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EC number: 251-718-8
CAS number: 33885-52-8
Summary of mean achieved concentrations throughout the study period
(deviations from theoretical concentrations in brackets)
Target dose level in mg/kg BW/day (dose in ppm)
(- 18 %)
(- 25 %)
(- 26 %)
(- 19 %)
(+ 10 %)
(- 31 %)
(- 28 %)
(- 27 %)
(- 23 %)
(- 22 %)
32 to 36
(- 3 to – 15 %)
114 to 136
(- 10 to – 24 %)
410 to 492
(- 18 to - 32 %)
56 to 83
(+ 51 to + 121 %)
214 to 309
(+ 43 to + 106 %)
784 to 1167
(+ 31 to + 95 %)
Actual lowest dose
Formulation analysis:All analyzed samples of fomulations
prepared at nominal concentrations of 450, 1800 and 7200 ppm of Pinyl
iso Butyraldehyde alpha in basic powder diet (A04C10 P2.5) taken from
each preparation, including the control, one day during the first week
of treatment were in agreement with acceptance criteria (± 20 %), except
group 2 formulation at 450 ppm showing a deviation from nominal
concentration of -20.2 % slightly above acceptance criteria of +/-20 %.
The deviations from the nominal concentrations of formulation at 1800
and 7200 ppm were -18.0 % to -18.4 %. Investigation of the result
outside acceptance criteria did not allowed identifying a root cause
which may explain the low concentration observed. Duplicate sample from
group 2 were not reanalyzed as stability of test item was limited to 5
days at room temperature (+15 to +25 °C) in open feeder and showed
degradation for further duration storage.
No test item was present in the vehicle sample.
Achieved dose:Throughout the pre-mating period, the
achieved intake of test item, calculated from the body weight and food
consumption data, was lower, at all dose levels, than the theoretical
concentrations, for males and females (-18 to -32 %), except at the
mid-dose where there was a +10 % higher achieved dose during the first
week for females only.
During the gestation period, the decreased achieved intake of test
item was more slight at the low and mid dose level (-3 to – 24 %), than
during the pre-mating period. At the high dose level, the decreased
achieved concentration ranged from -18 to -32 %.
During the lactation period, due to higher food consumption for
treated females (see section 11.7), the achieved intake of test item was
markedly higher than the theoretical concentrations (+31 to + 121 %).
In addition, after 24-hour storage in the food hopper at room
temperature, a decrease in test item formulation concentration of
approximately -20 % was noted when compared with the nominal
of salient mean body weight changes of females (in g - percent
difference from concurrent controls in brackets)
Dose level (ppm)
(- 64 %)
(- 34 %)
(- 86 %)
(- 10 %)
(- 29 %)
(- 24 %)
(- 20 %)
* p<0.05; *** p<0.001
Repeated dose and Reproductive screening tested in the OECD TG
Introduction and Method
Potential toxic effects of the test substance after repeated
exposure was investigated in an at least 28 -day repeated dose toxicity
study with the combined reproduction/developmental toxicity screening
test in rats, performed according to OECD guideline and in accordance
with GLP principles. Pinyl isobutyraldehyde was administered by daily
oral (dietary admixture) to male and female Wistar Han rats at dose
levels of 450, 1800 and 7200 ppm (10 rats/sex/dose level, intended doses
were 37.5, 120 and 450 mg/kg bw). A control group of 10 rats/sex was
given the vehicle (Basic powdered diet). Males were treated for 31 days,
i.e. 2 weeks prior to mating, during mating, and up to termination.
Females were treated during 2 weeks prior to mating, during mating,
during post-coitum, and up to the day before necropsy (i.e. on day 13 of
lactation for females delivered, on day 25 of gestation for unmated
females and on study Day 55 for failed to mate female).
Dietary exposure analysis: Throughout the
pre-mating period, the achieved intake of test item was generally lower,
at all dose levels, than the theoretical concentrations for males and
females (-18 to -31 %). During the gestation period, the achieved test
item concentration was close to the nominal concentration at the low and
mid dose level, whereas at the high dose level, the decreased achieved
concentration ranged from -18 to -32 %. During the lactation period, due
to higher food consumption in treated females, the achieved intake of
test item was markedly higher than the theoretical concentrations (+31
to + 121 %). In addition, after 24-hour storage in the food hopper at
room temperature, a decrease in test item formulation concentration of
approximately -20 % was noted when compared with the nominal
concentrations. The intake on a mg/kg bw bases was 21, 83 and 246 mg/kg
bw using the lower intake for either males or females.
Clinical signs: There was no death or clinical
sign during the study. There were decreased mean body weight gains and
food consumption at 1800 and 7200 ppm in both sexes up to the end of the
gestation period, leading to a relevant lower body weight at 7200 ppm
(246 mg/kg bw).
Functional battery observations: There was no
obvious effect of treatment on the auditory, pupillary and righting
reflexes or open field tests for the males or females at any dose level.
Lower gripping strength in treated rats was considered to be the
consequence of slightly lower body weights and not a direct effect of
the test item.
Heamatology, Clinical chemistry and T4 levels: There were
no test item-related changes.
Organ weights and histopathological effects: For males and
females at 7200 ppm (246 mg/kg bw), test item induced changes in organ
weights a.o. increase in relative liver weight up to 25% without showing
histopathological changes. At this 7200 ppm, relative kidney weights in
males only were increased up to 18%. This increase was associated with
tubular degeneration and tubular basophilia for males without hyaline
droplets and therefore the effects were not considered to be due to
alpha-hydrocarbon nephropathy. This means that this effect has to be
taken into account for the derivation of the NOAEL.
Fertility and Developmental toxicity:There
were no test item-related effects on mating performance for the males
and females or on fertility in any group. There was no effect of
treatment in length and regularity of the estrous cycle in any group.
There were 7, 9, 9 and 8 females that completed delivery in the control,
450, 1800 and 7200 ppm groups 21, 83 and 246 mg/kg bw), respectively.
There were no obvious test item-related effects on the number of
implantation, pre-birth loss, litter size, pup viability or body weight.
There were no test item-related effects on areola/nipple retention. For
none of the examined male pups nipples were observed at PND 13.
Anogenital distance (normalized for body weight) in male and female pups
was not affected by test item.
In view of the instability of the substance, the intake of the
substance was lower than anticipated for all doses. The substance may
have volatilised and/or degraded due to oxidation of the aldehyde. At
7200 ppm (246 mg/kg bw) slight (maximum -9%) body weight decrease was
considered treatment related. Several organ weights were increased e.g.
liver, thyroid and kidney. No histopathological effects were seen in
most organs but in kidneys tubular effects were seen in males, which
could not be attributed to alpha-hydrocarbon nephropathy in absence of
hyaline (eosinophilic) droplets. Based on these results and specifically
the histopathological effects in the kidneys, the dose of 1800 ppm,
corresponding to at least 83 mg/kg bw/day, respectively, was considered
as the parental No Observed Adverse Effect Level (NOAEL). For fertility
no adverse effects were seen up to the highest dose level (7200 ppm
corresponding to an actual intake of 246 mg/kg bw. For developmental
toxicity no adverse effects were seen.
Parental NOAEL is 83 mg/kg bw based on actual substance intake
from nominal 1800 ppm feed.
For fertility the NOAEL was > 246 mg/kg bw in absence of adverse
effects based on actual substance intake from nominal 7200 ppm feed.
Developmental toxicity the NOAEL was > 246 mg/kg bw in absence of
adverse effects based on actual substance intake from nominal 7200 ppm
In the study record on fertility also the developmental toxicity is
presented and will not be repeated here.
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