
|
2 |
0 |
ND |
- |
50 |
44.5 |
89 |
|
150 |
147 |
98 |
|
500 |
498 |
100 |
|
3 |
0 |
ND |
- |
50 |
50.6 |
101 |
|
150 |
153 |
102 |
|
500 |
509 |
102 |
Table 2. Summary report of effects on reproduction/development
Observations |
Dietary Concentrations (ppm) |
||||
0 (Control) |
50 |
150 |
500 |
||
Paired animals |
n |
12 |
12 |
12 |
12 |
Females showing evidence of copulation |
n |
12 |
12 |
12 |
12 |
Pregnant females |
n |
12 |
12 |
12 |
12 |
Conception Days 1-4 |
n |
12 |
12 |
12 |
12 |
Gestation = 22 Days |
n |
3 |
3 |
4 |
3 |
Gestation = 22 ½ Days |
n |
4 |
5 |
4 |
2 |
Gestation = 23 Days |
n |
3 |
3 |
3 |
4 |
Gestation = 23 ½ Days |
n |
2 |
1 |
1 |
3 |
Dams with live young born |
n |
12 |
12 |
12 |
12 |
Dams with live young at Day 4 post partum |
n
|
12 |
12 |
12 |
12 |
Corpora lutea/dam |
Mean |
10.8 |
12.5 |
12.3 |
11.4 |
Implants/dam |
Mean |
10.8 |
12.3 |
12.2 |
11.4 |
Live offspring/dam at Day 1 post partum |
Mean |
10.6 |
11.8 |
11.6 |
10.3 |
Live offspring/dam at Day 4 post partum |
Mean |
10.6 |
11.8 |
11.4 |
10.2 |
Sex ratio: % males at Day 1 post partum |
Mean |
62.3 |
56.5 |
56.3 |
48.6 |
Sex ratio: % males at Day 4 post partum |
Mean |
62.3 |
56.5 |
56.5 |
48.6 |
Litter weight (g) at Day 1 post partum |
Mean |
58.98 |
64.10 |
63.49 |
61.37 |
Litter weight (g) at Day 4 post partum |
Mean |
82.70 |
89.13 |
84.76 |
81.87 |
Male offspring weight (g) at Day 1 post partum |
Mean |
5.78 |
5.59 |
5.70 |
6.14 |
Male offspring weight (g) at Day 4 post partum |
Mean |
8.07 |
7.69 |
7.66 |
8.31 |
Female offspring weight (g) at Day 1 post partum |
Mean |
5.44 |
5.26 |
5.33 |
5.82 |
Female offspring weight (g) at Day 4 post partum |
Mean |
7.67 |
7.37 |
7.19 |
7.87 |
LOSS OF OFFSPRING/DAM |
|
|
|||
Pre-implantation (corpora lutea minus implantations) |
|
|
|||
0 |
n |
8 |
8 |
10 |
12 |
1 |
n |
0 |
3 |
2 |
0 |
Pre-natal (implantations minus live births) |
|
|
|||
0 |
n |
6 |
6 |
7 |
6 |
1 |
n |
1 |
4 |
3 |
1 |
2 |
n |
1 |
1 |
2 |
4 |
3 |
n |
0 |
0 |
0 |
1 |
Post natal (live births minus offspring alive on Day 4 post partum) |
|
|
|||
0 |
n |
11 |
12 |
10 |
10 |
1 |
n |
0 |
0 |
2 |
2 |
2 |
n |
1 |
0 |
0 |
0 |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test (OECD 421, GLP), the NOAEL is 500 ppm (equivalent to 31.0 and 34.0 mg/kg bw/day for males and females, respectively) for developmental and reproductive toxicity
- Executive summary:
See a complete summary at the reproduction/fertility.
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