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EC number: 239-556-6
CAS number: 15520-10-2
In a two generation study (Schardein,
1985), 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 starting already 56 days prior to mating (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 lactation 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 HMD was 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. - 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 and 38. 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
decreased food consumption. Therefore, this effect was likely due to the
low palatability of HMD.
-Fertility was not adversely affected by
the dietary administration of hexamethylenediamine over 2 generations.
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 were 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
ante mortem 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.
Under the test conditions, there were no
adverse effects on reproduction and fertility, therefore:
The NOAEL (Parental) = 500 mg/kg bw/day
(transiently decreased body weights of F0 males and F1 male and female
animals were likely due to the decrease of food consumption as the worst
The NOAEL (Developmental) = 500 mg/kg
bw/day (since the slightly decreased pup weights observed at high dose
in comparison to the control, could be attributed to the low
palatability of HMD thus inducing decrease in food consumption by the F0
and F1 parents).
The NOAEL (Fertility) = 500 mg/kg bw/day
(as the significant but slight decrease in litter size in the high dose
group is considered to be in the range of the control group and without
any other effects on reproduction).
In another study, 1,6 -hexanediamine
Dihydrochloride (HDDC) was administered to rats at dose level of 0, 16,
50 and 160 mg/m3 by whole-body inhalation for 13 weeks. The exposure
concentrations corresponded to 0, 10, 31 and 100 mg/m3 of HMD. Mating
trial animals were bred for 10 nights (approximately study days 68 to
80, weekdays only) prior to the end of the 13-week exposure period.
Females and pups were killed on
lactation Day 21. Adult females were weighed on gestation Days 0 and 20.
Adult males were weighed at the end of the mating period. Dams and pups
were individually weighed on lactation Days 0, 5, 14 and 21. Pups were
examined at birth for morphological abnormalities, viability and gender.
The number of live/dead offspring, percent neonatal survival, mean live
pup weight and sex ratio were recorded on lactation Days 0, 5, 14 and
21. Necropsies were performed only on mating-trial females selected for
breeding and examined for pregnancy 23 days after the conclusion of
breeding. Complete necropsy and investigation of clincal chemistry and
haematology data was performed on the base study animals (13 week
No reproductive toxicity was observed.
There was no effect on male or female fertility, body weight or body
weights gains, gestation length, litter size, neonatal survival, pup
weights, sex ratios or pups, or pup morphology in rats exposed to HDDC.
The same study regimen was applied to a
second species, i.e. mouse. In the experiment with mice three females
exposed to 16 mg/m3 and 1 female and 1 male exposed to 50 mg/m3 died
before schedules termination but these deaths were not considered
Reproductive effects of HDDC were
minimal. No body weights or body weights gains were recorded for both
sexes. No effects on male and female fertility were observed. A
statistically significant increase in the mean gestation length of mice
in the 50 and 160 mg/m3 exposure groups was noted but without biological
significance in the absence of other reproductive toxicity. HDDC had no
effect on litter size, neonatal survival, sex ratio of pups, or pup
morphology in mice. Pups in the 160 mg/m3 exposure group had mean
weights similar to that of controls at birth and on lactation day 5;
however, mean weights for pups in this exposure group were lower than
that of controls on lactation days 14 and 21. Therefore the NOAEC
(Parental) > = 100 mg/m3 and the NOAEC (F1) >= 100 mg/m3 (based on
In a OECD 422 study in rats the orally administered test material
(DCH) induced changes only in the highest dose tested; i.e. changes in
clinical appearance (slight salivation), functional observations (slight
hyperactivity), body weights and food consumption (decreased), clinical
laboratory investigations decreased eosinophils, ALT and AST activity
increased), macroscopic and microscopic examinations (liver, lung and
adrenal glands), which correlated with changes in organ weights. There
were also effects related to reproduction (decreased gestation index)
and litter observation (reduced average and total number of living pups)
that were considered to be an effect of treatment.
From the results presented in this report a No Observed Adverse
Effect Level (NOAEL) for parental and reproduction/developmental
toxicity for the test item of 150 mg/kg bw/day was established.
No dermal study was available.
Under the test conditions (oral gavage administration from GD7 to GD 16 in female rats), maternal toxicity was observed at 300 mg HMD/kg bw/day. In foetuses effects were seen secondary to this maternal toxicity. However, no adverse effect for maternal toxicity was observed at 184 mg HMD/kg bw/day. The NOAEL for developmental effects was established at 300 mg/kg bw/day.
In a study
similar to OECD Guideline 414 (Prenatal Developmental Toxicity Study),
pregnant female Sprague-Dawley rats (22/group) were treated by gavage
with different concentrations of diluted 85.8% w/w aqueous solution of
HMD at dose levels of 0, 112, 184 and 300 mg/kg bw/day on days 7-16 of
observations were carried out such as body weight changes, food
consumption, and cage side observation. Dams that survived to day 22 of
gestation were killed on that day and necropsy was performed. Finally,
fetals examinations were realized. The maternal parameters assessed
during the study included body weight, food consumption, clinical signs,
corpora lutea, implantations and resorptions. The fetal parameters
assessed during the study included litter size, placental weight, gross
malformations, fetal crown-rump length, fetal body weight, sex, visceral
and skeletal examinations.
maternal death occurred in each of the 0, 184 and 300 mg/kg b.w./day
groups and one animal in the latter group had to be sacrified prior to
term because she appeared moribund. Maternal body weight gain was
reduced as compared to concurrent controls for animals treated at 300 mg
HMD/kg b.w./day throughout the gestation. Other evidence of maternal
toxicity at this dosage was a transient decrease in food consumption and
clinical observations such as hunching, kemp fur, red stained fur,
wheezing and respiratory rattle.
was comparable in all groups. Fetal body weight was reduced by treating
the dams with 300 mg/kg b.w./day of HMD but lower dosages had no effect
on the body weights of the fetuses. Sex ratio, crown-rump length and
percent dead or resorbed fetuses were unaffected by the treatment.
Pre-implantation loss was significantly lower in the high-dose group,
but high in the control group.
with HMD at a dosage of 300 mg/kg b.w./day on days 7-16 of gestation
induced maternal toxicity as evidenced by reduced body weight gains,
transiently decreased food consumption, clinical observations, and by
the death of approximately 10% of the animals treated at this dosage
level. Dosage below 300 mg/kg b.w./day had no statistically significant
effects on the dams; however, the initial dosing at the mid dose level
caused a transient mean body-weight loss of 2 grams on day eight of
gestation. At the maternal toxicity dose level of 300 mg HMD/kg
b.w./day, the fetuses were slightly retarded in development as evidenced
by body weight, limited retardation of skeletal development, and
possibly by liver spottiness.
frequency of occurrence of fetuses with poorly ossified cervical
vertebral centra was significantly greater than for concurrent controls
in both the 184 and 300 mg HMD/kg b.w./day dosage groups and for the
latter group, there were significantly more fetuses in which the sacral
and caudal vertebra had unfused components. According to the authors,
both these observations are consistent with a slight retardation in
skeletal development and considered as a "fingerprint" of a generalized
delay in ossification in near term rats (sacrifice on the gestation day
22). Although the delay of ossification observed in the fetuses from the
dams treated at the highest dose were secondary to the maternal
toxicity, the retardation in skeletal development observed at the middle
dose level occurred in the absence of maternal toxicity.
A dosage of
112 mg/kg b.w./day clearly had no effect on the fetuses including poorly
ossified cervical vertebral centra frequency.
generalized delay is characterized by reduced ossification of bones that
normally exhibit rapid ossification during the last few days of
gestation such as the cervical, sacral and caudal vertebral centra. In
rodents, while bones such as ribs and long bones of the limbs ossify
early, other bones such as thoracic and lumbar vertebral centra are
among the regions that ossify rapidly during late gestation.
control data provide another means of characterizing the normal pattern
of skeletogenesis, and are extremely important for interpreting delayed
ossification. Moreover, the laboratory-specific data are needed to
interpret delayed ossification data because the criteria for scoring
criteria for certain bones are so detailed that the historical control
incidence of delayed ossification often approached 100%. This situation
suggests that the lab has not discriminated between the normal range of
variation in skeletal ossification and variation beyond the normal range
making the usefulness of the observations questionable. Hence, in the
absence of the historical control data (along with concurrent control)
in this study, it should be impossible to determine the designation and
the occurrence of the poorly ossified cervical vertebral centra in the
context of the background "noise" of the population on test or at risk.
common but questionable practice is to conduct independent statistical
analyses on different degrees of ossification for a single bone (e.g.,
for cervical vertebral centra = unossified, poor ossified, unarticulated
or bilobed). Although these distinctions can be identified readily by
experienced technicians from a developmental perspective, they are of
minimal significance. Problem can arise when these isolated findings are
interpreted solely on the basis of statistical significance rather than
considering the overall context of closely related variations. In
effect, the incidence of incompletely ossified vertebral centra may be
increased statistically, yet the unarticulated and bilobed vertebral
centra were decreased as demonstrated in this study. Hence, the
interpretation based solely on the statistically identified increase has
led to the inappropriate conclusion that ossification of the cervical
vertebral centra was delayed, when in fact, consideration of the
cervical vertebral centra data as a whole would indicate the lack of an
slight ossification retardation observed in the study at both high and
mid dose level is considered to be of low level of concern as nonlethal
and not detrimental to postnatal survival variations which are generally
reversible or transitory.
teratogenicity study is considered as acceptable. It does satisfy the
guideline requirement for a teratogenicity study for an OECD 414
guideline in the rat. Hence, this study can be considered as valid for
test conditions, no adverse effect for maternal toxicity was observed at
HMD dose of 184 mg/kg bw/day and no reliable developmental effect was
observed as 300 mg/kg bw/d. In conclusion, no classification for HMD is
required as demonstrated by the results observed in the developmental
on the above presented data no classification for reproductive and
developmental effects is necessary according to Regulation (EC) No
1272/2008 and Council Directive 67/548/EEC.
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