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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Oral: chronic toxicity, rat (OECD 453): NOAEL = 39 mg/kg bw/day, LOAEL = 200 mg/kg bw/day (RA from 2-phenylphenol, CAS 90-43-7)
Inhalation: no data available
Dermal: subacute toxicity, rat (OECD 410): NOAEL (systemic) ≥ 1000 mg/kg bw/day, local irritation (RA from 2-phenylphenol, CAS 90-43-7)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
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 (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The pronounced emetic response/resultant loss of test material after gavage precluded the administration of higher dose levels to the Beagle dog. The finding was not considered a true adverse effect.
Critical effects observed:
not specified
Conclusions:
The available oral subchronic toxicity study in dogs with the source substance (CAS 90-43-7) revealed a NOAEL ≥ 300 mg/kg bw/day, the highest dose level used in this study. Applying the RA-approach, similar results are expected for the target substance (CAS 132-27-4).
Endpoint:
chronic toxicity: oral
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:
39 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: corresponding to 800 ppm
Key result
Dose descriptor:
LOAEL
Remarks:
systemic toxicity
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: corresponding to 4000 ppm; based on structural alterations in the urinary bladder
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
248 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: corresponding to 4000 ppm
Key result
Dose descriptor:
LOAEL
Remarks:
systemic toxicity
Effect level:
647 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: female: corresponding to 10,000 ppm; based on renal mineralisation, renal cystic tubular dilatation, renal infarct
Critical effects observed:
not specified
Conclusions:
The available oral chronic toxicity study in rats with the source substance (CAS 90-43-7) revealed a NOAEL of 39 and 248 mg/kg bw/day in males and females, respectively. Applying the RA-approach, similar results are expected for the target substance (CAS 132-27-4).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
39 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
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
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects observed up to and including the highest tested dose level.
Key result
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Local irritation (erythema and scaling) of the application site was noted at 500 mg/kg bw/day and above
Critical effects observed:
not specified
Conclusions:
The available dermal subacute toxicity in rats with the source substance (CAS 90-43-7) revealed a systemic NOAEL of ≥ 1000 mg/kg bw/day in male and female rats. Local irritation (erythema and scaling) of the application site was noted at 500 mg/kg bw/day and above, therefore the NOAEL for local effects was considered to be 100 mg/kg bw/day. Applying the RA-approach, similar results are expected for the target substance (CAS 132-27-4).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

Justification for read-across

There are no data available regarding repeated dose toxicity 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, 8.6. 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).

Oral, subchronic:

Four Beagle dogs per sex and dose level were given 0, 30, 100, or 300 mg/kg bw/day of 2-phenylphenol (OPP) for 5 days/week in a peanut oil solution via gastric intubation for 52 weeks (Cosse, P. F. et al., 1990 and Bomhard, E. M. et al., 2002). Detailed pre-exposure and pre-terminal ophthalmoscopic examinations were performed. Body weights and feed consumption were recorded weekly for the first 13 weeks of dosing and monthly thereafter. All dogs were observed at least once daily during the workweek for evidence of treatment-related effects. Fasted blood samples for haematological determinations were obtained from all dogs twice prior to initiation of dosing, after approximately 3 and 6 months of dosing and just prior to necropsy via the jugular vein. Haematological, clinical chemistry and urinalysis were investigated. Blood smears were prepared from all dogs and stained with Wright’s stain. Differential leukocyte counts and evaluation of blood cell morphology were conducted. The eventual presence of occult blood in faeces and vomitus was assayed with a standard test kit. Urine specimens were collected from the dogs following approx. 6 months of dosing and during necropsy. A complete necropsy examination was conducted on all dogs surviving to scheduled termination.

Dose-related emesis was noted in all dogs during the in-life phase. Two high-dose males died after test days 137 and 138 due to the inadvertent deposition of dosing solution into the lungs. Emesis occurred more frequently and involved greater volumes in the high-dose group than in dogs that received lower dosages. Emesis was noted over the entire dosing period and was identified as a local transitory response of the mucosal lining of the upper alimentary tract rather than being initiated via the central nervous system. Regarding ophthalmology, food consumption, haematology, body weight and urinalysis no treatment-related and adverse effects were noted. Occult blood was not detected in faeces or emesis of treated dogs indicating the absence of gastrointestinal haemorrhage in these animals. For males and females of the low- and mid-dose groups, a time-dose interaction was statistically identified for the mean calcium values. Based on the intra- and inter-group fluctuations, the absence of a difference in the high-dose group and the lack of corresponding tissue pathology, these differences were interpreted to be of no toxicological significance. Phosphorus levels in high-dose males and females were statistically different from controls. However, the values were within the historical control range and showed high variability in all groups. This isolated observation was considered to be of no toxicological significance. A few spurious elevated CPK activities were observed in some dogs that were attributed to probable increased muscular activity during the blood sampling process. No treatment-related effects on kidney or liver weights were observed. The two dogs that died on test days 137 and 138, respectively, had dark regions in the pulmonary parenchyma, with or without the presence of bloody fluid. These lesions were consistent with administration of test material into the lungs, resulting in anoxia/shock. There were no other OPP-related gross pathological findings. There were no histopathological lesions attributable to OPP treatment. Dogs from all control and dose levels had a variety of minor inflammatory lesions in their lungs, trachea and larynx. The findings were interpreted as being secondary to the daily gastric intubation. Based on the results of this study, the NOAEL was derived to be 300 mg/kg bw/day.

 

Oral, chronic:

In the combined chronic toxicity/carcinogenicity OPP was administered ad libitum via the diet at concentrations of 0, 800, 4000, or 8000/10,000 ppm (male/female) to separate 1- and 2-year sacrifice groups of Fischer 344 rats (Wahle, B. S. and Christenson, W. R., 1996; Christenson, W. R., Wahle, B. S. and Cohen, S. M., 1996; Brusick, D., 2005 and Bomhard, E. M. et al., 2002). The mean daily intake of active ingredient (a.i.) of OPP was 39, 200, 402 mg/kg bw for males and 49, 248, 647 mg/kg bw for females, respectively. The 1-year group consisted of 20 males and 20 females in both the control a high-dose groups and 10 males and 10 females in both the low and intermediate dose levels. The 2-year group consisted of 50 animals per sex in all dose groups. For approximately the first month of treatment, an additional 5 rats/dose/sex were placed on study as potential replacement for animals that unexpectedly died or developed non-treatment-related problems at a very early stage of the study. Determination of body weight and food consumption and a detailed clinical examination of each animal were conducted weekly. Standard haematological, clinical chemistry and urinalysis endpoints were evaluated from retro-orbital blood samples and urine collected at 3, 6, 12, 18, and 24 nominal months within the course of the study. Pre-exposure ophthalmologic exams were conducted on all acclimated animals and then again on all surviving animals just prior to the scheduled sacrifice. All animals on study were subject to a post-mortem examination, which included documenting and saving all gross lesions, weighing designated organs, and collecting representative tissue specimens for histopathological evaluation. Systemic toxicity was noted as decreased body weight at mid and high doses for both sexes during all treatment periods. There was an increase in the urinary bladder hyperplasia at 12 and 24 months in high dose males and in high dose females at 24 months along with an increase in congestion, haemorrhage, mineralisation and necrosis. Non-neoplastic findings consisted of increased incidence of calculi in the kidneys in high dose males and in the urinary bladder at 12 and 24 months, respectively. High dose males and females also had an increase in cysts of the kidneys at 24 months. High dose females had an increase in hyperplasia of the kidney along with increase infarct, acute inflammation and mineralisation of the kidney. Regarding neoplastic findings, in male rats there was an increased incidence of urinary bladder papillomas, transitional cell carcinomas, and/or combined papillomas and/or transitional cell carcinomas at 8000 ppm. For males, the NOAEL for systemic long-term toxicity and for carcinogenicity was 800 ppm (39 mg/kg bw/day) and the LOAEL for systemic long-term toxicity was set at 4000 ppm (200 mg/kg bw/day). In females, the NOAEL systemic was set at 4000 ppm (248 mg/kg bw/day) and the LOAEL systemic was set at 10,000 ppm (647 mg/kg bw/day). The authors assumed that the mechanism of tumourigenesis in rats was non-genotoxic, probably based on chronic irritation of the epithelium by a combination of high pH, high sodium-ion concentration and/or high concentration of free metabolites at high doses.

 

Dermal, subacute

In a subacute repeated dose toxicity study performed according to OECD 410 and GLP, Fischer 344 rats (5/sex/dose) were administered 0, 100, 500 or 1000 mg/kg bw/day of OPP by dermal application once daily, 5 days per week for a total of 15 applications over 21 days (Zempel, J. A. and Szabo, J.R., 1993 and Bomhard, E. M. et al., 2002). The test substance was applied on the back Fischer 344 rats for 6 hours once daily, 5 days/week under occlusive conditions. Body weight, feed consumption, weekly observations of the skin at the application site, urinalysis, haematology and clinical chemistry evaluations, and organ weights (liver, kidneys, brain, testes) were recorded. All animals were examined for gross pathological and histopathological changes. Local irritation (erythema and scaling) of the application site was noted at 500 mg OPP/kg bw/day. Mortality did not occur and no effects were noted on the body weight, food consumption or at the ophtalmoscopic examination. Analysis of the haematological parameters, clinical chemistry and urinalysis did not reveal adverse findings. At the gross pathological examination, findings were limited to local skin irritation at the application site in mid- and high-dose animals. The histopathological examination revealed hyperkeratosis and acanthosis indicative of the OPP-induced irritation were found in the treated skin of the mid- and high-dose animals, therefore the NOAEL for local effects was set at 100 mg/kg bw/day. No other treatment-related findings were noted in either male or female rats at any dose level. Based on the results of the present study, the NOAEL systemic was set at 1000 mg/kg bw/day, which was the highest dose level tested.

Conclusion

Repeated dose administration of the read across substance 2-phenylphenol for 2 years in the diet revealed a NOAEL of 39 mg/kg bw/day, and repeated dermal administration for 21 days revealed a NOAEL for systemic toxicity of ≥1000 mg/kg bw/d.

Justification for classification or non-classification

Applying the RA approach, the registered substance does not meet the criteria to be classified for Specific Target Organ Toxicity - Repeated Exposure according to the criteria of the Regulation (EC) No 1272/2008.