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EC number: 418-370-0 | CAS number: 143925-92-2
- 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:
- 07.09. - 19.01.2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Version / remarks:
- adopted 1983
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 418-370-0
- EC Name:
- -
- Cas Number:
- 143925-92-2
- Molecular formula:
- C32-36 H67-74 N1 O1
- IUPAC Name:
- N-hexadecyl-N-octadecylhydroxylamine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
Males: Charles River Deutschland, Sulzfeld, Germany.
Females: Charles River Laboratories, Wilmington, MA, USA.
- Age at study initiation: Males 5-6 weeks and females 13-14 weeks.
- Housing:
Pre-mating animals were housed in groups of 4 animals/sex/cage in Macrolon cages (MIV type, height 18 cm).
Mating Females were caged together with males on a one-to-one-basis in Macrolon cages (M III type, height 18 cm).
Post-mating Males were housed in groups of 4 animals/sex/cage in Macrolon cages (MIV type, height 18 cm). Females were individually housed in Macrolon cages (M III type, height 18 cm).
Lactation Offspring was kept with the dam until termination.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days (males) or 4 days (females) prior to start of treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature of 21 ± 3°C (measured range: 19 -23.4°C)
- Humidity: 30 - 70 % (actual range: 35 - 100 %)
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES:
Males: from 06.09. to 18. and 28.12.2006
Females: from 01.11.2007 to 03.-19.2007
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5 % (w/w) carboxymethylcellulose and 0.1% (v/v) Tween-80 in Milli-U water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
From start study to 14 November 2006, formulations (w/w) were prepared weekly and were homogenised to a visually acceptable level. From 15 November 2006 to end of the study, formulations (w/w) were prepared daily within 4 hours prior to dosing and were homogenised to a visually acceptable level. No adjustment was made for specific gravity of the test substance, vehicle, and/or formulation.
VEHICLE
- Justification for use and choice of vehicle:appropriateness of vehicle was shown in a 90 d oral gavage study in rats
- Concentration in vehicle: 40, 10 or 2 mg/mL
- Amount of vehicle: 5 mL/kg bw - Details on mating procedure:
- - M/F ratio per cage: one female was cohabitated with one male of the same treatment group, avoiding sibling mating
- Length of cohabitation: 15 days
- Proof of pregnancy: Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of a intravaginal copulatory plug. This day was designated Day 0 post-coitum.
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility for an additional 5 days.
- Further matings after two unsuccessful attempts: no
- Any other deviations from standard protocol: no - Analytical verification of doses or concentrations:
- yes
- Remarks:
- The concentrations in the formulation of Group 4 were in agreement with target concentrations and homogenous. As no toxicity was observed up to and including the high dose group, the lower accuracies for group 3 and 2 did not affect the study integrity.
- Details on analytical verification of doses or concentrations:
- Accuracy, homogeneity and stability were determined for formulations prepared for use in Week 1, Week 8, Week 16 and Week 18 of study.
The concentrations analysed in the formulations of Group 4 (200 mg/kg bw/d) were in general in agreement with target concentrations (i.e. between 90% and 110%). The analysed concentrations of the formulations of Group 3 (50 mg/kg bw/d) were somewhat lower than the target concentrations. The formulations of Group 4 were homogeneous. Formulations were stable for at least 5 hours when stored at room temperature.
For formulations of Group 2 (10 mg/kg bw/d), relatively low accuracies and high coefficients of variation on the accuracies were obtained. As no toxicity was observed up to and including the high dose group, the relatively low accuracies and high coefficients of variation on the accuracies observed for the low dose formulations were not considered to have affected the study integrity. - Duration of treatment / exposure:
- F0-males: A minimum of 70 days prior to mating and continuing until necropsy.
F0-females: A minimum of 14 days prior to mating and continuing until necropsy.
F1-generation (F0-offspring): The F1-generation was potentially exposed to the test substance in utero and through nursing during lactation. - Frequency of treatment:
- Once daily for 7 days per week. Animals were dosed up to the day prior to scheduled necropsy.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were derived from a 90-day oral toxicity study in rats with a NOAEL of 50 mg/kg bw and effects on liver, kidney and mesenteric lymph nodes at doses of 200 and 1000 mg/kg bw/d.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
At least twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
At least once daily, detailed clinical observations were made in all animals. The time of onset, degree and duration were recorded.
Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No signs of difficult or prolonged parturition were noted among the pregnant females.
BODY WEIGHT: Yes
- Time schedule for examinations:
Males and females were weighed on the first day of exposure and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 of gestation, and during lactation on Days 1, 4, 7,14 and 21.
FOOD CONSUMPTION:
Weekly, for males and females. Food consumption was not recorded during the breeding period. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 postcoitum and after delivery on Days 1, 4, 7, 14 and 21 post-partum.
WATER CONSUMPTION:
Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
OTHER:
REPRODUCTION PROCESSES: Male number paired with, mating date, confirmation of pregnancy, and delivery date were recorded. - Oestrous cyclicity (parental animals):
- Not determined.
- Sperm parameters (parental animals):
- Parameters examined in all male parental generations: testis weight, epididymis weight, no sperm parameters examined
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
To reduce variability among the litters, on Day 4 of lactation, eight pups from each litter of equal sex distribution (if possible) were randomly selected. For litters consisting of fewer than eight pups, adjustments for litter size were not performed.
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
Mortality/ viability
The numbers of live and dead pups at the First Litter Check (=check at day 1 of lactation) and daily thereafter were determined.
Clinical signs
At least once daily, detailed clinical observations were made in all animals.
Body weigts
Live pups were weighed during lactation on days 1, 4, 7, 14 and 21.
Sex
Was determined for all pups on Days 1 and 4 of lactation (by assessment of the ano-genital distance). - Postmortem examinations (parental animals):
- SACRIFICE
All animals surviving to the end of the observation period and all moribund animals were anaesthetised using iso-flurane and subsequently exsanguinated. Males were killed as soon as possible after delivery of the litters. Females were killed on Day 21 postpartum or shortly thereafter.
GROSS NECROPSY
After sacrifice or death all animals were subjected to macroscopic examination of the cranial, thoracic and abdominal tissues and organs, with special attention being paid to the reproductive organs. Descriptions of all macroscopic abnormalities were recorded.
Samples of the following tissues and organs were collected from all animals at necropsy and fixed in 10 % buffered formalin: Cervix, Coagulation gland, kidneys, liver, meseneteric lymph nodes, epididymides, ovaries, pituitary gland, prostate gland, seminal vesicles, testes, uterus, vagina, all gross lesions.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following slides were examined by a pathologist:
The kidneys, liver, mesenteric lymph nodes of 10 mated animals/sex of Group 1 and Group 4.
On detection of possible treatment-related changes in the mesenteric lymph nodes of high dose males, histological examination was extended to that particular organ of 10 mated males of Group 2 and Group 3.
All abnormalities were described and included in the report. An attempt was made to correlate gross observations with microscopic findings.
The following organ weights (and terminal body weight) were recorded from the surviving animals on the scheduled day of necropsy:
Epididymides, kidneys, liver, ovaries, pituitary (weighed when fixed for at least 24 hours), prostate (weighed when fixed for at least 24 hours), seminal vesicles, testes, uterus. - Postmortem examinations (offspring):
- SACRIFICE
Pups, which were culled, were killed by decapitation. All remaining pups were sacrificed using an oxygen/carbon dioxide procedure.
Culling was performed on Day 4 of lactation or shortly thereafter. The remaining pups were killed at Day 21 post partum or shortly thereafter.
GROSS NECROPSY
Offspring found dead or killed before Day 14 of lactation was sexed and externally examined (if practically possible) with emphasis on developmental morphology. The stomach was examined for the presence of milk.
Offspring killed on or after Day 14 of lactation was sexed and subjected to external examination of the cranium, and macroscopic examination of the thoracic and abdominal tissues and organs with emphasis on developmental morphology. Descriptions of all macroscopic abnormalities were recorded. If possible, defects or cause of death were evaluated. No pups or tissues were fixed. - Statistics:
- The following statistical methods were used to analyze the data:
If the variables could be assumed to follow a normal distribution, the Dunnett-test (Dunnett, 1955) (many-to-one t-test) based on a pooled variance estimate, was applied for the comparison of the treated groups and the control groups for each sex.
The Steel-test (Miller, 1981 ) (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
The Fisher Exact-test (Fisher 1950) was applied to frequency data.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. - Reproductive indices:
- Percentage mating, fertility index, conception rate, gestation index, gestation duration.
- Offspring viability indices:
- Percentage live males at first litter check, percentage live females at first litter check, percentage of postnatal loss days 0-4 post partum, percentage of breeding loss day 5 until weaning, percentage live males at weaning, percentage live females at weaning, viability index, weaning index.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment related clinical signs were noted. The female of the high dose group (animal number 188) that was killed in extremis showed hunched posture for one day and piloerecfion and pale appearance for two days. Incidental findings consisted of chromodacryorrhoea of the snout and pale appearance. In addition, animals of all groups showed alopecia and/or scabs. These findings are occasionally noted in rats of this age and strain that are housed and handled under the conditions in this study and are therefore considered to be of no toxicological significance.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- At the high dose group, one female was killed in extremis on Day 42 of treatment. This female showed hunched posture, piloerection and pale appearance. Macroscopic examination revealed an enlarged spleen. In addition, four implantation sites were observed in the left uterus horn, ten mummified foetuses were observed in the right uterine horn and two mummified foetuses were noted in the cervix . This death was not regarded as treatment-related but considered related to delivery difficulties. No further unscheduled deaths occurred.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights and body weight gain of treated animals remained in the same range as controls over the complete study period.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food consumption before or after allowance for body weight was similar between treated and control animals. The statistically significantly increased value for relative food consumpfion observed for females of the intermediate dose group during the lactafion period was considered unrelated to treatment as no dose response relafionship was apparent and this finding was very slight and incidental.
- 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
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment related microscopic findings were observed.
Microscopic findings were present in the mesenteric lymph nodes of males. Macrophage foci were present in all groups: In Group 1 (5/10 males: minimal). Group 2 (7/10 males: minimal). Group 3 (4/10 males: minimal, 1/10 male: slight) and Group 4 (5/10 males: minimal, 2/10 males: slight). The findings in the mesenteric lymph nodes and the remainder of the microscopic findings recorded were considered to be within the normal range of background pathology encountered in Wistar rats of this age and strain. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Reproduction parameters were unaffected by treatment up to 200 mg/kg bw/d.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No test item-related effects up to and incl. the higher dose level of 200 mg/kg bw/d.
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Incidental clinical symptoms consisted of no milk, small and pale appearance, opacity of the eye, ptosis and watery discharge from eye (both not confirmed at macroscopic examination). In addition, pups showed alopecia, scabs, fissures in the axillary region, wound, blue abdomen, brown wrinkled tail, missing tail apex (not confirmed at macroscopic examination) and/or thickened (red-blue) area of the head. These findings are occasionally noted in rats of this age and strain that are housed and handled under the conditions in this study and are therefore considered to be of no toxicological significance.
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- Breeding parameters were unaffected by treatment up to 200 mg/kg bw/d. Postnatal loss, living pups on Day 4 post partum, breeding loss between Days 5-21 post partum, living pups on Day 21 post partum, viability index and weaning index were similar for the control and treated groups.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights of treated groups remained in the same range as controls.
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Macroscopic examination of the pups revealed small appearance, no milk, tail apex damaged and black discoloured (correlating to the brown wrinkled tail), pelvic dilation of the kidney, watery cyst at the left kidney and dilated left ureter, wound, hernia diaphragmatica liver, and grey-white discolourafion of the right eye (correlating to opacity of the eye). No relationship with treatment was established for these observations or they were considered to be within the normal biological variation for rats of this age and strain.
- Histopathological findings:
- not examined
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No test item-related effects up to and incl. the higher dose level of 200 mg/kg bw/d.
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
REPRODUCTION DATA
Number of females | Group 1 (control) | Group 2 (10 mg/kg) | Group 3 (50 mg/kg) | Group 4 (200 mg/kg) |
Paired | 24 | 24 | 24 | 24 |
Mated | 24 | 23 | 23 | 24 |
Pregnant | 24 | 23 | 23 | 24 |
Dams killed in extremis | 0 | 0 | 0 | 1 |
Females with living pups | 24 | 23 | 23 | 23 |
FERTILITY F0-GENERATION
Group 1 (control) | Group 2 (10 mg/kg) | Group 3 (50 mg/kg) | Group 4 (200 mg/kg) | |
Percentage mating | 100 | 95.8 | 95.8 | 100 |
Fertility index | 100 | 95.8 | 95.8 | 100 |
Conception rate | 100 | 100 | 100 | 100 |
Gestation index | 100 | 100 | 100 | 95.8 |
Applicant's summary and conclusion
- Conclusions:
- Based on these results, the definitive parental, reproduction, breeding and developmental No Observed Adverse Effect Level (NOAEL) and No Observed Effect Level (NOEL) was established as being 200 mg/kg body weight/day.
- Executive summary:
In this one-generation study, the test item was administered by oral gavage through one complete reproductive cycle to SPF-bred male and female Wistar rats. The dose levels tested were 0,10, 50 and 200 mg/kg body weight/day. The dose levels were derived from a 90-day oral toxicity study in Ralf (SPS) rats with a NOAEL of 50 mg/kg bw and effects on liver, kidney and mesenteric lymph nodes at doses of 200 and 1000 mg/kg body weight/day. There were no changes for mortality, clinical signs, body weight, food consumpfion, macroscopic examination, organ weights, reproduction, breeding data and pup development that were considered to be an effect of treatment. In the mesenteric lymph nodes of males, macrophage foci were slighty increased in the higher dosed animals. This was considered to be within the normal range for Wistar rats of this age and strain. Treatment with the test item by oral gavage in male and female Wistar rats at dose levels of 10, 50 and 200 mg/kg body weight/day revealed no parental, reproduction, breeding and developmental toxicity for treatment up to 200 mg/kg body weight/day. Based on these results, the definitive parental, reproduction, breeding and developmental No Observed Adverse Effect Level (NOAEL) and No Observed Effect Level (NOEL) was established as being 200 mg/kg body weight/day.
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