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Key value for chemical safety assessment

Effects on fertility

Description of key information

Two-generation reproduction toxicity (OECD 416, oral): NOAEL fertility (rat) ≥ 500 mg/kg bw/day

(RA from 2-phenylphenol, CAS 90-43-7)

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Sex:
male/female
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
35 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects were observed at the lowest dose level.
Key result
Dose descriptor:
LOAEL
Remarks:
systemic toxicity
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effects in the urinary tract reported for parental animals: calculi in kidney and/or urinary bladder as well as cell hyperplasia in the urinary bladder at 125 and 460 mg/kg bw/day; increased relative kidney weights in males at 460 mg/kg bw/day.
Key result
Dose descriptor:
NOAEL
Remarks:
reproduction toxicity
Effect level:
460 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse or treatment-related effects regarding reproduction toxicity were noted.
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Generation:
F1
Effect level:
35 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects were observed at the lowest tested dose level.
Key result
Dose descriptor:
LOAEL
Remarks:
systemic
Generation:
F1
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effects in the urinary tract reported for F1 parents: calculi in kidney and/or urinary bladder as well as cell hyperplasia in the urinary bladder at 125 and 460 mg/kg bw/day; increased relative kidney weights in F1 males at 460 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
460 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse or treatment-related effects in the offspring were observed.
Key result
Dose descriptor:
NOAEC
Remarks:
reproduction toxicity
Generation:
F1
Effect level:
460 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse or treatment-related effects regarding reproduction toxicity were noted.
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F2
Effect level:
460 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects were observed in the offspring.
Reproductive effects observed:
not specified
Conclusions:
The source substance (CAS 90-43-7) had no effect on reproductive performance. The NOAEL regarding reproduction was set at 460 mg/kg bw/d, 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/d. Applying the read across approach, similar results are expected for the target substance (CAS 132-27-4).
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
100 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects observed at 20 and 100 mg/kg bw/day
Key result
Dose descriptor:
LOAEL
Remarks:
systemic toxicity
Effect level:
500 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: decreased body weights and toxicity to the urogenital tract in males
Key result
Dose descriptor:
NOAEL
Remarks:
fertility
Effect level:
>= 500 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects observed
Key result
Dose descriptor:
NOAEL
Remarks:
fertility
Effect level:
500 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects observed
Remarks on result:
other: F1 generation can be considered as P1 generation after mating
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects observed at 20 and 100 mg/kg bw/day
Key result
Dose descriptor:
LOAEL
Remarks:
systemic toxicity
Generation:
F1
Effect level:
500 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: decreased body weights at the highest dose level
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Generation:
F2
Effect level:
100 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects at 20 and 100 mg/kg bw/day observed
Key result
Dose descriptor:
LOAEL
Generation:
F2
Effect level:
500 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: decreased body weights at the highest dose level
Reproductive effects observed:
not specified
Conclusions:
The source substance had no effect on reproductive performance. Applying the RA-approach, similar results are predicted for the target substance.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available data comprise adequate and reliable (Klimisch score 1) studies. The database is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7.3 of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read-across

There are no data available on toxicity to reproduction of sodium 2-biphenylate (CAS 132-27-4). Thus, read-across from an appropriate structural analogue substance (2-phenylphenol, CAS 90-43-7) is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 in order to fulfil the standard information requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.7. Common functional groups and structural similarities combined with similar toxicokinetic properties of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

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 for two generations. The P and F1 test groups consisted 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 microscopic 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 a further study by Eigenberg dated 1990 and performed according to the OECD Guideline 416 (1983), the EPA OTS 798.4700, the EPA OPP 83-4 (1984), and the MAFF, 59 NohSan No. 4200, (1985), the rats received the test item in the diet at nominal dose levels of 40, 140, and 490 mg/kg bw/day, 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 those reported above 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 did 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 Regulation (EC) No 1272/2008 is not warranted.

Effects on developmental toxicity

Description of key information

Pre-natal developmental toxicity (OECD 414): NOAEL developmental toxicity (rabbit, oral) = 250 mg/kg bw/day

RA from 2-phenylphenol (CAS 90-43-7)

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity and developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The source substance (CAS 90-43-7) had no effect on intrauterine development in rabbits. Applying the RA-approach, similar results are expected for the target substance (CAS 132-27-4).
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEL
Effect level:
700 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 700 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity and developmental toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Key result
Dose descriptor:
LOAEL
Effect level:
700 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity
Key result
Developmental effects observed:
no
Conclusions:
The pregnant rats were treated by gavage with the source substance (CAS 90-43-7) 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 developmental toxicity, 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/kg bw/day. However, these effects occurred at maternally toxic dose levels.
Applying the RA-approach, similar results are expected for the target substance (CAS 132-27-4).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The available data comprise adequate and reliable (Klimisch score 1 and 2) studies for 2 different species, one non-rodent (rabbit) and one rodent (rat). The database is thus sufficient to fulfill the standard information requirements set out in Annex IX, 8.7.2 of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read-across

There are no data available on toxicity to reproduction of sodium 2-biphenylate (CAS 132-27-4). Thus, read-across from an appropriate structural analogue substance (2-phenylphenol, CAS 90-43-7) is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 in order to fulfil the standard information requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.7. Common functional groups and structural similarities combined with similar toxicokinetic properties of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

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 bw/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 bw/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 (2008), 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 rats. The study was conducted prior to the implementation of current guidelines. Nevertheless, the test was in principle similar to the OECD Guideline 414. In this study, pregnant 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/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 Regulation (EC) No 1272/2008 is not warranted.

References

EFSA (2008): Peer review of the pesticide risk assessment of the active substance 2 -phenylphenol. EFSA Scientific Report (2008) 217, 1-67

Justification for classification or non-classification

Applying the RA-approach, the registered substance does not meet the criteria to be classified for toxicity to reproduction according to Regulation (EC) No 1272/2008.

Additional information