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EC number: 247-063-2 | CAS number: 25513-64-8
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
The results of the two generation study (IBR, 1988) indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamin to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1987-03-23 to 1988-01-04
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Principles of method if other than guideline:
- and U.S. EPA Guidelines, Fed. Reg. 47, No. 100 (1982)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ORGANISMS
- Strain: Han/WIST (SPF) Wistar rats
- Origin: Zentralinstitut für Versuchstierkunde (Hannover, Germany)
- Number: 28 per sex and dose = 112 males + 112 females in P generation (F0)
- Age at first dosing: males 5-6 weeks, females 9-10 weeks
- Weight at study initiation: males 86-153 g, females 150-210 g
- Housing: single in conventional Makrolon cages, escept during mating and breeding periods
- Diet:. ad libitum, standard fixed-furmula diet "Ssniff R"
- Water: ad libitum, tab water
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 +/- 1.5 °C
- Humidity (%): 65 % +/- 10 %
- Air changes (per hr): 16 air changes per hour
- Photoperiod (hrs dark / hrs light): 12h / 12 h - Route of administration:
- oral: gavage
- Vehicle:
- other: aqua deionized
- Details on exposure:
- ADMINISTRATION / EXPOSURE
- Duration of test/exposure: Generally, exposure was continuous from pre-mating treatment until death / sacrifice.
Treatment of offspring was installed at the age of 4 weeks.
- Vehicle: Deionized water
- Concentration in vehicle: 0.1, 0.6, or 1.2 %, solutions prepared each day before treatment
- Total volume applied: 10 ml/kg bw per dose, adapted to weekly determined body weights - Details on mating procedure:
- MATING PROCEDURES:
- Monogamous mating was allowed for a maximum of 21 days by caging partners together only at night. Each morning every female was checked
for copulation plugs or subjected to a vaginal smear preparation. When a plug or sperms was found, partners were separated.
- A second (similar) mate of the P generation was started 10 days post weaning for the teratology studies. All mated P females were hysterectomized after 20 gestation days for a teratological assessment.
- Mating of F1 animals was begun at 16 weeks of age avoiding brother-sister mating. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of compound solutions were analyzed upon identity (by gas-chromatography), concentration and stability at study start, after 16 and 26
weeks. In a stability study prior to the study start was found out that the test substance was stable in water for at least 18 days, analysis method:
potentiometric titration. Concentration analyses resulted in recovery values within acceptable limits and were performed by potentiometric titration
- Duration of treatment / exposure:
- Exposure period: see Test Conditions
Premating exposure period (males): 10 weeks during growth into adulthood
Premating exposure period (females): 2 weeks including two complete estrous cycles
Duration of test: Until day 21 post partum of F2 generation = 287 days - Frequency of treatment:
- once daily (midmorning), 7 days/week
- Details on study schedule:
- Number of generation studies: 2
- Remarks:
- Doses / Concentrations:
10, 60, 120 mg/kg bw d
Basis:
nominal conc. - No. of animals per sex per dose:
- F0: 28 males and females in parent generation
F1: 24 males and females selected on day 21 postpartum - Control animals:
- yes, concurrent vehicle
- Details on study design:
- OTHER EXAMINATIONS: Teratology study, see separate entry in chapter 7.8.2 of IUCLID
- Positive control:
- no positive control
- Parental animals: Observations and examinations:
- PARAMETERS ASSESSED DURING STUDY P AND F1:
- Clinical signs: Daily recording, weekly reports: Sensory and motor behavior, hair coat, body orifices, urine and fecal excretion, general health
status and dose responses. Reflex examinations were performed weekly in 10 rats per dose group and sex with special regard to awareness,
emotion, coordination and autonomic functions (modified IRVING screen). Body weight and food consumption were determined weekly and
individually (body weights daily during mating period).
- Mortality: Twice daily - Oestrous cyclicity (parental animals):
- Mean mating period data did not differ significantly between control and dose groups
- Litter observations:
- STANDARDIZATION OF LITTERS: Determination of number, potential loss (mortalities / cannibalism), body weight (days 1+4 post partum per litter,
day 21 individually), sex (days 1+21). Selection of 24 males + 24 females from F1 generation on day 21 post partum for the next generation,
weights as close as possible to weight mean of each sex. Sacrifice of excessive F1 pups / all F2 pups on day 21 post (respective) partum for gross
pathology examination.
PARAMETERS ASSESSED DURING STUDY F1 AND F2:
- Clinical observations and frequency: F1, day 21 post partum: Special behavior examinations (Irvin screen, righting reflex, visual-placing test,
startle-response test and pupil-reflex test) on 2 male and 2 female pups of each litter. - Postmortem examinations (parental animals):
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
Sacrifice and autopsy of all parents when no longer needed for mating or rearing purposes. Females showing no signs of implantations in the
teratogenicity study were disregarded from evaluation.
P and F1: Complete macroscopic examination.
- Organ weights P and F1: F1 and F2: Heart, liver, kidneys, spleen (2 pups per sex and litter).
- Histopathology P and F1: Preservation of organs from animals which died or were were killed in extremis during the study.
- Histopathology F1 not selected for mating, F2: Preservation of heart, liver, kidneys, spleen (2 pups per sex and litter) plus macroscopically
changed organs. - Postmortem examinations (offspring):
- F1, day 21 post partum: Physical anomalies, behavior, development; including hairgrowth, pinna unfolding, eye opening and teething.
- Statistics:
- STATISTICAL METHODS:
- Body weight changes, food consumption, fetal weights, placenta weights, number of corpora lutea, implantations, fetuses and offspring: One
factorial analysis of variance
- Comparison of group mean values: Method of Tukey
- Organ weights: Covariance analysis, correction for body weight, comparison of mean values with Scheffé test.
- Comparison of indices: Mann-Whitney U-test
- Group means of gestation length and copulation attempts: Multiple t-test. - Reproductive indices:
- Fertility index: Significantly reduced in high-dose P females (56.0% vs 78.6% in control), not notably affected in F1 females (85.0% in high-dose vs
83.3% in control). During delivery, one low-dose female and one high-dose female of the P generation plus two low-dose females of the F1
generation destroyed their litters by cannibalism. The second mating of the P animals, which was done for teratology studies, led to a reduced
number of pregnant females in all dosed groups, which was in the normal range only at the low-dose level: 81.5% / 72% / 64% / 60% in control /
low / mid / high dose groups. It was associated with a significantly increased pre-implantation loss of ova for the high-dose females
(61.0% vs 36.% in control). - Offspring viability indices:
- F1: Mean number of pubs per dam and groups and indices did not differ remarkably between testgroups, and from day 4 to day 21 the only change (dead pups) occured in the control group
F2: Mean number of pups was nearly equal in all testgroups and during the entire 3-week breeding period. No great drop of viability was found in
any testgroup - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- Dose descriptor:
- LOEL
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on results (offspring)"
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (offspring)"
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see "Details on result (parental animals)"
- Histopathological findings:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Reproductive effects observed:
- not specified
- Conclusions:
- The results of the two generation study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.
- Executive summary:
In a two generation study with integrated teratological investigation, dose levels of 10, 60, 120 mg/kg 2,2,4(or 2,4,4)- trimethylhexane-1,6-diamine were administered once daily by oral gavage to male and female rats. Following a 10-weeks pre-mating treatment period for male animals and a 2 -weeks treatment period for females, this generation of animals (F0) was mated to produce the F1 generation. After gestation, delivery of F1, and a 3-week lactation period, F0 females were mated for a second time. F0 -generation males were sacrificed after this second mating period and F0 -generation females were sacrificed for hysterectomy after 20 gestation days.
24 males and 24 femals of F1 generation were selected per dose-group to form the basis of next generation. Treatment was installed at the age of 4 weeks.
The results of the present study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.
Dose levels of 60 mg/kg (group II) and 120 mg/kg (group III) led to dose-related maternal and paternal reduced increase of weight gains and reduced food consumption. Some mortalities (3 males and 4 females in parental F0- generation and 2 males and 3 females in the F1 -generation of the highest dose group) most likely are due to the test compound administration. At this high (slight toxic) dose level pregnancy rate was distinctly reduced among F0 -females (probably due to pre-implantation loss), which was found to be significantly increased among high dosed females in the teratology segment (120 mg/kg). Above all no adverse effect on litter development, e.g. malformations, behaviour dysfunctions or increased death rates were noticed in any phase of the study. Only liver-(and kidney) weights increased in both, F1- and F2- pups and F2 -pups showed a slight tendency towards decreased weight gains in the highest dose group.
Reference
- Body weight: During the growth period (weeks 1-10), gain rates of P males were unaffected in the low-dose group and significantly reduced in the mid-dose (-8.3%) and high-dose (-12.1%) groups. In the P females, body weight changes were comparable between controls and dose groups
during the growth period. During gestation, the weight development of high-dose P females was at the borderline of statistical significance
(-15.6%). During lactation, no great differences were observed in P females. During the subsequent teratology study, the bodyweight gain in the
high-dose females was significantly reduced (-29.0%). In the F1 generation, the body weight gain of high-dose males (-14.1%) and females
(-11.3%) was significantly reduced during the first 6 weeks of the treatment period. During gestation, the bodyweight gain rates of high-dose
females were insignificantly lower than those of the controls. During lactation, the initially determined weight deficiencies of mid- and high-dose
F1 females were compensated. This led to a statistically significant increase in the mid-dose group which is considered to be coincidental.
- Food/water consumption: During the growth period of the P generation (weeks 1-10), food intake (-8.0%) and food conversion ratio were
significantly reduced only the in high-dosed males. No great intergroup differences were observed in P females during their growth period.
During gestation, the reduction in the high-dose females did not attain statistical significance, and during lactation no great intergroup
differences were observed. During the second gestation, food consumption of high-dose females was significantly reduced (-9.3%). In the F1
generation, food consumption was significantly reduced in the high-dose males during growth (all 12 weeks: -7.4%; weeks 1-6: -9.2%). No
significant differences in food consumption and food conversion rate between treated and control were observed in the F1 females from growth
through lactation.
- Description, severity, time of onset and duration of clinical signs:
In the P generation, male mid-dose and high-dose rats showed a slightly reduced righting-reflex from treatment week 5 on. There were no
abnormal findings in low-dose males and in all females, also in the teratology phase.
In the F1 generation, all mid- and high-dose animals had salivation shortly after the daily treatment during the entire growth period. This effect
continued in the females during gestation and breeding.
- Fertility index: Significantly reduced in high-dose P females (56.0% vs 78.6% in control), not notably affected in F1 females (85.0% in high-dose vs
83.3% in control). During delivery, one low-dose female and one high-dose female of the P generation plus two low-dose females of the F1
generation destroyed their litters by cannibalism. The second mating of the P animals, which was done for teratology studies, led to a reduced
number of pregnant females in all dosed groups, which was in the normal range only at the low-dose level: 81.5% / 72% / 64% / 60% in control /
low / mid / high dose groups. It was associated with a significantly increased pre-implantation loss of ova for the high-dose females
(61.0% vs 36.% in control).
- Precoital interval: Mean mating period data did not differ significantly between control and dose groups both in the P and the F1 generation.
- Duration of gestation: Almost equal in all groups (P: 21.3 - 21.6 days; F1: 21.5 - 21.8 days)
- Mortality, P generation:
Mid-dose: Two females died, one during the first mating period, the other one day after weaning.
High-dose: Three males died, one after two weeks of the 10-week treatment phase, the second four weeks later, the third after the first mating
period. Four females died, one during the first treatment week, two during the mating period, one during the second gestation period.
F1 generation: Two high-dose males died, one during treatment week 1, the second after treatment week 12. Three high-dose females died
during/after treatment weeks 1, 2, and 6.
Mortalities were considered to be treatment related.
- Gross pathology incidence and severity: Hyperemic lungs were the most common finding in the P animals that died during the study (8/9). All
other findings were identified in only one animal each. At terminal necropsy, no macroscopic organ changes in P animals were found which could
be attributed to test compound administration.
Findings occurring in more than one of the F1 animals that died during the study were hyperemic lungs (3/5), tympanitis (3/5), and redness in
gastric or intestinal mucous membranes (2/5). At terminal necropsy, no macroscopic treatment related findings were observed in F1 animals.
- Organ weight changes: No significant intergroup differences were found in the terminal weights of the testes of P and F1 males. Terminal
placenta weights of P females were also comparable, and uterus weights decreased insignificantly with increasing dose level.
- Litter size: In the fertility study, there were no remarkable differences between test groups (F1: 8.1 - 9.6; F2: 8.9 - 9.4). A distinct, though not
statistically significant reduction was observed in the second gestation of high-dose P females (teratology study: 4.1 vs 7.6 in control).
- Sex and sex ratios: Statistically insignificant differences between test groups (F1: m/f = 0.96, 0.99, 0.91, 1.53 in control, low-, mid-, and high-dose groups, respectively. F2: 0.92, 1.17, 1.02, 0.86. Second mate of P: 1.2, 1.4, 1.4, 1.5).
- Viability index: No remarkable differences between test groups (F1: 96.7 - 99.0%; F2: 95.8 - 98.9%)
- Post natal survival until weaning: All litters remaining (after initial cannibalism) developed normally.
- Effects on offspring: No adverse effect due to P maternal treatment was observed in any F1 litter during the breeding period.
- Postnatal growth, growth rate: Mean bodyweights of F1 pups were similar in all groups on days 1, 4, and 21 of breeding. A slight weight deficiency of high-dose F2 pups (-4.5% on day 1) became statistically significant on breeding day 21 (-11.0%). Mean weights of fetuses from the second P
mate were comparable in all groups.
- Organ weights: F1 high-dose males selected for organ weight determinations had significantly increased terminal liver (+8.9%) and kidney
(left +10.6%, right +8.1%) weights. The liver weights of the F2 rats showed a dose-dependent increase at the mid-dose and high-dose levels:
Males: Mid-dose +9.7%, high-dose +10.2%
Females: Mid-dose +9.6%, high dose +11.5%
- Terminal necropsy: Findings in F2 animals were considered to be unrelated to treatment with an incidence within the normal spontaneous
variation range in rats.
No external abnormalities were found in the fetuses from the dosed groups of the teratology study (1 small hematoma in a control fetus).
Skeletal examination revealed a comparable development stage for all test groups and variations (wavy ribs) at incidences often seen in this strain of rats. One cystic dilated renal pelvis each in low- and mid-dose fetuses was considered to be within the normal rate of spontaneously
occurring anomalies.
no further remarks
Effect on fertility: via oral route
- Dose descriptor:
- NOAEL
- 10 mg/kg bw/day
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In a two generation study (OECD TG 416, IBR, 1988) with integrated teratological investigation, dose levels of 10, 60, 120 mg/kg 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were administered once daily by oral gavage to male and female rats. Following a 10-weeks pre-mating treatment period for male animals and a 2 -weeks treatment period for females, this generation of animals (F0) was mated to produce the F1 generation. After gestation, delivery of F1, and a 3-week lactation period, F0 females were mated for a second time. F0 -generation males were sacrificed after this second mating period and F0 -generation females were sacrificed for hysterectomy after 20 gestation days.
24 males and 24 femals of F1 generation were selected per dose-group to form the basis of next generation. Treatment was installed at the age of 4 weeks.
The results of the present study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.
Dose levels of 60 mg/kg (group II) and 120 mg/kg (group III) led to dose-related maternal and paternal reduced increase of weight gains and reduced food consumption. Some mortalities (3 males and 4 females in parental F0- generation and 2 males and 3 females in the F1 -generation of the highest dose group) most likely are due to the test compound administration. At this high (slight toxic) dose level pregnancy rate was distinctly reduced among F0 -females (probably due to pre-implantation loss), which was found to be significantly increased among high dosed females in the teratology segment (120 mg/kg). Above all no adverse effect on litter development, e.g. malformations, behaviour dysfunctions or increased death rates were noticed in any phase of the study. Only liver-(and kidney) weights increased in both, F1- and F2- pups and F2 -pups showed a slight tendency towards decreased weight gains in the highest dose group.
Short description of key information:
The results of the two generation study (IBR, 1988) indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamin to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.
Effects on developmental toxicity
Description of key information
Under the conditions of a oral two generation study with integrated teratological investigation with rats, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was not teratogenic up to the highest test concentration of 120 mg/kg bw. In a second oral teragonicity study, a daily exposition to a 0.05 % 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine concentration in drinking water did not exert signs of maternal toxicity and a 0.25 % concentration did not adversely affect fetal development of New Zealand White-rabbits.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1987-03-23 to 1988-01-04
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Principles of method if other than guideline:
- OECD Guideline 416 (1983) and U.S. EPA Guidelines, Fed. Reg. 47, No. 100 (1982)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ORGANISMS
- Strain: Han/WIST (SPF) = Crl:Wi/Br Wistar rats
- Source: Zentralinstitut für Versuchstierkunde (Hannover, Germany)
- Number: 28 per sex and dose = 112 males + 112 females in P generation (F0).
For the teratology study, 27 mated control females and 25 mated females per dosed group were available.
- Age at first dosing: males 5-6 weeks, females 9-10 weeks
- Weight at study initiation: males 86-153 g, females 150-210 g
- Housing: single in conventional Makrolon cages, escept during mating and breeding periods
- Diet:. ad libitum, standard fixed-furmula diet "Ssniff R"
- Water: ad libitum, tab water
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 +/- 1.5 °C
- Humidity (%): 65 % +/- 10 %
- Air changes (per hr): 16 air changes per hour
- Photoperiod (hrs dark / hrs light): 12h / 12 h - Route of administration:
- oral: gavage
- Vehicle:
- other: deionized water
- Details on exposure:
- ADMINISTRATION / EXPOSURE
- Duration of test/exposure: Exposure was continuous from pre-mating treatment until death / sacrifice. Pre-mating treatment was 10 weeks
during growth into adulthood for males and 2 weeks including two complete estrous cycles for females.
- Vehicle: Deionized water
- Concentration in vehicle: 0.1, 0.6, or 1.2 %, solutions prepared each day before treatment
- Total volume applied: 10 ml/kg bw per dose, adapted to weekly determined body weights - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of compound solutions were analyzed upon identity (by gas-chromatography), concentration and stability at study start, after 16 and 26
weeks. In a stability study prior to the study start was found out that the test substance was stable in water for at least 18 days, analysis method:
potentiometric titration. Concentration analyses resulted in recovery values within acceptable limits and were performed by potentiometric titration
- Details on mating procedure:
- MATING PROCEDURES:
- Monogamous mating was allowed for a maximum of 21 days by caging partners together only at night. Each morning every female was checked
for copulation plugs or subjected to a vaginal smear preparation. When a plug or sperms was found, partners were separated. The first mating
was for the fertility study.
- A second (similar) mate of the P generation with identical partners was started 10 days post weaning for the teratology studies. All mated P females were sacrificed on day 20 of pregnancy for hysterectomy and judgment of the uterine content.
- For the fertility study, 24 males + 24 females from the F1 generation (resulting from the first P mating) were selected on day 21 post partum for
the next generation, with their weights as close as possible to the weight mean of each sex. Further data are presented in a separate entry in
chapter 7.8.1. - Duration of treatment / exposure:
- see Test Conditions
- Frequency of treatment:
- once daily (midmorning), 7 days/week
- Duration of test:
- Duration of test: Until gestation day 20 of a second F1 generation
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- control
- Dose / conc.:
- 10 mg/kg bw/day
- Remarks:
- low dose
- Dose / conc.:
- 60 mg/kg bw/day
- Remarks:
- intermediate dose
- Dose / conc.:
- 120 mg/kg bw/day
- Remarks:
- high dose
- No. of animals per sex per dose:
- 28
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Sex: male/female
OTHER EXAMINATIONS: Fertility study, see separate entry in chapter 7.8.1 - Maternal examinations:
- PARAMETERS ASSESSED DURING STUDY:
- Mortality: Twice daily
- Clinical signs: Daily recording, weekly reports: Sensory and motor behavior, hair coat, body orifices, urine and fecal excretion, general health
status and dose responses. Reflex examinations were performed weekly in 10 rats per dose group and sex with special regard to awareness,
emotion, coordination and autonomic functions (modified Irving screen).
- Body weight gain: weekly and individually, daily during mating period, every 5th day during second gestation period
- Food consumption: weekly and individually, for 5 day intervals during second gestation period
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
Sacrifice and autopsy of all parents when no longer needed for mating or rearing purposes. Females showing no signs of implantations in the
teratogenicity study were disregarded from evaluation. P (and F1): Complete macroscopic examination of organs. - Ovaries and uterine content:
- - Examination of uterine content: For each uterus horn: Fetuses (alive / dead), birth position (anterior / posterior), early and late resorptions,
placentae, implantation sites.
- Examination of ovaries: Number of corpora lutea - Fetal examinations:
- P (and F1): Complete macroscopic examination of organs.
- Examination of fetuses: Individual weight and sex (ano-genital distance), externally visible deviations from normal, visceral imperfections
(approx. 1/3 of the fetuses, slightly thawn frozen samples), skeletal defects (approx. 2/3 of the fetuses). - Statistics:
- STATISTICAL METHODS:
- Body weight changes, food consumption, fetal weights, placenta weights, number of corpora lutea, implantations, fetuses and offspring: One
factorial analysis of variance
- Comparison of group mean values: Method of Tukey
- Organ weights: Covariance analysis, correction for body weight, comparison of mean values with Scheffé test.
- Comparison of indices: Mann-Whitney U-test - Group means of gestation length and copulation attempts: Multiple t-test. - Indices:
- Fertility Index, , Viability Index, Resorption Index, Pre-Implantation Loss Index, Post-Implantation Loss Index, Runts Index, Variation Index,
Number of litters having abnormalities, Number of abnormalities per litter - Historical control data:
- no data
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
see below: "Any other information on results..." - Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
see below: "Any other information on results..." - Dose descriptor:
- NOAEL
- Effect level:
- 120 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Under the conditions of this oral two generation study with integrated teratological investigation with rats, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was not teratogenic up to the highest test concentration of 120 mg/kg bw.
- Executive summary:
In a two generation study with integrated teratological investigation, dose levels of 10, 60, 120 mg/kg 2,2,4(or 2,4,4)- trimethylhexane-1,6-diamine were administered once daily by oral gavage to male and female rats. Following a 10-weeks pre-mating treatment period for male animals and a 2 -weeks treatment period for females, this generation of animals (F0) was mated to produce the F1 generation. After gestation, delivery of F1, and a 3-week lactation period, F0 females were mated for a second time. F0 -generation males were sacrificed after this second mating period and F0 -generation females were sacrificed for hysterectomy after 20 gestation days. 24 males and 24 femals of F1 generation were selected per dose-group to form the basis of next generation. Treatment was installed at the age of 4 weeks.
The results of the present study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal in any stage of the study. Therefore, under the conditions of this oral teratogenicity study with rats, the NOAEL for maternal toxicity was determined to be 10 mg/kg bw.
Dose levels of 60 mg/kg (group II) and 120 mg/kg (group III) led to dose-related maternal and paternal reduced increase of weight gains and reduced food consumption. Some mortalities (3 males and 4 females in parental F0- generation and 2 males and 3 females in the F1 -generation of the highest dose group) most likely are due to the test compound administration. At this high (slight toxic) dose level pregnancy rate was distinctly reduced among F0 -females (probably due to pre-implantation loss), which was found to be significantly increased among high dosed females in the teratology segment (120 mg/kg). No external abnormalities were found in the fetuses from the dosed groups of the teratology study (1 small hematoma in a control fetus). One cystic dilated renal pelvis each in one low- (10 mg/kg bw) and one mid-dose (60 mg/kg bw) fetus was considered to be within the normal rate of spontaneously occurring anomalies. Skeletal examination revealed a comparable development stage for all test groups and variations
(wavy ribs) at incidences often seen in this strain of rats.
Above all no adverse effect on litter development, e.g. malformations, behaviour dysfunctions or increased death rates were noticed in any phase of the study. Only liver-(and kidney) weights increased in both, F1- and F2- pups and F2 -pups showed a slight tendency towards decreased weight gains in the highest dose group.
Therefore, under the conditions of this oral two generation study with integrated teratological investigation with rats,
2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was not teratogenic up to the highest test concentration of 120 mg/kg bw.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1987-02-16 to 1987-05-12
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Principles of method if other than guideline:
- Teratogenicity study designed according to the FDA-Guideline for Safety Assessment of Direct Food Additives (App. II), FDA-Red Book.
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ORGANISMS
- Source: H. Schriever, Rabbitfarm, Bremervörde (Germany)
- Age: Approx. 4 months at study initiation
- Weight at study initiation: 2.6 - 4.6 kg
- Number of animals: 12 per dosed group, 10 in control group
- Housing: single
- Diet:. ad libitum, standard fixed-furmula diet "Ssniff Mümmel Z"
- Water: ad libitum, tab water
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3 °C
- Humidity (%): 50 % - 85 %
- Air changes (per hr): 16 air changes per hour
- Photoperiod (hrs dark / hrs light): 12h / 12 h - Route of administration:
- oral: drinking water
- Vehicle:
- other: Tap water (aqua fontana)
- Details on exposure:
- ADMINISTRATION / EXPOSURE
- Vehicle: Tap water (aqua fontana)
- Concentration in vehicle: 0.01; 0.05; 0.25 % (w/w) (significantly reduced water intake at 0.3 % in dose finding study)
- Doses: Proportional to water consumption (ad libitum), which was monitored daily during dosing period - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of compound solutions were analyzed upon identity (gas-chromatographically), concentration and stability at study start.
In a stability study prior to the study start was found out that the test substance was stable in water for at least 18 days, analysis method: potentiometric titration. Concentration analyses resulted in recovery values within acceptable limits and were performed by potentiometric titration.
- Details on mating procedure:
- MATING PROCEDURES: Females were mated with untreated, fertile and proven bucks (day 0 of gestation). Non-gravid females were substituted by
additional, gravid animals. - Duration of treatment / exposure:
- 13 days (days 6 - 18 of gestation)
- Frequency of treatment:
- permanent
- Duration of test:
- Duration of test: 29 days
- No. of animals per sex per dose:
- 12 female per dose group
10 female control group - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Sex: female
Duration of test: 29 days - Maternal examinations:
- PARAMETERS ASSESSED DURING STUDY:
- Mortality: Daily
- Clinical signs: Daily over the entire study period with special regard to sensory and motor behavior, hair coat, urine and fecal excretion, and
conditions of orifices.
- Body weight gain: Days 0, 5, 10, 15, 20
- Food consumption: Days 0-5, 5-15, 15-20 -
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): "Complete" autopsy and macroscopic examination of organs in all
pregnant females. Weights of placentae and uteri. - Ovaries and uterine content:
- Examination of uterine content (sacrifice on day 29 of gestation): For each uterine horn: Fetuses (alive / dead); birth position (anterior /posterior);
early- and late resorptions; placentae; implantation sites
For each ovary: Number of corpora lutea - Fetal examinations:
- Examination of fetuses: Individual weights and sex (ano-genital distance), gross external examination (all), evaluation for visceral imperfections
(approx. 1/3 of fetuses in each litter), evaluation for skeletal defects (approx. 2/3 of fetuses in each litter) - Statistics:
- STATISTICAL METHODS: One factorial analysis of variance for growth parameters and reproduction parameters (number of fetuses, implantations,
corpora lutea, weights of fetuses, placentae and uteri). Comparison of group mean values according to the method of Tukey. Comparison of indices with Mann-Whitney U-test. - Indices:
- Abortion Rate, Runts Index, Life Birth Index, Resorption Index, Post-Implnatation Loss Index, Still birth Index, Variation Index, Malformation Index
- Historical control data:
- own laboratory experiences
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
see below: "Any other information on results..." - Dose descriptor:
- NOAEL
- Effect level:
- 0.05 other: %
- Based on:
- dissolved
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 44 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 0.25 other: %
- Based on:
- dissolved
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 77.9 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
see below: "Any other information on results..." - Dose descriptor:
- NOAEL
- Effect level:
- 0.25 other: %
- Based on:
- dissolved
- Basis for effect level:
- other: teratogenicity
- Dose descriptor:
- NOAEL
- Effect level:
- 77.9 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:
- Under the experimental conditions of this study, a daily exposition to a 0.05 % 2,2,4(or 2,4,4)-trimethylhexamethylenediamine concentration in drinking water did not exert signs of maternal toxicity and a 0.25 % concentration did not adversely affect fetal development of New Zealand White-rabbits.
- Executive summary:
2,2,4(or 2,4,4)-trimethylhexamethylenediamine was administered daily via drinking water to pregnant rabbits during the organogenetic phase of gestation (Day 6 - 18), concentrations of 0.01 %, 0.05 % and 0.25 % were used, a concurrent control group received tap water only.
The only sign of maternal response to treatment were reduced bodyweights and reduced water consumption in the high dose group. Maternal uterine and intrauterine parameters (e.g. number and weight of fetuses, number of resorptions, implantations, corpora lutea and weights of placentae or uteri) did not reveal significant differences between groups. The index of resorptions and thus the postimplantion-loss index was slightly increased for dose group III - females. This was, however, only due to two dams showing 6 or 5 early resorptions. Since the difference to the controls did not attain statistical significance, this increase is considered to be coincidental and not treatment related.
Examination of fetuses (external, skeletal and visceral) demonstrated one malformed fetus in dose group I only. Therefore no treatment related effect was indicated from data obtained during this study.
Under the experimental conditions of this study, a daily exposition to a 0.05 % 2,2,4(or 2,4,4)-trimethylhexamethylenediamine concentration in drinking water did not exert signs of maternal toxicity and a 0.25 % concentration did not adversely affect fetal development of New Zealand White-rabbits.
Referenceopen allclose all
Result: not teratogenic
MATERNAL TOXIC EFFECTS BY DOSE LEVEL:
- Mortality and day of death, P generation:
Mid-dose: Two females died, one during the first mating period, the other one day after weaning.
High-dose: Three males died, one after two weeks of the 10-week treatment phase, the second four weeks later, the third after the
first mating period. Four females died, one during the first treatment week, two during the mating period, one (not pregnant) during
the second gestation period.
- Mortalities were considered to be treatment related.
- Description, severity, time of onset and duration of clinical signs:
In the P generation, male mid-dose and high-dose rats showed a slightly reduced righting-reflex from treatment week 5 on. There
were no abnormal findings in low-dose males and in all females. In the teratology phase, all mated females showed a healthy
general habit without clinical signs throughout gestation.
- Food/water consumption:
During the growth period of the P generation (weeks 1-10), food intake (-8.0%) and food conversion ratio were significantly
reduced only the in high-dosed males. No great intergroup differences were observed in P females during their growth period.
During gestation, the reduction in the high-dose females did not attain statistical significance, and during lactation no great intergroup
differences were observed. During the second gestation, food consumption of high-dose females was significantly reduced (-9.3%).
- Body weight:
During the growth period (weeks 1-10), gain rates of P males were unaffected in the low-dose group and significantly reduced in
mid-dose (-8.3%) and high-dose (-12.1%) groups. In the P females, body weight changes were comparable between controls and
dose groups during the growth period. During gestation, the weight development of high-dose P females was at the borderline
of statistical significance (-15.6%). During lactation, no great differences were observed in P females. During the subsequent
teratology study, the bodyweight gain in the high-dose females was significantly reduced (-29.0%).
- Gross pathology incidence and severity:
Hyperemic lungs were the most common finding in the P animals that died during the study (8/9). All other findings were identified
in only one animal each. At terminal necropsy, no macroscopic organ changes in P animals were found which could be attributed
to test compound administration.
- Organ weight changes: No significant intergroup differences were found in the terminal weights of the testes of P and F1 males.
Terminal placenta weights of P females were also comparable, and uterus weights decreased insignificantly with increasing dose
level.
- Number pregnant per dose level: The second mating of the P animals, which was done for teratology studies, led to a reduced
number of pregnant females in all dosed groups, which was in the normal range only at the low-dose level:
81.5% / 72% / 64% / 60% in control / low / mid / high dose groups.
- Number aborting: No abortions or premature delivery in any group.
- Number of resorptions: No relevant effect (1.1 / 0.9 / 0.4 / 0.8 in control / low / mid / high dose groups, 0.8 / 0.8 / 0.4 / 0.5
thereof early resorptions).
- Number of implantations: Lower values at mid- and high-dose levels were not significant
(8.7 / 7.9 / 6.8 / 4.9 in control / low / mid / high dose groups).
- Pre and post implantation loss: Pre-implantation loss of ova was significantly increased for the teratology study high-dose females
(61.0% vs 36.% in control). Post implantation loss varied insignificantly between groups (11.9% / 13.8% / 8.9% / 34.8% in
control / low / mid / high dose groups)
- Number of corpora lutea: Similar in all groups (12.3 - 13.7 per dam).
- Duration of pregnancy: Terminated after 20 days
FETAL DATA: F1 and F2 data are presented in chapter 7.8.1. Only data resulting from the second mating of the P animals are
presented here:
- Litter size: A distinct, though not statistically significant reduction was observed at the high dose level: 4.1 vs 7.6 in control. Left
and
righ uterine horns were similarly affected. Anterior or posterior birth position was equally distributed.
- Litter weights: Mean weights of fetuses from the second P mate were comparable in all groups (3.49 - 3.81).
- Number viable: Only in the high-dose group there was one dead fetus.
- Sex ratio: Not notably affected by treatment (1.2, 1.4, 1.4, 1.5 in control, low-, mid-, and high-dose groups, respectively).
- External abnormalities: No external abnormalities were found in the fetuses from the dosed groups of the teratology study
(1 small hematoma in a control fetus).
- Soft tissue abnormalities: One cystic dilated renal pelvis each in one low- and one mid-dose fetus was considered to be within the
normal rate of spontaneously occurring anomalies.
- Skeletal abnormalities: Skeletal examination revealed a comparable development stage for all test groups and variations
(wavy ribs) at incidences often seen in this strain of rats.
Result: not teratogenic
ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX: 9.1 / 44.0 / 77.9 mg/kg bw day
MATERNAL TOXIC EFFECTS BY DOSE LEVEL: No treatment related effects on the reproductive system were observed.
- Mortality and day of death: No mortality occurred during the study.
- Description, severity, time of onset and duration of clinical signs: No differences between control and dosed animals (healthy habit
and appearance, normal defecations of all animals)
- Food/water consumption: Water consumption was significantly reduced (-55.3 %) in the high dose group during the exposure
period.
- Body weight: Reduced in high dose group during exposure period (mean -15.0 g vs +292.0 g in control group). No significant
intergroup differences during days 0-6, 18-29, or 0-29.
- Gross pathology incidence and severity: No signs of treatment related organ alterations were found.
- Organ weight changes: No significant intergroup differences (placenta and uteri)
- Number pregnant per dose level: 100 % (Non-gravid females were substituted leaving only 10 pregnant females for the control
group).
- Number aborting: None in any group; 1 low dose animal with only one implantation site
- Number of resorptions: No significant intergroup differences. Index slightly (not statistically significant) increased in high dose
females due to two dams showing 6 or 5 early resorptions
- Number of implantations: No significant intergroup differences
- Pre and post implantation loss: No significant intergroup differences. Post implantation loss index slightly (not statistically significant) increased in high dose females due to two dams showing 6 or 5 early resorptions.
- Number of corpora lutea: No significant intergroup differences
FETAL DATA: The data obtained did not indicate treatment related teratogenic effects.
- Litter size and weights: No significant intergroup differences
- Number viable: No significant intergroup differences (no dead fetuses in any group)
- Sex ratio: No significant intergroup differences
- Grossly visible abnormalities: One malformed fetus in low dose group only
- External abnormalities: None except same malformed fetus in low dose group
- Soft tissue abnormalities: No adverse effects of treatment was indicated from the fetal examinations by free-hand serial sectioning.
- Skeletal abnormalities: None except same malformed fetus in low dose group, which showed:
Head: Left side rudimentary, right side missing
Thorax, abdomen: Sternochisis, umbilical hernia with a prolaps of the liver.
STATISTICAL RESULTS: Type and incidence of the observed malformations is considered to be within the spontaneous
malformation rate for this strain of rabbits.
Effect on developmental toxicity: via oral route
- Dose descriptor:
- NOAEL
- 120 mg/kg bw/day
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
In a two generation study with integrated teratological investigation, dose levels of 10, 60, 120 mg/kg 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were administered once daily by oral gavage to male and female rats. Following a 10-weeks pre-mating treatment period for male animals and a 2 -weeks treatment period for females, this generation of animals (F0) was mated to produce the F1 generation. After gestation, delivery of F1, and a 3-week lactation period, F0 females were mated for a second time. F0 -generation males were sacrificed after this second mating period and F0 -generation females were sacrificed for hysterectomy after 20 gestation days. 24 males and 24 femals of F1 generation were selected per dose-group to form the basis of next generation. Treatment was installed at the age of 4 weeks.
The results of the present study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal in any stage of the study. Therefore, under the conditions of this oral teratogenicity study with rats, the NOAEL for maternal toxicity was determined to be 10 mg/kg bw.
Dose levels of 60 mg/kg (group II) and 120 mg/kg (group III) led to dose-related maternal and paternal reduced increase of weight gains and reduced food consumption. Some mortalities (3 males and 4 females in parental F0- generation and 2 males and 3 females in the F1 -generation of the highest dose group) most likely are due to the test compound administration. At this high (slight toxic) dose level pregnancy rate was distinctly reduced among F0 -females (probably due to pre-implantation loss), which was found to be significantly increased among high dosed females in the teratology segment (120 mg/kg). No external abnormalities were found in the fetuses from the dosed groups of the teratology study (1 small hematoma in a control fetus). One cystic dilated renal pelvis each in one low- (10 mg/kg bw) and one mid-dose (60 mg/kg bw) fetus was considered to be within the normal rate of spontaneously occurring anomalies. Skeletal examination revealed a comparable development stage for all test groups and variations (wavy ribs) at incidences often seen in this strain of rats.
Above all no adverse effect on litter development, e.g. malformations, behaviour dysfunctions or increased death rates were noticed in any phase of the study. Only liver-(and kidney) weights increased in both, F1- and F2- pups and F2 -pups showed a slight tendency towards decreased weight gains in the highest dose group.
Therefore, under the conditions of this oral two generation study with integrated teratological investigation with rats,
2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was not teratogenic up to the highest test concentration of 120 mg/kg bw.
In a second oral teratogenicity study 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was administered daily via drinking water to pregnant rabbits during the organogenetic phase of gestation (Day 6 - 18), concentrations of 0.01 %, 0.05 % and 0.25 % were used, a concurrent control group received tap water only.
The only sign of maternal response to treatment were reduced bodyweights and reduced water consumption in the high dose group. Maternal uterine and intrauterine parameters (e.g. number and weight of fetuses, number of resorptions, implantations, corpora lutea and weights of placentae or uteri) did not reveal significant differences between groups. The index of resorptions and thus the postimplantion-loss index was slightly increased for dose group III - females. This was, however, only due to two dams showing 6 or 5 early resorptions. Since the difference to the controls did not attain statistical significance, this increase is considered to be coincidental and not treatment related.
Examination of fetuses (external, skeletal and visceral) demonstrated one malformed fetus in dose group I only. Therefore no treatment related effect was indicated from data obtained during this study.
Under the experimental conditions of this study, a daily exposition to a 0.05 % 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine concentration in drinking water did not exert signs of maternal toxicity and a 0.25 % concentration did not adversely affect fetal development of New Zealand White-rabbits.
Justification for classification or non-classification
Regarding toxicity to reproduction (embryotoxicity and fertility) the substance 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is not classified according to the criteria of EC Directive 67/548/EEC and EC Regulation 1272/2008.
Additional information
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