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EC number: 266-582-5
CAS number: 67124-09-8
NOAEL for systemic toxicity was determined to be 167 mg/kg/day based on an one-generation study in rats.
reproduction toxicity study (OECD TG 415)
study was conducted to evaluate the potential effects of oral
administration of 1-(tert-dodecylthio)
on the integrity and performance of the reproductive system in male and
female rats, including gonadal function, mating behavior, conception,
gestation, parturition, lactation and weaning (Thorsrud, 2002). This
study was also conducted to provide preliminary information concerning
the effects of the test substance on neonatal moribundity, mortality and
postnatal developmental toxicity. This standardized procedure was
conducted according to OECD guidance 415.
study consisted of a vehicle control and three treatment groups, with 28
males and 28 females in each group. 1-(tert-dodecylthio)
F0 parental animals and F1 offspring were closely examined for
indications of toxicity. Experimental endpoints for F0 animals included
clinical observations, body weights, food consumption, mating,
parturition, lactation, hematology determinations and offspring growth
and viability. All F0 and F1 animals were subjected to a gross necropsy
examination at the time of death or terminal euthanasia.
administration of the test substance to F0 male rats for a minimum of 70
days prior to mating and until completion of parturition produced
clinical signs including salivation prior to dosing and a dose-related
increase in post-dose salivation in the 167 and 500 mg/kg/day groups and
lower mean body weights (reduced approximately 5-7 % compared to
controls) in the 500 mg/kg/day group.
food consumption of F0 males in the 50, 167 and 500 mg/kg/day groups was
comparable to controls throughout the study. There were no
toxicologically meaningful differences between the control, 50, 167 and
500 mg/kg/day groups with respect to the F0 male mating and fertility
indices. The F0 male hematology parameters, F0 male gross necropsy
observations, F0 male absolute or relative organ weights or the F0 male
sperm parameters were evaluated and no statistically significant
differences were observed. In addition, no toxicologically meaningful
microscopic lesions were observed in any of the F0 male tissues/organs
examined from this study.
administration of the test substance to F0 female rats for a minimum of
14 days prior to mating and throughout lactation produced clinical signs
for F0 females in the 50, 167 and 500 mg/kg/day groups. The clinical
signs included a low incidence of reddish vaginal discharge, swelling
(mammary glands), dark material around the eyes and dark material around
the nose in the 50, 167 and 500 mg/kg/day groups; a low incidence of
salivation prior to dosing, an increased incidence of urine stain and a
dose-related increase in post-dose salivation in the 167 and 500
mg/kg/day groups; and a low incidence of ocular discharge in the 500
were no toxicologically meaningful differences between the control, 50,
167 and 500 mg/kg/day groups with respect to F0 female mean body
weights, body weight change, food consumption, mating and fertility
indices, precoital intervals, gestation lengths or the hematology
parameters evaluated. Gross necropsy findings for one F0 female in the
500 mg/kg/day group euthanized on post breeding day 25 included dark
brownish-red fluid in the uterus and vagina and one small placenta and
two nonviable pups in the vagina. No other remarkable findings were
noted in the F0 females at necropsy and no toxicologically meaningful
microscopic lesions were observed in any of the F0 female tissues/organs
examined from this study.
toxicologically meaningful differences were noted in F1 pup viability
during lactation. Mean F1 pup weights were statistically lower than
controls in the 167 mg/kg/day group on lactation day 14 and in the 500
mg/kg/day group on lactation days 14 and 21; however, mean F1 pup
weights in these groups remained within the range of the test laboratory
historical control data. With the possible exception of a slight
increase in the incidence of pups cool to the touch, no remarkable F1
pup observations were noted during lactation. No remarkable findings
were noted at necropsy for F1 pups stillborn, found dead, culled on day
4 or euthanized on lactation day 21.
to the study director, a dosage level of 50 mg/kg/day was considered to
be the no-observed-adverse-effect level (NOAEL) for parental (F0)
toxicity. There were no indications of impaired fertility or other
reproductive effects in the F0 males or females at dosage levels up to
500 mg/kg/day. A dosage level of 50 mg/kg/ay was considered the
no-observed-adverse-effect level (NOAEL) for developmental effects, as a
result of decreased pup weights noted for the 167 and 500 mg/kg/day
group pups during the latter half of lactation.
The study results were re-examined and new
NOAELs for for parental and developmental toxicity were determined.
Comparing to 50 mg/kg/day, the additional clinical observations included
salivation and urine stain in females treated with 167 mg/kg/day test
substance. Because 1) salivation was considered to be a reflex to
administration of the test substance, 2) urine staining did not
correlate with urination pattern or kidney gross necropsy, and 3) the
severity of the effects is limited.
on the decreased body weight gains in F0 animals treated with 500
mg/kg/day, a dosage level of 167 mg/kg/day was considered to be the
NOAEL for parental (F0) toxicity.
dosage level of 167 mg/kg/day was considered the NOAEL for developmental
effects, since the decreased pup weights noted for the 167 and 500
mg/kg/day group pups during the latter half of lactation were within the
range of historical control data.
28 -day oral toxicity study (OECD TG 407)
This study was
carried out according to OECD 407 guidelines (Auletta, 1991). The doses
used were 1000 (10 rats/sex/group), 300 and 100 mg/kg/day (5
rats/sex/group) for a period of 28 days. Vehicle control animals (10
rats/sex/group) received corn oil at the same dose volume as
administrated to the high-dose animals. The control and high-dose groups
(5 rats/sex/group) were held for another 2-week treatment free recovery
period to evaluate reversibility of any effects seen during the dosing
observations were performed on all animals daily and on the remaining
animals during the recovery period. Body weight and food consumption
measurements were performed pretest and weekly thereafter. Hematology,
clinical chemistry, and urinalyses parameters were evaluated for 5
animals/sex/group at the end of the treatment period and for all animals
sacrificed at the end of the recovery period.
After 28 days of
treatment, 5 animals/sex/group were sacrificed. The remaining animals
were sacrificed after additional 14 days. Selected organs were weighed
and organ/body weight ratio calculated for all animals. Complete gross
postmortem examinations were conducted on all animals. Histopathological
evaluation of the selected tissues was conducted on all animals in the
control and high dose groups. In addition, histopathological evaluation
of the kidney and liver were conducted on selected animals.
survived throughout the study. Physical
examinations were generally unremarkable. Other
apparent effects of OS 81067 administration consisted of a transient
decrease in food consumption and body weight gain in high-dose males
during the first week of study and slight, reversible decreases,
relative to control values, in hemoglobin and hematocrit values for
high-dose females. This difference was seen at termination of dosing but
was not clearly evident after a 2-week recovery period.
the liver and kidneys of treated animals were observed during the organ
weights and gross and microscopic pathology examinations. Dose-related
elevation in mean liver and liver/body weight ratio were seen at study
termination in males at all dose levels and in females at the mid-and
high-dose groups. Recovery was apparent during the two-week post dose
period. At termination of this interval, liver/body weight ratios for
high-dose males were within 10% of the control value and although liver
weights, liver/body weight ratios for females remained higher than
control values, the difference (27 %) was less than that seen at
termination of dosing (60 %).
examination of the liver (5 per sex) revealed an accentuated lobular
pattern in 2 of 5 mid-dose and 4 of 5 high-dose females at termination
of the dosing period, but not termination of the recovery period.
Microscopic examination of the liver revealed hepatocyte hypertrophy in
1 of 5 control males, 4 of 5 low-dose males, and in all mid- and
high-dose animals (5 of 5 animals /sex/ group) at termination of dosing.
This observation was present in 5 of 5 high-dose males and 2 of 5
high-dose females but was not present in any of the control animals at
termination of the recovery period, these affects appears to be an
adaptive change in response to test substance administration.
alterations were seen primarily in males. Kidney weights and kidney/body
weight ratios for high-dose males were 45% higher than control values at
termination of dosing but were comparable at termination of the recovery
period. Similar effects were not apparent in low- or mid-dose males.
Gross postmortem examination of the kidneys revealed pale or tan
discoloration in 1 of 5 low-dose, 2 of 5 mid-dose and 5 of 5 high-dose
males. Microscopic alterations consisted of increased incidences of
globular casts and hyaline droplets in treated males, relative to the
control incidence. Globular casts were seen primarily in the
cortico-medullary junction and were present in 3 of 5 mid-dose and 5 of
5 high-dose males at termination of the dosing period, and in 3 of 5
high-dose males at termination of the recovery period. Similar casts
were seen, unilaterally, in the renal cortex of 1 of 5 control males at
termination of the dosing period. Hyaline droplets in the proximal
tubules were seen at termination of dosing only, indicating this change
was reversible after cessation of test substance administration.
Although this finding was observed in one control male, its occurrence
in 3 of 5 low-dose, 3 of 5 mid-dose and 5 of 5 high-dose males at
termination of the treatment period was indicative of an effect of the
test item administration.
and hepatic changes were evident at all dose levels (100, 300 and 1000
mg/kg/day), evaluation of clinical chemistry and urinalysis studies
revealed no evidence of renal or hepatic functional alterations, or any
other signs of systemic effects of test substance administration,
therefore, the renal changes seem to be species-specific and the hepatic
changes are probably adaptive in nature.
Based on the
decreased body weight gains in males treated with 1000 mg/kg/day, the
NOEL for oral administration of test material to rats, for four weeks,
under conditions of this study was 300 mg/kg/day.
In all test
substance - treated animals, the observed renal changes were likely to
be male-rat-specific, and the hepatic changes were probably adaptive in
nature; in the high dose groups, the toxicological effects were
reversible after cessation of treatment. Therefore, the NOAEL was
proposed to be 1000 mg/kg/d.
In accordance with
EU CLP (Regulation (EC) No. 1272/2008) classification of this substance
is not required for systemic organ toxicity.
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