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EC number: 201-545-9
CAS number: 84-61-7
The NOAEL for fertility 240 ppm (16-21
mg/kg bw/d) based on decreased sperm head counts and focal seminiferous
tubule atrophy in F1 males at 1200 ppm (80-107 mg/kg bw/d).
The reproductive toxicity (Hoshino N, Iwai
M, Okazaki Y., 2005) of dicyclohexyl phthalate (DCHP) was evaluated in a
two generation test in which male and female Sprague-Dawley (SD) rats of
parental (F0) and F1 generation were exposed to DCHP in the diet at
concentrations of 0 (control), 240, 1200 or 6000 ppm. With regard to the
effects on the F0 and F1 parental animals, changes included inhibition
of body weight gain and food consumption, diffuse hypertrophy of
hepatocytes, and hypertrophy of thyroidal follicular epithelial cells at
the doses of 1200 ppm and 6000 ppm. The following changes were observed
in the 6000 ppm group: increase weights of the liver and thyroid,
increased hyaline droplets in the renal proximal tubular epithelium (F0
and F1 males), reduction of prostatic weight (F1 males), and diffuse
and/or focal atrophy of testicular seminiferous tubules (F1 males). In
addition, slight prolongation of the estrous cycle was noted in the F0
females of the 6000 ppm group, along with reduced spermatid head counts
in the testes (homogenation resistant spermatids) in F1 male receiving
doses of 1200 ppm or 6000 ppm. It is thought that the prolonged estrous
cycle was secondary to the suppression of body weight gain. There were
no test substance related changes in clinical signs and reproductive
capability (mating, fertility, gestation and birth index), or in data
for the delivery and lactational periods, or serum hormone levels. With
regard to effects on the offspring, inhibition of body weight gain was
found in the F1 and F2 6000 ppm, and decrease of anogenital distance
(AGD) and appearance of areola mammae were observed in the F1 male 6000
ppm and F2 male receiving doses of 1200 ppm or 6000 ppm. No effects of
DCHP treatment on the offspring were observed on results of clinical
signs, the number of the pups delivered, sex ratio, viability, physical
development, reflex and response tests, external abnormalities, organ
weights, or necropsy findings. From the present study of DCHP
administered to rats over two-generations, the no observed effect level
(NOEL) for effects on the parental animals including the endocrine
system, is considered to be 240 ppm. With regard to the reproductive
toxicological effects on the parental animals, the NOEL is 240 ppm for
males and 1200 ppm for females. For offspring, the NOEL values are
concluded to be 240 ppm for males and 1200 ppm for females.
The NOAEL for fertility was 240 ppm (16 -
21 mg/kg bw/d; m-f) based on decreased sperm head counts and focal
seminiferous tubule atrophy in F1 males at 1200 ppm (80-107 mg/kg bw/d;
m-f). Therefore the average of 16 -21, 18 mg/kg bw/day was used as the
NOAEL for effect level of fertility.
The NOAEL for developmental effects is 240 ppm (16-21 mg/kg bw/d) based on decreased anogenital distance and retained nipples in F2 males at 1200 ppm (80-107mg/kg bw/d).
was tested in a well-performed two-generation study in rats (Hoshino N,
Iwai M, Okazaki Y., 2005). The NOAEL for developmental effects is 240
ppm (16-21 mg/kg bw/d) based on decreased anogenital distance and
retained nipples in F2 males at 1200 ppm (80-107mg/kg bw/d). These
effects occurred at doses that were associated with decreased maternal
food consumption, final body weight and increased liver weight. The
developmental effects were more severe and occurred at a lower dose in
the F2 compared with F1 generation. These evidences can also be found in
another study focused on the developmental toxicity of DCHP (Saillenfait
et al., 2009). In the test pregnant Sprague–Dawley rats were exposed to
DCHP at doses of 0 (olive oil), 250, 500 and 750 mg kg-1per
day, by gavage, on gestational days (GD) 6-20. Maternal food consumption
and body weight gain were significantly reduced at 500 and 750 mg/kg per
day of DCHP. Slight changes in liver weight associated with peroxisomal
enzyme induction were seen in dams treated with DCHP. DCHP produced
fetal growth retardation at 750 mg kg-1per day, as evidenced
by significant reduction of fetal weight. DCHP induced a significant and
dose-related decrease in the anogenital distance of male fetuses at all
doses. Therefore, DCHP showed no clear embryolethality and
teratogenicity. However, as Absolute AGD was significantly reduced in
male fetuses at all doses, the lowest-observable-adverse-effect-level
(LOAEL) for developmental toxicity well aligned with the NOAEL of 240
ppm (16-21 mg/kg bw/d) in the two generation study was judged to be 250
mg kg-1(ppm) per day, and which fulfill the toxicological
principles (LOEAL is a little higher than the NOAEL ). These two
individual tests give conclusion of the NOAEL for developmental toxicity
of DCHP is 240 ppm (16-21 mg/kg bw/d). Therefore the average of 16 -21,
bw/day was used as the NOAEL for effect level of developmental toxicity.
anogenital distance and retained nipples in F2 males at 1200 ppm
(80-107mg/kg bw/d) occurred at doses that were associated with
decreased maternal food consumption, final body weight and increased
liver weight while the developmental effects were more severe and
occurred at a lower dose in the F2 compared with F1 generation.
substance of DCHP should be classified as reproductive toxicity category
1B, H360D, according to the table 3.1, Annex VI of the CLP Regulation
(EC) No 1272/2008.
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