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EC number: 412-570-1
CAS number: 119462-56-5
In a two-generation study performed according to OECD 416 groups of 28
male and female Wistar rats received diets containing PERKALINK 900 in
concentrations of 0, 800, 1600 and 3200 ppm. F0 and F1 males were
sacrificed after at least 11 weeks of exposure, including the premating
and mating period. F0 and F1 dams were sacrificed after weaning their
pups, this is after about 18 weeks of continuous treatment.
The calculated mean substance intake in males (overall intake during
entire study) was 57.4, 119.6 and 236.7 mg/kg bw/day for the low, mid
and high dose groups. In females the overall intake during the study
(except lactation days 14-21) was 70.7, 139.2, and 268.5 mg/kg bw/day
for the low, mid, and high dose groups.
In dams the substance intake was strongly enhanced during lactation days
1-14 with calculated amounts of about 104/98, 197/201, and 346/371 mg/kg
bw/day for F0/F1 dams of the low, mid, and high dose group. In this
period the substance intake was thus about 30% higher than the mean
substance intake. As pups start eating during the end of the lactation
period (LD 14-21) this period was not included in the substance intake
calculation. (The overall test substance consumption in this week was
twice as high as the mean substance intake.)
In F0 males of the highest dose group a reduced body weight/body weight
gain was recorded. Some changes in organ weights were observed in
high-dosed parental F0 and F1 males but these were inconsistent and/or
related to the body weight reduction and thus judged as not adverse. No
treatment-related histopathological changes could be detected in males
and there were no treatment related effects on reproductive performance
In most high-dosed F0 and F1 females changes in weight and
histopathology of reproductive organs were observed that, however, did
not influence the reproductive performance. Since these females were
sacrificed and examined shortly after weaning their pups, their test
substance uptake was very high in the last weeks of their life (about
346/371 mg/kg bw/day during LD 1-14, and presumably even higher during
LD 14-21). These rats showed strongly reduced ovary and uterus weights
together with slight to moderate atrophy of the vaginal epithelium,
slight atrophy of the uterus and a uterine lumen that was lined by
optically clear tall columnar cells, with oval instead of round nuclei.
The number of corpora lutea in the ovaries was reduced in 7/28 (F0) and
15/28 (F1) of the high-dosed females. These observations, together with
the fact that the reproductive cycle could not be determined in most
high-dosed females (F0: 25/28; F1: 18/28), point to a strong arrest to
the onset of the reproductive cycle at the end of the lactation period.
In the F0 and F1 females of the mid-dose group slightly reduced ovary
and uterus weights (statistically significant) were recorded and one F0
dam showed histopathological findings in uterus and vagina comparable to
those of the high-dose females. In the mid-dose group, a significant
number of rats was in a persistent anestrus phase (F0: 17/28; F1: 8/28).
No effects on organ weight and no histopathological findings were seen
in the low-dose F0 and F1 dams. However, the number of rats in a
persistent anestrus phase (F0: 10/28; F1: 6/28) was increased in
comparison to the control group (F0: 1/28; F1: 2/28).
It seems as if the ‘re-‘activity of the ovaries (estrogen production)
after giving birth to the pups is disturbed in a dose-dependent manner,
already observable in the low dose dams of F0 and F1. It is not clear if
this effect is reversible or persistent since in this type of study the
dams were killed after weaning their pups and the development of the
reproductive cycle is not further observed. I should be, however, kept
in mind, that the reproductive performance of neither the F0 nor the F1
dams (that were treated with the test stubstance during their entire
development and growth) in at least the first pregnancy was not affected
The F1 and F2 pups showed birth weights that were not significantly
affected by treatment of the dams. However, body weight gain of the pups
was dose-dependently reduced during lactation days 1-14 and further more
on LD 14-21 when the pups started eating. At LD 21 the weight of F1/F2
pups (mean of males and females) was reduced by 12/7% in the mid dose
group and by 34/25% in the high dose group. As a consequence the animals
selected for growing up as F1 generation were much lighter in the mid
(about -12%) and high dose groups (about – 40%) than in the control
group. This lower body weight could not be completely made up in the
course of the study. Significantly reduced spleen weights were recorded
in F1/F2 pups at postnatal days 21-23 that, however, fully recovered
during the growth of the animals. In adult males and females spleen
weights were not consistently affected. A delayed preputial separation
and vaginal opening seen in F1 and F2 pups can also be judged as
NOAEL for parental toxicity – males and females
The NOAEL for parental toxicity was determined with 57.4 and 70.7 mg/kg
bw/day for males and females, respectively, mainly based on a decreased
body weight gain of F1/F2 animals starting at lactation up to at least
mating at the mid and high dose.
NOAEL for developmental toxicity – males and females
The NOAEL for developmental toxicity was determined with 57.4 and 70.7
mg/kg bw/day for males and females, respectively, based on decreased pup
weight gain and decreased spleen weight (reversible) in F1 and F2 pups.
These effects on pups were considered consequences of test substance
uptake during and after lactation and not during pregnancy via dam.
NOAEL for reproductive toxicity - males
No treatment related effects were seen in F0 and F1 males for
reproductive toxicity, therefore the NOAEL for reproductive toxicity in
males was 236.7 mg/kg bw/day, the highest dose tested.
LOEL for reproductive toxicity - females
Most F0 and F1 females of the high-dose group and one female of the mid
dose group showed reduced ovary and uterus weights and histopathological
findings in reproductive organs at sacrifice. Although these alterations
did not influence the reproductive performance of neither F0 nor F1
females, they should be judged as adverse.
Reproductive cycle determinations at sacrifce revealed that treated F0
and F1 females remained in a persistent anestrus phase after weaning
their pups. This effect was seen throughout all doses in a
dose-dependent manner. Nevertheless, the reproductive performance of
female rats (fertility) was not affected at all, neither in the F0 nor
in the F1 female groups, latter beeing potentially exposed to the test
substance in their fetus-, pup-, adolescent- and adult- lifestage. This
observation points to the presumption that the cycle arrest seen in the
treated females may be a temporary, reversible effect. However, this
hypothesis cannot be proven based on the study design of a standard
In summary, the reproductive cycle arrest was considered as of unclear
origin, potentially reversible and thus as not assessable (not known if
adverse). To account for this situation setting a LOEL was considered
adequate for reproductive toxicity in females. This LOEL was determined
with the lowest dose in females, i.e. 70.7 mg/kg bw/day.
For risk assessment it was decided to follow worst-case considerations
and judge this effect as ‘potentially adverse’ and to take the LOEL as
starting point for DNEL derivation. For hazard assessment a precautious
classification with Repr.Cat 2 fertility is considered adequate for the
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