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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
18 mg/kg bw/day
Additional information

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.

Short description of key information:
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).

Effects on developmental toxicity

Description of key information
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).
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
18 mg/kg bw/day
Additional information

DCHP 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, 18mg/kg bw/day was used as the NOAEL for effect level of developmental toxicity.

Justification for classification or non-classification

Decreased 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.

The 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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