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EC number: 700-503-1 | CAS number: 101238-01-1
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline study. A reliability of 2 is assigned because of read-across.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Remarks:
- Biosafety Research Center, Food, Drugs and Pesticides (An-Pyo Center), Japan
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 10 weeks old for female and male animals
- Weight at study initiation: 359 - 400g for males; 227 - 282g for females - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: at most 3 days, until proof of pregnancy
- Proof of pregnancy: vaginal plug or sperm in vaginal smear - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- Male: for 48 days from 2 weeks prior to mating
Female: for 41-52 days from 2 weeks prior to mating to day 3 postpartum throughout mating and pregnancy - Frequency of treatment:
- once daily
- Remarks:
- Doses / Concentrations:
0, 60, 200, 600
Basis:
actual ingested - No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day
BODY WEIGHT: Yes
- Time schedule for examinations: for males: once a week, the first and the last day of the administration, the sacrificed day; for pregnant females: on day 0, 14 and 20 of gestation, on day 0 and 4 of lactation
FOOD CONSUMPTION: Yes
- Time schedule: once a week, on the same day when body wt. determined - Oestrous cyclicity (parental animals):
- estrus cycle assessed during study
- Sperm parameters (parental animals):
- Parameters examined in P male parental generations:
testis weight, epididymis weight - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
OTHER: General appearance once a day - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after 49 days
- Maternal animals: All surviving animals after the last litter of each generation was weaned
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights (brain, thymid gland, liver, kidney, spleen, adrenal, thymus and for males, testes and epididymis. Dead animals in 60 and 600 mg/kg group, and the parent from which all pups died in 600 mg/kg group : brain, spinal cord, pituitary gland, eyeball, harderian gland, salivary gland, tongue, thyroid gland (including parathyroid gland), thymus, heart, trachea, bronchus, esophagus, lung, liver, kidney, adrenal, spleen, stomach, duodenum, small intestine, large intestine, pancreas, urinary bladder, sternum, bone marrow, sciatic nerve, lymph node, testes, epididymis, prostate, seminal vesicle, ovary, uterus, vagina, mammary gland, skin. All pregnant males and females in 60 and 200 mg/kg group: kidney and any organs which might be expected to have histopathological changes at the higher doses. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at #4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows: Full macroscopic examination on all of pups
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. - Statistics:
- Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data
- Reproductive indices:
- copulation index (No. of pairs with successful copulation/No. of pairs mated x 100), fertility index (No. of pregnant animals/No. of pairs with successful copulation x 100), implantation index (No. of implantation sites/No. of corpora lutea x 100), gestation index (No. of females wilth live pups/No. of living pregnant females x 100), delivery index (No. of pups born/No. of implantation sites x 100)
- Offspring viability indices:
- live birth index (No. of live pups on day 0/No. ofpups born x 100), viability index (No. of live pups on day 4/No. of live pups on day 0 x 100)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Dose descriptor:
- LOEL
- Remarks:
- systemic toxicity
- Effect level:
- 60 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical signs at 60 mg/kg bw : 8/12 of the male and in all female rats blepharoptosis was found. The substance caused mortality in four rats of the high dose group (600 mg/kg bw) and strongly affected body weight gain in both genders.
- Dose descriptor:
- NOEL
- Remarks:
- fertility
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: other: estrus cycle increased significantly in the 600mg/kg group. Incidences of mortality occured at 600 mg/kg bw.
- Dose descriptor:
- NOEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: pups of the 600mg/kg group showed lower body weight on day 4 of lactation
- Reproductive effects observed:
- not specified
- Conclusions:
- On the basis of these findings, NOEL of 2,2,6,6-tetramethyl-4-hydroxypiperidine for reproductive and developmental toxicity was considered to be 200 mg/kg/day. Higher doses caused slight effects on reproductive parameters (increased estrous cycle length, reduced pup weight on day 4), but also incidences of mortality in parental animals. Therefore, these effects are considered secondary to the poor condition of the parental animals and no specific hazard for reproductive/developmental toxicity is identified.
Reference
See also entries in the section of repeated-dose toxicity.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Low body weight gain during the premating period in females at 200 mg/kg was observed (Dunnets test p < 0.05).
Food/water consumption: For males, a tendency for increase in food consumption during administration period was observed at 600 mg/kg, and statistical significant difference from controls was noticed on day 8 to 48 of the administration. For females, statistical significant difference from controls was observed during premating period (on day 8- 15) and gestation period (on day 7 - 14), respectively.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Estrous cycle examination: continuous diestrus was observed in three females of the 600 mg/kg group and the mean estrous cycle of this group showed extension compared with the control group (p < 0.05).
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No statistical significant difference from controls.
GROSS PATHOLOGY (PARENTAL ANIMALS): No statistically significant effects were observed in all groups.
Reproduction results of rats treated orally with 2,2,6,6 -Tetramethylpiperidin-4 -ol:
Dose level (mg/kg/day) | 0 | 60 | 200 | 600 |
No. of pairs mated | 12 | 11 | 12 | 10 |
No. of pairs mated with successful copulation | 12 | 11 | 12 | 10 |
Copulation index (%) | 100 | 100 | 100 | 90.9 |
No. of pregnant females | 12 | 11 | 12 | 10 |
Fertility index (%) | 100 | 100 | 100 | 100 |
Pairing days until copulation (mean ± S.D.) | 2.9±1.1 | 2.3±0.9 | 2.4±0.7 | 3.1±0.8 |
No. of corpora lutea (mean ± S.D.) | 18.8±1.5 | 20.6±2.9 | 19.6±2.5 | 18.6±1.7 |
No. of implantation sites (mean ± S.D.) | 17.6±1.6 | 17.2±3.3 | 18.2±1.9 | 17.0±2.3 |
Implantation index (%, Mean ± S.D.) | 93.4±5.4 | 83.5±14.3 | 93.2±7.5 | 91.3±8.0 |
No. of pregnant females with parturition (mean ± S.D.) | 12 | 11 | 12 | 10 |
Gestation length (days, mean ± S.D.) | 22.7±0.5 | 22.3±0.5 | 22.6±0.5 | 22.4±0.5 |
Gestation index (%) | 100 | 100 | 100 | 100 |
Estrus cycle (days, mean ± S.D.) | 4.1±0.3 | 4.1±0.3 | 4.3±0.5 | 4.5±0.4? |
Copulation index (%) = (No. of pairs with successful copulation / No. of pairs mated) x 100
Fertility index (%) = (No. of pregnant females / No. of pairs with successful copulation) x 100
Gestation index (%) = (No. of females with live pups / No. ofpregnant females) x 100
Significant difference from control group
? = P<0.05
Litter results of rats treated orally with 2,2,6,6 -Tetramethylpiperidin-4 -ol:
Dose level (mg/kg/day) | 0 | 60 | 200 | 600 |
No. of pups born | 16.3±2.0 | 15.3±3.3 | 15.4±1.5 | 15.7±2.7 |
Delivery index (%) | 92.9±7.0 | 90.3±16.2 | 85.2±6.9 | 92.1±6.0 |
No. of pups alive on day 0 of lactation | ||||
Total | 16.3±2.0 | 15.2±3.3 | 15.3±1.4 | 15.7±2.7 |
Male | 8.2±2.2 | 7.7±2.3 | 7.9±1.8 | 7.0±3.0 |
Female | 8.2±1.5 | 7.5±2.6 | 7.4±2.2 | 8.7±2.3 |
Live birth index (%) | 100±0.0 | 99.5±1.8 | 99.5±1.7 | 100±0.0 |
Sex ratio (Male/Female) | 1.05±0.37 | 1.15±0.46 | 1.22±0.60 | 0.90±0.57 |
No. of pups alive on day 4 of lactation | ||||
Total | ||||
Male | 7.8±2.0 | 7.5±2.2 | 6.5±2.7 | 4.3±2.9 |
Female | 7.4±1.1 | 6.5±2.5 | 6.3±2.5 | 6.4±3.7 |
Viability index (%) | ||||
Total | 96.1±7.5 | 96.8±5.4 | 82.7±28.4 | 67.2±39.2 |
Male | 91.9±9.9 | 86.2±10.4 | 85.8±20.3 | 70.7±35.0 |
No. of total dead pups born (mean±S.D.) | 0.0±0.0 | 0.1±0.3 | 0.1±0.3 | 0.0±0.0 |
Stillbirth | 0.0±0.0 | 0.0±0.0 | 0.0±0.0 | 0.0±0.0 |
cannibalism | 0.0±0.0 | 0.1±0.3 | 0.1±0.3 | 0.0±0.0 |
Delivery index (%) = (No. of pups born/No. of implantation sites) x 100
Live birth index (%) = (No. of live pups on day 0/No. of pups born) x 100
Viability index (%) = (No. of live pups on day 4/No. of live pups on day 0) x 100
Sex ratio = Total No. of male pups/ Total No. of female pups
Values are expressed as Mean±S.D. except sex ratio
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Species:
- rat
- Quality of whole database:
- valid with restriction. Screening study with active metabolite.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Subchronic feed dosing at dose levels of up to 10000 ppm did not cause adverse effects on reproductive organs, nor did it affect the estrous cycle or sperm parameters (BASF 2014). The study followed OECD guideline 408 and was performed under GLP. This indicates absence of adverse effects on fertility.
Additional evidence is available from a screening study (OECD 422, GLP) with the relevant ester hydrolysis product HTMP (MHLW 1998). As the other fragment generated by hydrolysis is a food-borne fatty acid, no further assessment is required.
HTMP is a stronger base than the substance itself and classified for corrosive properties. Subacute gavage dosing of 600 mg/kg bw caused mortality in four parental animals..
Short description of key information:
The test substance undergoes enzymyatic and pH-dependent hydrolysis to HTMP and a short-chain fatty acid. HTMP was found to have no adverse effects on fertility in a GLP-compliant screening study (OECD 422). No adverse effects on reproductive organs were observed in the 90-day study (OECD 408).
Effects on developmental toxicity
Description of key information
The substance did not cause developmental toxicity or teratogenicity in rats (GLP, OECD 414).
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD 414 and GLP compliant study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:WI (Han)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: About 10-12 weeks
- Weight at study initiation: 146.5 – 189.0 g
- Housing: single caging
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: six days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2013-06-25 To: 2013-07-16 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The oily test substance preparations were prepared at the beginning of the administrationperiod and thereafter at maximum intervals of 7 days, which took into account the period of established stability. For the test substance preparations, the specific amount of test substance were weighed, topped up with corn oil in a graduated flask and intensely mixed by shaking until it is dissolved.
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test item is soluble in the vehicle. It is not soluble in water.
- Amount of vehicle (if gavage): 4 ml/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC-method
- Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
The day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. - Duration of treatment / exposure:
- gestation days 6- 19
- Frequency of treatment:
- daily
- Duration of test:
- 14 days
- Remarks:
- Doses / Concentrations:
0, 30 ,100 and 300 mg/kg bw
Basis:
actual ingested - No. of animals per sex per dose:
- 25
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Based on range-finder study with pregnant rats
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality/Morbidity, pertinent behavioral changes and/or signs of overt toxicity. were checked twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays (GO 0 to 20).
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: GO 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.
POST-MORTEM EXAMINATIONS: Gross pathology
- Sacrifice on gestation day: GD 20 - 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
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Site of implantations in the uterus - Fetal examinations:
- - External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [ half per litter ]
- Skeletal examinations: Yes: [ half per litter ]
In the present study the glossary of WISE et al. (1997) and its updated version of MAKRIS et al. (2009) was essentially used to describe findings in fetal morphology. Classification of these findings was based on the terms and definitions proposed by CHAHOUD et al. (1999) and SOLECKI et al. (2001, 2003):
Malformation
A permanent structural change that is likely to adversely affect the survival or health.
Variation
A change that also occurs in the fetuses of control animals and/or is unlikely to adversely affect the survival or health. This includes delays in growt or morphogenesis that have otherwise followed a normal pattern of development.
The term "unclassified observation" was used for those fetal findings, which could not be classified as malformations or variations. - Statistics:
- DUNNETT's test: Food consumption, body weight, body weight change, DUNNETT's test
corrected body weight gain, carcass weight, weight of
the unopened uterus, weight of the placentas and
fetuses, corpora lutea, implantations, pre- and
postimplantation losses, resorptions and live fetuses
FISHER's exact test
Number of pregnant animals at the end of the study, FISHER's exact test mortality rate (of the dams) and number of litters with fetal findings
WILCOXON test
Proportion of fetuses with findings per litter - Indices:
- sex ratio
conception rate (in %)
preimplantation loss (in %)
postimplantation loss (in %) - Historical control data:
- Included in the final report.
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
High-dose female No. 94 (300 mg/kg bw/d) died on GD 15. The gross pathological examination of this animal revealed findings indicative of a gavage error. There were no further substance-related or spontaneous mortalities in any females of all test groups (0, 30, 100 or 300 mg/kg bw/d).
All females of the high-dose group (300 mg/kg bw/d), nearly all females (23 out of 25) of the mid-dose group (100 mg/kg bw/d) and 16 females of the low-dose group (30 mg/kg bw/d) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals for some minutes after daily gavage dosing (i.e. up to 10 minutes) and was initially observed on GD 7. No further clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any female at dose levels of 100, 300 or 1000 mg/kg bw/d during the entire study period.
The mean food consumption of the high-dose dams (300 mg/kg bw/d) was statistically significantly reduced on GD 6-10 and GD 15-17. If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the dams of test group 3 consumed 12% or 7% less food, respectively, in comparison to the concurrent control group. Furthermore, the mean food consumption of the mid-dose dams (100 mg/kg bw/d) was statistically significantly reduced on GD 6-8. If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the dams of test group 2 consumed 4% less food, respectively, in comparison to the concurrent control group. The mean food consumption of the dams in test group 1 (30 mg/kg bw/d) was generally comparable to the concurrent control throughout the entire study period.
The mean body weights of the high-dose females (300 mg/kg bw/d) were statistically significantly reduced from GD 8 onwards until terminal sacrifice on GD 20. At the beginning of treatment these dams even lost weight, thus, the average body weight gain was statistically significantly reduced on GD 6-8 and GD 17-19. If calculated for the entire treatment period (GD 6-19) or entire study period (GD 0-20), these dams gained 21% or 13% less weight than the concurrent control animals, respectively.
The mean body weights of the mid-dose group (100 mg/kg bw/d) were slightly lower than the concurrent control values (without attaining statistical significance), mainly caused by the statistically significantly reduced mean body weight gain value on GD 6-8. If calculated for the
entire treatment period (GD 6-19) or entire study period (GD 0-20), these dams gained 8% or 7% less weight than the concurrent control animals (without attaining statistical significance). The impairments of body weights in the mid- and high-dose groups were considered to be treatment-related, whereas the statistically significantly increased body weight gain value on GD 1-3 (test group 3) was an incidental occurrence.
The mean body weights and the average body weight gains of the low-dose rats (30 mg/kg bw/d) were in general comparable to the controls throughout the entire study period. This includes the statistically significantly reduced body weight gain value on GD 17-19 which was considered as an accidental finding.
The corrected body weight gain (terminal body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6) was distinctly and statistically significantly lower in test groups 2 (100 mg/kg bw/d – about 20% below the concurrent control value) and 3 (300
mg/kg bw/d – about 29% below the concurrent control value). Furthermore, the carcass weight of the high-dose dams was statistically significantly lower in comparison to the control group (about 5% below controls).
These effects are assessed as direct, test substance-related signs of maternal toxicity.
The corrected body weight gain of test group 1 (30 mg/kg bw/d) revealed no difference of any biological relevance to the corresponding control group. Mean carcass weights remained also unaffected by the treatment.
No necropsy findings which could be attributed to the test substance were seen in any dam. One finding indicative for misgavaging, i.e. thoracic cavity filled with serous fluid, was recorded for dam No. 94 (300 mg/kg bw/d), which died on GD 15.
Although without attaining statistical significance, the mean gravid uterus weight of the animals of test group 3 (300 mg/kg bw/d) was reduced in comparison to the control group (about 10% below controls), which is likely to be a subsequent effect of the increased number of resorptions in this test group (see 4.2.2.3. Reproduction data). The mean gravid uterus weights of the low- and mid-dose animals (30 and 100 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance. - Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
There were statistically significant differences in the values calculated for the postimplantation loss (5.2%/4.5%/4.0%/13.8%** [p<=0.01] in test groups 0-3), the number of resorptions and viable fetuses (94.8%/95.5%/96.0%/86.2%** [p<=0.01]. These differences were exclusively caused by an increased number of early resorptions in this dose group. All values were outside of the historical control range of the test facility.
There were no test substance-related and/or biologically relevant differences between the test groups 0, 1 and 2 in the values calculated for the pre- and postimplantation losses, the number of resorptions and viable fetuses.
The sex distribution of the fetuses in test groups 1-3 (30, 100 and 300 mg/kg bw/d) was comparable to the control fetuses. Any observable differences were without biological relevance.
The mean placental weights of the low-, mid- and high-dose groups (30, 100 and 300 mg/kg bw/d) were comparable to the corresponding control group.
The mean fetal weights of test groups 1, 2 and 3 (30, 100 and 300 mg/kg bw/d) were not influenced by the test substance and did not show any biologically relevant differences in comparison to the control group.
The high-dose of the test item (300 mg/kg bw/d) caused a significant increase of early resorptions and, subsequently, postimplantation loss as well as a decrease in the number of viable fetuses. All values for these parameters were outside of the historical control range of the test facility. This effect is considered to be treatment–related. However, it occurred exclusively in the presence of distinct maternal toxicity, which was most pronounced during the early phase of the treatment, i.e. in the days shortly after implantation (GD 6-8). A relationship between the profound disturbance of maternal nutritive status during this sensitive window of development and an adverse effect on the number of surviving early implants is assumed.
No influence of the test compound on fetal weight and sex distribution of the fetuses was noted at any dose. Particularly, the surviving high-dose fetuses showed a normal prenatal development in terms of fetal weight gain, which is correlated to the lower average litter size in these animals.
Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. - Dose descriptor:
- NOAEL
- Effect level:
- >= 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The substance does not cause developmental toxicity or teratogenicity in rats.
Reference
All females of the high-dose group (300 mg/kg bw/d), nearly all females (23 out of 25) of the mid-dose group (100 mg/kg bw/d) and 16 females of the low-dose group (30 mg/kg bw/d) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals for some minutes after daily gavage dosing (i.e. up to 10 minutes).
Table 1: Total external variations
Test group 0 0 mg/kg bw/d |
Test group 1 30 mg/kg bw/d |
Test group 2 100 mg/kg bw/d |
Test group 3 300 mg/kg bw/d |
||
Litter Fetuses | N N | 25 261 |
25 243 |
25 267 |
23 218 |
Fetal incidence | N (%) | 2 (0.8) | 0.0 | 0.0 | 0.0 |
Litter incidence | N (%) | 2 (8.0) | 0.0 | 0.0 | 0.0 |
Affected fetuses/litter | Mean% | 0.7 | 0.0 | 0.0 | 0.0 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 2: Total soft tissue malformations
Test group 0 0 mg/kg bw/d |
Test group 1 30 mg/kg bw/d |
Test group 2 100 mg/kg bw/d |
Test group 3 300 mg/kg bw/d |
||
Litter Fetuses | N N | 25 121 |
25 114 |
25 127 |
23 105 |
Fetal incidence | N (%) | 0.0 | 0.0 | 0.0 | 2 (1.9) |
Litter incidence | N (%) | 0.0 | 0.0 | 0.0 | 2 (8.7) |
Affected fetuses/litter | Mean% | 0.0 | 0.0 | 0.0 | 2.0 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Soft tissue malformations were recorded for male high-dose fetus No. 83-06 (300 mg/kg bw/d, Tab. 2.). Female high-dose fetus No. 78-08 had more than one malformation affecting the liver, lung and heart. The total incidence of soft tissue malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data.
Table 3: Fetal soft tissue variations
Test group 0 0 mg/kg bw/d |
Test group 1 30 mg/kg bw/d |
Test group 2 100 mg/kg bw/d |
Test group 3 300 mg/kg bw/d |
||
Litter Fetuses | N N | 25 121 |
25 114 |
25 127 |
23 105 |
Fetal incidence | N (%) | 5 (4.1) | 3 (2.6) | 6 (4.7) | 0.0 |
Litter incidence | N (%) | 5 (20) | 3 (12) | 6 (24) | 0.0 |
Affected fetuses/litter | Mean% | 3.9 | 2.8 | 5.3 | 0.0 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Some soft tissue variations were detected in the test groups 0-2 (0, 30 or 100 mg/kg bw/d), i.e. short innominate, dilated renal pelvis and dilated ureter. These variations were neither statistically significantly different from control nor dose-dependent and therefore, not
considered biologically relevant.
Table 4: Total fetal skeletal malformations
Test group 0 0 mg/kg bw/d |
Test group 1 30 mg/kg bw/d |
Test group 2 100 mg/kg bw/d |
Test group 3 300 mg/kg bw/d |
||
Litter Fetuses | N N | 25 140 |
25 129 |
25 140 |
25 113 |
Fetal incidence | N (%) | 3 (2.1) | 1 (0.8) | 0.0 | 4 (3.5) |
Litter incidence | N (%) | 3 (12) | 1 (4.0) | 0.0 | 4 (17) |
Affected fetuses/litter | Mean% | 2.0 | 0.8 | 0.0 | 5.6 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Some skeletal malformations were detected in the test groups 0, 1 and 3 (0, 30 and 300 mg/kg bw/d) affecting the skull, sternum and forelimbs (Tab. 4). The incidences of these malformations were neither statistically significantly different from control nor dose-dependent and therefore, not considered biologically relevant.
Table 5: Total fetal skeletal variations
Test group 0 0 mg/kg bw/d |
Test group 1 30 mg/kg bw/d |
Test group 2 100 mg/kg bw/d |
Test group 3 300 mg/kg bw/d |
||
Litter Fetuses | N N | 25 140 |
25 129 |
25 140 |
25 113 |
Fetal incidence | N (%) | 139 (99) | 128 (99) | 139 (99) | 111 (98) |
Litter incidence | N (%) | 25 (100) | 25 (100) | 25 (100) | 23 (100) |
Affected fetuses/litter | Mean% | 99.4 | 99.2 | 99.2 | 98.4 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeleton and appeared without a relation to dosing (Tab. 5). The overall incidences of skeletal variations were comparable to the historical control data.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Species:
- rat
- Quality of whole database:
- valid without restriction
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The substance was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an oily solution to groups of 25 time-mated female Wistar rats by gavage at doses of 30, 100, and 300 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (corn oil) in parallel. A standard dose volume of 4 mL/kg body weight was used for each test group. At terminal sacrifice on GD 20, 24-25 females per group had implantation sites. On GD 20, all females were sacrificed by cervical dislocation (under isoflurane anesthesia) and assessed by gross pathology (including weight determinations of the unopened uterus and the placentae). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated between resorptions, live and dead fetuses) were determined.
The fetuses were removed from the uterus, sexed, weighed and further investigated for external findings. Thereafter, one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal (inclusive cartilage) findings.
The stability of the test substance preparations was demonstrated analytically over a period of 7 days at room temperature.
The following test substance-related, adverse effects/findings were noted for dams at the high dose group:
• Reduced food consumption; if calculated for GD 6-19 or GD 0-20: -12% or -7% less
consumed food than control.
• Reduced body weights from GD 8-20; reduced body weight gain, if calculated for GD 6-19
or GD 0-20: -21% or -13% less gained weight.
• Lower corrected body weight gain (about 29% below control).
• Reduced carcass weight (about 5% below controls)
• Increased number of early resorptions; consequentially increased postimplantation loss
(13.8%** [p<=0.01] vs. 5.2% in control), as well as reduced number of viable fetuses
(86.2%** vs. 94.8% in control).
At the beginning of treatment dams even lost weight, thus, the average body weight gain was statistically significantly reduced on GD 6-8 and GD 17-19.
The following test substance-related, adverse effects/findings were noted for dams at the intermediate dose group:
• Reduced food consumption on GD 6-8, if calculated for GD 6-19 or GD 0-20: -4% less
food.
• Reduced mean body weight gain on GD 6-8.
• Lower corrected body weight gain (about 20% below control).
No effects were noted on the fetuses. No effects were noted at the low dose group for either dams or fetuses.
From other studies it is known that the highly irritating substance affects the stomach and intestine. Salivation after treatment was observed in a dose-dependent manner.
No differences of toxicological relevance between the control and treated groups 1 and 2 (30 or 100 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. The high-dose of the test item (300 mg/kg bw/d) caused a significant increase of early resorptions and, subsequently, postimplantation loss as well as a decrease in the number of viable fetuses. All values for these parameters were outside of the historical control range of the test facility. This effect is considered to be treatment–related. However, it occurred
exclusively in the presence of distinct maternal toxicity, which was most pronounced during the early phase of the treatment, i.e. in the days shortly after implantation (GD 6-8). A relationship between the profound disturbance of maternal nutritive status during this
sensitive window of development and an adverse effect on the number of surviving early implants is assumed.
No influence of the test compound on fetal weight and sex distribution of the fetuses was noted at any dose. Particularly, the surviving high-dose fetuses showed a normal prenatal development in terms of fetal weight gain, which is correlated to the lower average litter size in these animals.
Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.
Justification for classification or non-classification
Dangerous Substance Directive (67/548/EEC)
The available developmental toxicity study is considered reliable and suitable for classification purposes under 67/548/EEC. No adverse effects on development or malformations were noted at the highest tolerable dose. The slight increase in post-implantation loss is considered to be secondary to the significant maternal toxicity during the first days of treatment.
There is no suspicion for an adverse effect on fertilty based on the outcome of a subchronic feeding study and a screening study with the relevant ester hydrolysis product.
As a result the substance is not considered to be classified for fertility or developmental toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive2009/2/EG.
Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008
The OECD 414 study is reliable and suitable for classification purposes under Regulation 1272/2008. No adverse effects on development or malformations were noted at the highest tolerable dose. The slight increase in post-implantation loss is considered to be secondary to the significant maternal toxicity during the first days of treatment.
There is no suspicion for an adverse effect on fertilty based on the outcome of a subchronic feeding study and a screening study with the relevant ester hydrolysis product.
As a result the substance is not considered to be classified for fertility or developmental toxicity under Regulation (EC) No. 1272/2008, as amended for the fifth time in Directive EC944/2013.Additional information
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