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EC number: 221-375-9 | CAS number: 3081-14-9
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP study comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- N,N'-bis(1,4-dimethylpentyl)-p-phenylenediamine
- EC Number:
- 221-375-9
- EC Name:
- N,N'-bis(1,4-dimethylpentyl)-p-phenylenediamine
- Cas Number:
- 3081-14-9
- Molecular formula:
- C20H36N2
- IUPAC Name:
- N1,N4-bis(5-methylhexan-2-yl)benzene-1,4-diamine
- Details on test material:
- Santoflex, assume 100% active ingredient
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: 77PD contained in the diet
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 92 to 93 days (depending on the day of necropsy)
- Frequency of treatment:
- daily (7 days per week)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
males: 0, 100, 250, 500 ppm, females: 0, 250, 500, 750 ppm
Basis:
- No. of animals per sex per dose:
- 10 per dose and sex
- Control animals:
- yes, plain diet
Results and discussion
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 100 ppm
- Based on:
- test mat.
- Sex:
- male
- Dose descriptor:
- LOAEL
- Effect level:
- 250 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: slight body weight reduction (-5% at study termination), reduced body weight gain (-9%)
- Dose descriptor:
- LOAEL
- Effect level:
- 250 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: slight body weight reduction (-11% body weight at study termination), body weight gain reduced (-23%)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
- Glutamic oxaloacetic transaminase mean serum level: were significantly reduced in the 100 ppm (p<0.05), 250 ppm and 500 ppm (p<0.01) males at Month 1.5 but not at Month 3 (1.5 months: 100 ppm: 108 ± 15, 250 ppm 96 ± 14, 500 ppm 90 ± 16 vs. control 136 ± 32 IU/l)
- Calcium2+ was slightly increaed in males of the 250 ppm and 500 ppm groups at 1.5 months but not at 3 months (1.5 months: 250 ppm: 9.9 ± 0.3, 500 ppm: 9.9 ± 0.2 mg/dl vs. control . 9.5 ± 0.3 mg/dl)
- Creatinine was significant increased (p<0.05) at 100 ppm but not in the higher dose groups at 3 months (100 ppm 0.7 + 0.1 vs. control 0.6 + 0.1 mg/dl)
- Alkaline phosphatase was significant (p<0.05) increased in males of the 500 ppm group at 3 months (500 ppm: 83 ± 17 vs. control 63 ± 14 IU/l)
- Serum Glutamic Pyruvic transaminase mean serum level: were significantly reduced (p<0.01) in females at 750 ppm at 1.5 months (750 ppm: 17 + 3 vs. control 27 + 10 IU/l) and in 500 ppm (p<0.05) and 750 ppm (p<0.01) females at 3 months (500 ppm: 23 + 4, 750 ppm: 21 + 3 vs. control 30 + 8 IU/l)
- Fastin glucose was significant reduced (p<0.05) in 750 ppm females at 1.5 months but not at 3 months (750 ppm: 95 + 11 vs. 110 + 11 mg/dl)
- total Bilirubin was significant reduced (p0.01) in females of the 500 ppm group at 1.5 months, but not at 3 months (500 ppm: 0.2 + 01 vs. control 0.4 + 0.1 mg/dl)
- Blood Urea Nitrogen: significantly elevated (p<0.01) in the Group V (750 ppm) females at 3 months (20.2 + 2.6 vs. control 15.3 + 2.2 mg/dl)
- Alkaline Phosphatase: significantly elevated (p<0.05) in Group V (750 ppm) females at 3 months (67 + 21 vs. control 40 + 9 IU/l)
Dietary Analysis:
Dietary analysis conducted during the course of this study indicate that the treated animals were presented diets which were homogeneously prepared at the intended dietary concentrations.
The nominal concentrations of Santoflex 77 in rat diet assayed were 100 ppm, 250 ppm, 500 ppm and 750 ppm for Groups II, III, IV and V, respectively. A homogeneity analysis perfomed on Groups II and V yielded mean and standard deviation values of 98.0% + 2.21 and 101% + 1.25, respectively. Analysis performed during the study yielded mean and standard deviation
values of 104% + 5.10, 99.8% + 3.29, 100% + 1.34 and 102% + 2.99 for Groups II, 111, IV and V, respectively.
Mortality:
All of the control and treated animals survived the duration of the study
Physical Observations:
Clinical observations were the type commonly seen in rodent studies. Isolated occurrences of nasal discharge, chromodacryorrhea, lacrimation, alopecia and scabs were noted in 1 or 2 males and females. These are not unusual and were not attributed to treatment.
Ophthalmoscopic Examination:
There were no ophthalmoscopic findings noted following three months of treatment which were attributed to the administration of the test substance.
Body Weights:
Mean body weights and mean body weight gains were reduced in the males treated at the 250 and 500 ppm dose levels and in the females treated at the 250, 500 and 750 ppm dose levels.
Mean body weight in grams
Males
Dose control 100 ppm 250 ppm 500 ppm
weeks 1 211.8 ± 14.0 214.2 ± 13.5 211.7 ± 14.9 207.0± 17.0
weeks 2 267.2 ± 15.6 269.0 ± 16.6 263.8 ± 20.1 252.9 ± 23.4
weeks 3 307.3 ± 18.1 305.8 ± 19.5 298.3 ± 24.5 285.1 ± 30.4
weeks 4 341.9 ± 19.6 338.0 ± 27.1 327.8 ± 30.2 310.5 ± 36.5
weeks 5 377.5 ± 22.3 368.4 ± 34.1 359.5 ± 34.6 336.7 ± 41.9
weeks 6 398.5 ± 24.4 389.5 ± 34.6 376.9 ± 36.5 349.2* ± 36.8
weeks 7 424.7 ± 24.4 417.3 ± 35.9 401.6 ± 41.5 373.1*± 40.7
weeks 8 440.2 ± 27.0 433.3 ± 43.1 414.0 ± 44.7 386.9*± 42.9
weeks 9 433.6 ± 29.1 430.1 ± 44.1 406.8 ± 45.0 382.9*± 40.4
weeks 10 456.8 ± 29.1 450.0 ± 48.4 429.2 ± 47.4 399.4*± 46.2
weeks 11 467.3 ± 32.7 466.6 ± 51.2 439.5 ± 48.0 407.3*± 45.2
weeks 12 473.9 ± 31.4 478.8 ± 50.4 452.5 ± 47.7 417.6*± 47.7
weeks 13 482.6 ± 27.3 489.1 ± 55.7 456.2 ± 43.7 422.1*± 48.4
terminal weights %: 100% 101% 95% 88 %
Females
Dose control 250 ppm 500 ppm 750 ppm
weeks 1 174.0 ± 8.2 169.2 ± 7.3 171.5 ± 10.0 166.7 ± 9.2
weeks 2 197.7 ± 10.5 190 ± 9.7 193.4 ± 11.0 185.2 ± 13.0
weeks 3 213.6 ± 11.9 203 ± 12.3 203.0 ± 10.6 195.1* ± 14.3
weeks 4 230.6 ± 12.8 217.8 ± 13.8 214.7 ± 12.8 207.6* ± 23.5
weeks 5 246.0 ± 17.4 230.0 ± 15.4 228.0 ± 15.7 221.5* ± 21.4
weeks 6 254.3 ± 14.3 234.0* ± 15.5 233.3* ± 15.3 228.4** ± 20.7
weeks 7 265.7 ± 19.1 246 ± 18.2 239.3* ± 14.6 234.7**± 24.1
weeks 8 274.3 ± 26.3 248.6*± 16.0 242.0** ± 12.6 233.3**± 21.9
weeks 9 272.1 ± 18.9 247.3*± 15.0 245.1**± 12.8 235.1**± 22.1
weeks 10 282.0 ± 16.2 258.8*± 14.6 256.8 *± 14.4 244.6**± 24.3
weeks 11 289.9 ± 17.3 260.5**± 14.5 257.9**± 12.7 246.3**± 24.7
weeks 12 294.2 ± 18.3 267.5*± 16.5 262.9**± 17.1 252.5**± 24.8
weeks 13 300.2 ± 17.0 268.5**± 16.8 265.9**± 15.7 256.1**± 26.4
terminal weights %: 100% 89% 89% 85 %
*significant different from control (p<0.05)
** significant different from control (p< 0.01)
Mean body weight gain calculated from week 0 through week 13:
Males
Dose control 100 ppm 250 ppm 500 ppm
Mean weight gain g + 292 +298 +266 +232**
Mean weight gain % 100% 102% 91% 80%
Females
Dose control 250 ppm 500 ppm 750 ppm
Mean weight gain g + 138 +107** +107** +94**
Mean weight gain % 100 % 77.5% 78% 68%
* *significant differenr from control (p<0.01)
The authors concluded that the differences noted in males at 250 and 500 ppm and in females at 250 ppm, 500 ppm and 750 ppm were attributed to the administration of the test substance.
Food Consumption:
In general with the exception of Week 1, the mean food consumption values of the treated males and females were comparable to control throughout the study. During Week 1 the mean food consumption values of the males in Groups III (250 ppm) and IV (500 ppm) and of the females in Groups III (250 ppm), IV (500 ppm) and V (750 ppm) were significantly reduced compared to controls. These reduced mean food consumption values were attributed to the administration of the test substance, possibly due to poor initial palatability.
Test Substance Intake:
Mean test substance intake values calculated based on individual body weight and food consumption data and nominal dose levels were as follows:
Santoflex 77 (mg/kg bw/day)
Dose 100 ppm 250 ppm 500 ppm
Males 6.6 15.9 32.4
Dose 250 ppm 500 ppm 750 ppm
Females 18.1 36 54.5
Laboratory Studies:
Hematology
The mean hematology data of the treated males and females was unremarkable. There were no findings which were attributed to the administration of the test substance.
Clinical Chemistry:
Several clinical chemistry parameters exhibited statistically significant differences from control which were attributed to the administration of the test substance. These included:
Males:
Females:
The significance of the changes noted in serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase are unclear. Other sporadic differences from control (some statistically significant) were observed in the clinical chemistry data. However, there were no treatment-related findings noted in any of the other clinical chemistry parameters.
Terminal Organ and Body Weights and Organ/Body Weight Ratios:
Several organs in the treated males and females exhibited alterations in mean absolute and/or relative (to body weight or to brain weight) weight data as follows:
a) The mean brain to body weight ratio was increased in the Group IV (500 ppm) males.
b) The mean testes/epididymides to body weight ratio of the Group IV (500 ppm) males were increased.
c) The mean liver weight of the Group IV (500 ppm) males was reduced.
d) The mean brain to body weight ratios were increased in the females in Groups III (250 ppm), IV (500 ppm) and V (750 ppm).
e) The mean liver to body weight ratios of the females in Groups III (250 ppm), IV (500 ppm) and V (750 ppm) were increased.
f) The mean kidney/brain weight ratios of the Group IV (500 ppm) and Group V (750 ppm) females were slightly reduced.
g) The mean spleen to body weight ratios of the Group III (250 ppm), Group IV (500 ppm) and Group V (750 ppm) females were slightly increased.
These alterations noted in absolute and relative (to body weight and brain weight) organ weight data were generally consistent with the reductions noted in terminal body weights. These organ weight changes were considered secondary effects and were not considered indicative of significant organ toxicity.
Pathology
Various tissue alterations were observed at the time of necropsy in males and females of all groups. Microscopic assessment of the tissues revealed no histomorphological evidence of a treatment relationship. Many of the "gross lesions" were iatrogenic and associated with the orbital bleeding technique. Reddened foci in the lungs were due to inhalation of blood which had accumulated in the nasopharyngeal region. Reddened tracheobronchial lymph nodes were also associated with the bleeding technique and were related to erythrophagocytosis. Enlarged submandibular lymph nodes were often noted. The enlargement was associated with lymphoid hyperplasia and/or plasma cell hyperplasia which commonly occurs in the nodes receiving drainage from the oropharyngeal region. Fluid in the uterus, noted frequently, is a normal physiological change associated with estrus. It does not represent a pathological process. Various other miscellaneous tissue changes were observed but were not representative of a treatment effect.
Histopathology:
Microscopic evaluation of the tissues revealed no histomorphological evidence of a treatment induced or related effect. Tissues from the dietary controls were comparable histologically with those from the treated rats. Various tissue alterations were encountered; however, none was considered to have been treatment-related. All occurred with approximately equal frequency and degree in control rats as in treated animals. Occasional subintimal mineralized concretions were observed in the pulmonary veins of numerous rats. These concrements were not treatment associated but were thought to have been possibly induced through dietary imbalances of vitamin D and/or calcium. All other tissue findings were sporadic in occurrence and were changescommonly encountered in rats of this age and strain.
Under the conditions of this test it was concluded that Santoflex 77 when administered via the diet at levels of up to 500 ppm to males and 750 ppm to females for 3 months causes no histomorphological tissue alteration.
Based on the body weight data generated during this 13 week study, the authors concluded a no effect level (NOEL) for Santoflex 77 of 100 ppm in males. A no effect level was not established for the females based on reduced body weights observed at the 250 ppm dose level.
Applicant's summary and conclusion
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