Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 222-037-3 | CAS number: 3323-53-3
- 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:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- A Two-Generation Reproduction Study in Rats Receiving Diets Containing Hexamethylenediamine.
- Author:
- Short RD et al.
- Year:
- 1 991
- Bibliographic source:
- Fund Appl Toxicol 16: 490-494.
Materials and methods
- Principles of method if other than guideline:
- Sprague-Dawley rats were treated with the test compound by oral feeding over two generations for about 40 weeks. Litters were examined for size, stillbirths, live births, and gross anomalies. Pubs were selected for F1 parents of the F2 offspring. After 98 days of treatment the F1 parents were mated. F2 pubs were killed on day 21. Gross necropsies were performed on F0 and F1 parents as well as F2 pubs. Histological evaluation of tissue of different organs was conducted.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Hexamethylenediamine
- EC Number:
- 204-679-6
- EC Name:
- Hexamethylenediamine
- Cas Number:
- 124-09-4
- Molecular formula:
- C6H16N2
- IUPAC Name:
- hexane-1,6-diamine
- Details on test material:
- Component of the test substance.
- Name of test material (as cited in study report): 1,6-hexanediamine, 78% aqueous solution
No further data.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI)
- Age at study initiation: (P) ca. 8 weeks; (F1) 3 weeks
- Housing: individually in wire mesh cages or plastic cages with wood chip bedding; except for the 20-day cohabitation (mating)
- Diet (ad libitum): control or experimented diet prepared with ground Purina Certified Rodent Chow No. 5002 (Ralston Purina Co., St. Louis, MO)
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
All rats were housed in environmentally controlled rooms; no further details
- Photoperiod (hrs dark / hrs light): 12/12
No further data
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- water
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Test diets for the control, low, and mid dose groups were prepared weekly, while the diet for the high dose group was prepared every 4 days in order to maintain adequate levels of test material.
- Mixing appropriate amounts with (Type of food): ground Purina Certified Rodent Chow No. 5002
A weighed amount of test material was diluted with ethanol and mixed with ground Purina Certified Rodent Chow to form a premix. This premix was further diluted with additional feed to obtain diets formulated to provide 0, 50, 150, and 500 mg/kg/day of hexamethylenediamine. Dietary concentrations were based on the most recent weekly body weights except during the 20-day mating period when concentrations were based on the most recent female values obtained prior to mating.
Diets were analyzed for homogeneity, stability, and concentration of test material. - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 20 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Diets were analyzed for homogeneity, stability, and to the concentration of test material. A dansylated derivative of hexamethylenediamine was prepared and quantified at 254 nm using a UV detector.
- Duration of treatment / exposure:
- Exposure period: over two generations
Duration of test: 40 weeks - Frequency of treatment:
- continuously in the diet
- Details on study schedule:
- After a minimum of 56 days of treatment, the F0 rats were mated to produce the F1 offspring.
After a minimum of 98 days of treatment the F1 parents were mated to produce the F2 offspring.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 26 males and 26 females per group
- Control animals:
- yes, plain diet
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: No data - Oestrous cyclicity (parental animals):
- no
- Sperm parameters (parental animals):
- no
- Litter observations:
- Pregnant F0 females were allowed to give birth to F1 pups and the day all pups were delivered was designated Day 0 of lactation.
Litters were examined for size, stillbirths, live births, and gross anomalies. Litter size was reduced to a total of 8 pups of equal sex, when possible, on Day 4 of lactation. Pups were housed with their mothers and weighed at intervals for 3 weeks after birth. Afterward, 26 pups of each sex from group were selected to become F1 parents of the F2 offspring. - Postmortem examinations (parental animals):
- Gross necropsies were performed on F0 and F1 parents as well as F2 pups. The following tissues were taken from F0 and F1 rats for histopathological evaluation: kidneys, liver, lung, ovaries, prostate, seminal vesicles, spleen, testes with epididymes, uterus, and vagina. Tissues were preserved in neutral buffered formalin and stained with hematoxylin and eosin. No further data.
- Postmortem examinations (offspring):
- The F2 pups were sacrificed on day 21 of lactation and subjected to gross necropsy. No further data.
- Statistics:
- Several different statistical methods were used to compare measurements made on test animals to the corresponding values determined for controls. The methods and the measurements to which they applied were analysis of variance and Dunnett's test for body weight and litter size, Chi square test with Yates' correction or Fisher's exact probability test for fertility indices; and Mann-Whitney U test for pup survival. The level of significance was selected as p < 0.05.
Results and discussion
Results: P0 (first parental generation)
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
Results: F1 generation
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- other: reduced litter size
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
No treatment-related mortality was observed in any of the groups.
The
ability of rats to successfully mate and produce litters was not
adversely affected by daily doses of up to 500 mg/kg.
The weight of male F0 and F1 parent animals was significantly reduced by
about
10% at 500 mg/kg at the end of the treatment period. The body
weight
of the females was not altered at that time but the weight gain
was
reduced by about 10% during gestation (no further data).
The
litter size
at birth was significantly reduced in the F1 generation (13.8 vs 11.7)
and not significantly reduced in the F2 generation (13.0 vs. 11.0)
at
500 mg/kg. Pup weight was normal at birth but was significantly lower at
day 21 in male F1 pups and female F2 pups at 500 mg/kg. There was no
effect on their survival and they appeared normal during lactation.
The
treatment with up to 150 mg/kg did not adversely affect reproduction or
fertility. No differences between control and treated rats in either
generation with regard to clinical observations, copulation, gestation
length, nesting behaviour, appearance of pups. No treatment related
effects on testes weights, no microscopic and macroscopic effects on
tissues.
No
data are given on malformations.
Table 7.8.1/2: F0 Males: Group Mean Body Weight, Standard Deviation and Survival.
|
Hexamethylene Diamine (mg/kg/day) |
|||||||||||
Week of Study |
0 (Control) |
50 |
150 |
500 |
||||||||
Mean Body Weight (g) |
± S.D. |
Survival |
Mean Body Weight (g) |
± S.D. |
Survival |
Mean Body Weight (g) |
± S.D. |
Survival |
Mean Body Weight (g) |
± S.D. |
Survival |
|
0 |
269 |
11.4 |
26/26 |
274 |
10.1 |
26/26 |
272 |
11.6 |
26/26 |
267 |
10.0 |
26/26 |
1 |
317 |
15.4 |
26/26 |
320 |
13.8 |
26/26 |
320 |
15.7 |
26/26 |
308 |
14.4 |
26/26 |
2 |
347 |
17.3 |
26/26 |
351 |
17.3 |
26/26 |
352 |
19.3 |
26/26 |
332 |
15.8 |
26/26 |
3 |
371 |
19.2 |
26/26 |
376 |
19.8 |
26/26 |
381 |
22.3 |
26/26 |
353 |
16.9 |
26/26 |
4 |
392 |
21.5 |
26/26 |
398 |
22.1 |
26/26 |
401 |
25.8 |
26/26 |
367 |
18.7 |
26/26 |
5 |
415 |
25.1 |
26/26 |
422 |
23.2 |
26/26 |
424 |
27.9 |
26/26 |
389 |
20.4 |
26/26 |
6 |
432 |
26.6 |
26/26 |
438 |
26.8 |
26/26 |
438 |
33.9 |
26/26 |
404 |
20.9 |
26/26 |
7 |
446 |
30.1 |
26/26 |
451 |
31.6 |
25/26 |
454 |
33.0 |
26/26 |
413 |
21.9 |
26/26 |
8 |
458 |
34.8 |
26/26 |
464 |
28.7 |
25/26 |
467 |
38.2 |
26/26 |
421** |
23.6 |
26/26 |
9 |
452 |
34.1 |
26/26 |
465 |
30.8 |
25/26 |
468 |
37.5 |
26/26 |
425 |
22.7 |
26/26 |
10 |
470 |
34.1 |
26/26 |
476 |
30.8 |
25/26 |
474 |
39.3 |
26/26 |
429 |
23.1 |
26/26 |
11 |
482 |
35.0 |
26/26 |
486 |
30.5 |
25/26 |
486 |
42.0 |
26/26 |
438 |
25.5 |
26/26 |
12 |
488 |
35.0 |
26/26 |
487 |
47.6 |
25/26 |
492 |
44.8 |
26/26 |
439 |
26.8 |
26/26 |
13 |
501 |
36.7 |
26/26 |
510 |
35.2 |
25/26 |
505 |
45.8 |
25/26 |
446 |
27.5 |
26/26 |
14 |
509 |
38.8 |
26/26 |
519 |
36.8 |
25/26 |
515 |
44.7 |
25/26 |
450 |
28.1 |
26/26 |
15 |
513 |
39.3 |
26/26 |
523 |
36.9 |
25/26 |
521 |
46.4 |
25/26 |
450** |
26.4 |
26/26 |
** Significantly different from the control group, p < 0.01
S.D. : Standard Deviation
Table 7.8.1/3: F0 Females: Group Mean Body Weight, Standard Deviations and Survival
|
Hexamethylene Diamine (mg/kg/day) |
|||||||||||
Week of Study |
0 (Control) |
50 |
150 |
500 |
||||||||
Mean Body Weight (g) |
± S.D. |
Survival |
Mean Body Weight (g) |
± S.D. |
Survival |
Mean Body Weight (g) |
± S.D. |
Survival |
Mean Body Weight (g) |
± S.D. |
Survival |
|
0 |
193 |
10.1 |
26/26 |
194 |
11.2 |
26/26 |
199 |
8.9 |
26/26 |
1199 |
10.7 |
26/26 |
1 |
216 |
12.1 |
26/26 |
216 |
13.5 |
26/26 |
222 |
10.0 |
26/26 |
220 |
12.3 |
26/26 |
2 |
226 |
18.1 |
26/26 |
229 |
15.2 |
26/26 |
236 |
13.7 |
26/26 |
229 |
12.9 |
26/26 |
3 |
238 |
11.9 |
26/26 |
239 |
18.1 |
26/26 |
247 |
13.0 |
26/26 |
239 |
12.9 |
26/26 |
4 |
247 |
14.1 |
26/26 |
248 |
17.5 |
26/26 |
258 |
21.7 |
26/26 |
249 |
15.8 |
26/26 |
5 |
256 |
14.2 |
26/26 |
260 |
20.5 |
26/26 |
265 |
14.7 |
26/26 |
259 |
13.9 |
26/26 |
6 |
265 |
16.2 |
26/26 |
265 |
19.9 |
26/26 |
274 |
13.0 |
26/26 |
263 |
15.0 |
26/26 |
7 |
272 |
15.9 |
26/26 |
274 |
21.4 |
26/26 |
263 |
15.7 |
26/26 |
268 |
14.6 |
26/26 |
8 |
274 |
15.2 |
26/26 |
276 |
22.4 |
26/26 |
286* |
16.6 |
26/26 |
270 |
16.5 |
26/26 |
9 |
289 |
15.5 |
26/26 |
291 |
20.0 |
26/26 |
298 |
17.5 |
26/26 |
282 |
14.1 |
26/26 |
10 |
310 |
17.9 |
26/26 |
315 |
23.7 |
26/26 |
320 |
21.8 |
26/26 |
299 |
14.9 |
26/26 |
11 |
351 |
31.5 |
26/26 |
358 |
36.3 |
26/26 |
356 |
36.7 |
26/26 |
343 |
26.6 |
26/26 |
12 |
325 |
23.7 |
26/26 |
327 |
33.1 |
26/26 |
327 |
21.9 |
26/26 |
309 |
19.1 |
26/26 |
13 |
34 |
29.3 |
26/26 |
352 |
28.5 |
26/26 |
347 |
30.3 |
26/26 |
325 |
22.7 |
26/26 |
14 |
334 |
22.5 |
26/26 |
342 |
25.1 |
26/26 |
343 |
22.6 |
26/26 |
343 |
26.9 |
26/26 |
15 |
311 |
22.5 |
26/26 |
315 |
25.2 |
26/26 |
317 |
16.9 |
26/26 |
314 |
17.0 |
26/26 |
16 |
310 |
22.2 |
26/26 |
314 |
19.4 |
26/26 |
317 |
17.7 |
26/26 |
312 |
18.6 |
26/26 |
17 |
314 |
17.4 |
26/26 |
321 |
21.5 |
26/26 |
321 |
18.7 |
26/26 |
312 |
18.7 |
26/26 |
18 |
315 |
18.1 |
26/26 |
321 |
19.9 |
26/26 |
325 |
19.5 |
26/26 |
310 |
20.1 |
26/26 |
* Significantly different from the control group, p<0.05
S.D. : Standard Deviation
Applicant's summary and conclusion
- Executive summary:
In a two generation study 26 males and 26 females SD- rats/group received Hexamethylenediamine (HMD) orally in the diet at dosage levels of 0, 50, 150 or 500 mg/kg/day for 56 days prior to mating, then throughout the study in accordance with Series 83 -4 of the Environmental protection Agency Pesticide Assessment Guidelines, Subdivision F., Hazard Evaluation: Human and Domestic Animals, issued November, 1982 (similar to OECD 416) and in accordance with GLP.
The parental rats and pups were observed twice each day for signs of overt toxicity, changes in general appearance and behavior, and mortality. Individual body weights were recorded weekly for the adult rats; In addition, females were weighed on gestation days 0, 6, 15 and 20 and lacation days 0, 4, 7, 14 and 21. Parental food consumption was measured weekly for individual parental rats except during mating. Specific reproductive observations included tabulation of male and female fertility indices, and the length of cohabitation and gestation were recorded.Gross necropsies were performed on F0 and F1 parents as well as F2 pups. The following tissues were taken from F0 and F1 rats for histopathological evaluation: kidneys, liver, lung, ovaries, prostate, seminal vesicles, spleen, testes with epididymis, uterus, and vagina.
The results of this study were:
- Dietary analysis indicated that greater than 90% of the target concentration of hexamethylenediamine were fed to rats in all groups. The actual doses consumed, however, averaged between 123 and 132% of the target doses in these groups.
- No treatment-related mortality was observed in any of the groups. Some deaths occurred, however, they were singular events in specific groups and there was no pattern indicative of a dose-response relationship. Mortality ratios for the F0 males were 0/26, 1/26, 1/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively. Mortality ratios for the F0 females were 0/26, 0/26, 0/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively. Mortality ratios for the F1 males were 0/26, 0/26, 0/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively. Mortality ratios for the F1 females were 1/26, 1/26, 0/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively.
- Body weights of male F0 and F1 rats in the 500 mg/kg group were reduced by about 10%, relative to control values, at the end of study weeks 15 and38. The body weights of females, in contrast, were comparable to control values at these intervals. During gestation, the female weight gain was reduced by about 10% in the high-dose group. Decreased body weight is correlated with a decreased food consumption. Therefore, this effect was likely due to the unpalatability of HMD.-Fertility was not adversely affected by the dietary administration of hexamethylenediamine over 2 generations (See Table ). The F0 and the F1 litter size in the 500 mg/kg group was significantly reduced without an increase in the number of dead pups. There was no biological meaningful or statistically significant differences in the number of viable and dead pups on lactation day 1, as compared to control for either generation in the mid and low-dose treatment groups. Pup survival was not significantly reduced in any of the treated groups. At birth, pup body weights were not adversely affected by treatment, but during lactation, reduced weights were apparent in pups of each sex from the high dose group
-No meaningful differences were noted between the control and treated rats of either generation with regard to antemortem observations, copulatory interval, gestation length, nesting and nursing behavior, and appearance of the pups. No treatment related effects were noted on testes weights and no effects were noted by macroscopic or microscopic examination of tissues evaluated.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.