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EC number: 201-993-5 | CAS number: 90-43-7
The following compound-related effects were found in the high-dose group:- urine staining in P + F1 males- decrease in bodyweight in P1 and F1 males and females- decrease in pup bodyweights in the group- increase in food consumption in females during lactationThe following findings were considered to be compound-related:- one high-dose group male died from kidney failure- urinary bladder calculi in high dose group males - Debris in the renal pelvis, chronic active inflammation, increase severity of background lesions in high-dose group P and F1 males- Transitional cell hyperplasia, calculi and chronic inflammation in the urinary bladder of high-dose group P and f1 males- Dilation and hyperplasia of the ureter in high-dose group P and F1 malesNo compound-related effects on reproductive and litter parameters, organ weights and clinical signs in pups were found.
A key study for toxicity to reproduction (fertility) in the rat was conducted with the test substance 2-phenylphenol (OPP) (Eigenberg, D. A. and Lake, S. G., 1995 and Bomhard, E. M. et al., 2002). The methods complied with the OECD Guideline 416 (1983), the EPA OTS 798.4700, the EPA OPP 83-4 (1984), and the MAFF, 59 NohSan No. 4200, (1985). CD Sprague Dawley rats received technical grade OPP (99.5-100% purity) via feed at dietary doses of 0, 20, 100 and 500 mg/kg bw/day to for two generations. The P and F1 adults were comprised of 30 rats/sex/group. The P and F1 adults received OPP in the diet throughout the entire study, beginning at eight weeks of age for the P adults and at weaning for the F1 adults. Prior to breeding, the animals received treated feed for a 10-week period (F1 pre-mating period began approx. two weeks following the weaning of the last F1b litter). P adults were mated to produce F1a and F1b litter and F1 adults (randomly selected F1b pups) were mated to produce F2a and F2b litters. During the study, adult animals were evaluated for the effect of OPP on body weight, food consumption, clinical signs, oestrus cycling, mating, fertility, gestation length, and litter size. However, there was no examination of sperm parameters conducted in this study. The offspring were evaluated for OPP-related effects on sex ratio, pup viability, body weight gain and clinical signs. Gross necropsy evaluations were performed on all adults and pups. Histopathological evaluation of reproductive organs, the pituitary, kidneys with ureter attached, urinary bladder, and gross lesions was performed on all P and F1 adults. There were no compound-related effects on reproductive performance and fertility noted in any of the dose groups. However, treatment with OPP induced signs of systemic toxicity. The following compound-related effects were found in the high-dose group (500 mg/kg bw/day): One high-dose group male died from kidney failure and urinary bladder calculi were observed in high dose group males. Urine staining in P + F1 males, decrease in bodyweight in P1 and F1 males and females, decrease in pup bodyweights in the group and increase in food consumption in females during lactation were reported. Debris in the renal pelvis, chronic active inflammation, increased severity of background lesions in high-dose group P and F1 males were further observed at mircroscopic examination, as well as transitional cell hyperplasia, calculi and chronic inflammation in the urinary bladder, and dilation and hyperplasia of the ureter of high-dose group P and F1 males. No compound-related effects on reproductive and litter parameters, organ weights and clinical signs in pups were found.
In the study by Eigenberg dated 1990, The rats received the test item in the diet at nominal dose levels of 40, 140, and 490 mg/kg bw/day nominal, corresponding to measured doses of 35, 125, and 460 mg/kg bw/day, respectively. Regarding systemic toxicity, the results of this 2-generation study are in accordance with previously published literature since they revealed the urinary tract as a target. The NOAEL regarding systemic toxicity was set at 35 mg/kg bw/day, which was the lowest substance level tested. Regarding reproduction, none of the examined parameters was altered by the treatment, thus indicating that the test item does not affect reproduction. The NOAEL regarding reproduction was set at ≥460 mg/kg bw/day, which was the highest substance level tested. Regarding offspring, treatment-related effects could be evidenced neither in the F1 nor in the F2 generation; thus for offspring the NOAEL also was set at ≥460 mg/kg bw/day.
Based on the results of the studies mentioned above and regarding toxicity to reproduction, a NOAEL of ≥500 mg/kg bw/day can be retained for fertility. Regarding systemic toxicity, the more sensitive NOAEL was provided by the earlier study as 35 mg/kg bw/day whereas the LOAEL was 125 mg/kg bw/day. In the more recent study (1995), the NOAEL was 100 mg/kg bw/day and the LOAEL was set at 500 mg/kg bw/day.
Since the effects observed in the study did not concern fertility and reproduction performance, classification for toxicity to reproduction (fertility) according to EU Directive 67/548/EEC and Regulation (EC) No 1272/2008 is not warranted.
1)- prenatal developmental toxicity study (OECD 414), rabbit, NOAEL (developmental toxicity)≥250 mg/kg bw/day; NOAEL (maternal toxicity)=100 mg/kg bw/day; LOAEL (maternal toxicity)=250 mg/kg bw/day2)- prenatal developmental toxicity study (in principle similar to OECD 414), rat, NOAEL (maternal toxicity) =300 mg/kg bw/day; LOAEL (maternal toxicity) ≥700 mg/kg bw/day; NOAEL (foetotoxicity) ≥700 mg/kg bw/day; NOAEL (teratogenicity) =300 mg/kg bw/day3)- prenatal developmental toxicity study, mouse, NOAEL (maternal toxicity) not identified since toxic effects including mortality occurred from the lowest test dose of 1450 mg/kg bw; NOAEL (developmental toxicity) not identified since effects occurred from the lowest test dose of 1450 mg/kg bw. Since the effects on the development occurred at high dose levels with obvious maternal toxicity, no impact on classification is expected from these data regarding toxicity to reproduction including developmental toxicity according to EU Directive 67/548/EEC and Regulation (EC) No 1272/2008.
A key study for prenatal developmental toxicity/teratogenicity in the rabbit was conducted with the test substance 2-phenylphenol (OPP) (Zablotny, C. L., 1991a/b and Bomhard, E.M. et al., 2002). The methods complied with the OECD Guideline 414 (1981), the EU Method B.31 (1988), the EPA OPP 83-3 (1984), and the MAFF, 59 NohSan No. 4200, (1985). Groups of 16-24 artificially inseminated adult female New Zealand White rabbits were administered OPP in corn oil via oral gavage on Days 7-19 of gestation at targeted dose levels of 25, 100 or 250 mg/kg bw/day, while concurrent control animals received the vehicle only. In-life parameters evaluated included clinical observations, body weight and body weight gain. On Day 28 of gestation, all surviving rabbits were euthanized prior to necropsy. Liver, kidney and gravid uterine weights, and the number of implantations, resorptions, corpora lutea and live/dead foetuses were recorded at necropsy. All foetuses were removed from the uterus, weighed, sexed and examined for external, visceral and skeletal alterations. The kidneys from all rabbits were examined microscopically. Oral administration of OPP to inseminated females rabbits resulted in maternal toxicity at the 250 mg/kg/day dose level as evidenced by treatment-related increased mortality (13%), gross pathological alterations (ulceration and haemorrhage of the gastric mucosa, haemolysed blood in the intestinal tract and decreased ingesta) and histopathologic alterations (renal tubular degeneration and inflammation). No significant maternal effects were observed at 25 or 100 mg/kg/day of OPP and no adverse embryonal/foetal effects were observed at any dose level tested.
Based on the results of this study, a NOAEL of ≥250 mg/kg bw/day can be deduced for developmental toxicity. Whereas an increased incidence of litters with resorptions was noted, other parameters were without findings (EFSA 2008). There is evidence that the increase in the percentage of litters with resorptions was mainly the result of the resorptions in the high-dose group being distributed across more litters, whereas the control group resorptions tended to be concentrated in fewer litters. Using the best overall indicator of resorption rate (percent post-implantation loss), the data from the OPP rabbit developmental toxicity study show no treatment-related increase in fetal resorption. In line with assessments in the original study report, the most recent assessment by the performing laboratory (Zablotny et al., (1991), ortho-Phenylphenol (OPP): Gavage Teratology Probe Study in New Zealand White Rabbits with Report Amendment no. 1, dated 2015) and by e.g. EFSA, the NOAEL for developmental toxicity for the rabbit is 250 mg/kg bw/day.
For maternal toxicity, the NOAEL is =100 mg/kg bw/day and the LOAEL is =250 mg/kg bw/day.
Regarding rodent species, a study was performed 1978 by John and coworkers. In this study, rats were treated by gavage with the test item in cotton seed oil during gestation at dose levels of 100, 300 and 700 mg/kg bw/day. Regarding maternal toxicity, since statistically significantly impaired body weight gain and increased liver weight were noticed at 700 mg/kg bw/day, the NOAEL was set at 300 mg/kg bw/day. Regarding foetotoxicity, since no treatment-related effects could be evidenced, the NOAEL was set at ≥700 mg/kg bw/day. Regarding teratogenicity, based on the increased incidence of skeletal variations noticed at ≥700 mg/kg bw/day(delayed ossification of sternebrae, occurrence of a foramen in the skull bones, occurrence of bone island), the NOAEL was set at 300 mg/kgbw/day.
A further rodent species was considered. In the study performed by Ogata et al. (1978) pregnant mice were treated by gavage with the test item in olive oil during gestation at dose levels of 1450, 1740 and 2100 mg/kg bw/day. Regarding maternal toxicity, since mortality and increase in liver weight were reported from the lowest tested dose level of 1450 mg/kg bw/day, the LOAEL was set at 1450 mg/kg bw/day; the NOAEL was not identified. Regarding developmental toxicity, for all dose levels, reduced foetal body weights with clear dose-dependency for males and reduced number of live foetuses, were reported; thus the NOAEL was not identified since the lowest dose level of 1450 mg/kg bw/day was the LOAEL. Shrinking and fissures of sternal nuclei occurred significantly more often at 1740 and 2100 mg/kg bw/day as compared to control and showed dose-dependency.It has to be noticed that obvious retardation in ossification in a significant manner only was reported as evident at 2100 mg/kg bw/day.
Since the effects on the development occurred at high dose levels with obvious maternal toxicity, classification regarding toxicity to reproduction including developmental toxicity according to EU Directive 67/548/EEC and Regulation (EC) No 1272/2008 is not warranted.
Based on the available data for the registered substance, 2-phenylphenol does not meet the criteria to be classified for toxicity to reproduction according to EU Directive 67/548/EEC and Regulation (EC) No 1272/2008.
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