Registration Dossier

Administrative data

Description of key information

Combined chronic toxicity and carcinogenicity study, oral (OECD 453), rat:

NOAEL carcinogenicity: >= 10000 ppm (equivalent to 558.9 and 743.5 mg/kg bw/day in males and females, respectively)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
558.9 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex X, 8.5, of Regulation (EC) No 1907/2006.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data available regarding carcinogenicity of sodium p-chloro-m-cresolate (CAS 15733-22-9). The assessment was therefore based on a study conducted with the analogue substance p-chloro-m-cresol (CAS 59-50-7) as part of a read across approach, which is in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. Structural similarities and similarities in properties and/or activities 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).

CAS 59 -50 -7

The oncogenic potential and the chronic toxicity of the source substance p-chloro-m-cresol were assessed in a study performed according to OECD Guideline 453 (1981) and in compliance with GLP (Leser, 1993). Fifty Bor:WISW (SPF Cpb) Wistar rats per sex and dose level were fed diet containing 0, 400, 2000 or 10000 ppm of the test substance in a peanut oil solution daily for 104 weeks. Satellite groups, for interim sacrifice, of 10 rats per sex and dose-level received the same doses for 52 weeks. These animals were sacrificed after 52 weeks. The other animals were necropsied after 104 weeks of treatment. The mean achieved dose levels of the test substance received by the animals over the 104 week period were 21.0, 103.1 and 558.9 mg/kg bw/day in males as well as 27.7, 134.3 and 743.5 mg/kg bw/day in females, corresponding to the dietary levels of 400, 2000 and 10000 ppm in both sexes. Observations for clinical signs and mortality were made twice daily (once daily on weekends and holidays). Individual body weights were determined before start of treatment, weekly thereafter and prior to necropsy. Food consumption and water-intake were performed once per week during week 1 to 13 and then monthly thereafter. Water-uptake was recorded once per month. A detailed physical examination of all animals was performed before treatment and then weekly thereafter. Detailed pre-exposure ophthalmoscopic examinations were performed on 20 animals per sex per dose group. Additional 20 rats per sex of the control and highest dose group were examined ophthalmoscopically after 53 and 104 weeks. Blood samples for haematology and clinical chemistry examination were taken after 6, 12, 18 and 24 months. Urine specimens were collected in 16 h intervals in weeks 26, 51, 78 and 103. Gross pathological examinations were performed on all surviving animals at termination as well as on all animals dying or killed moribund during the study. Gross pathology was also performed on 10 rats per sex and group sacrificed after 52 weeks of treatment. Organ weights of brain, heart, kidneys (in pairs), liver, ovaries (in pairs), testicles (in pairs) and spleen were determined for all surviving animals at interim and terminal sacrifice. Histopathological examinations were performed with the tissues of all surviving animals at termination and on 10 rats per sex and group sacrificed after 52 weeks of treatment. No treatment-related deaths occurred. No treatment-related clinical signs were recorded for males of all groups and for females up to and including 2000 ppm. A significant number of females treated with 10000 ppm was of poor general condition. No indications of treatment-related clinical signs were recorded for males. Ophthalmological and histopathological investigations showed no toxicological effects on the eyes. At 10000 ppm body weight development was delayed in both sexes. Feed intake was comparable in all dose groups. Water intake was comparable for all treated females and for males up to and including 2000 ppm. At 10000 ppm, absolute water intake and water intake related to body weight of males was higher than that of controls. No treatment-related damages on haematological parameters or haematopoietic organs were found. Urinalysis revealed reduced total protein excretion at 10000 ppm in both sexes accompanied with reduced urinary density in males often in conjunction with a slightly enhanced urinary volume. Clinical chemistry investigation revealed decreased potassium and phosphate concentrations at 10000 ppm. At terminal necropsy increased relative kidney weights were noted in males at 2000 and 10000 ppm and in females at 10000 ppm. Urinalysis findings in conjunction with increased water intake and kidney weights correlated with histopathological findings in the kidney of males (papillary necroses, cortical dilatation and fibroses) at 10000 ppm. No histopathological findings were recorded in males at 2000 ppm or in females of all dose groups. Gross pathological and histopathological investigations into other organs and tissues gave no indication of substance-related functional or morphological changes up to and including 10000 ppm. A significant increase in the incidence of pituitary adenomas was observed in the mid- and high dose groups of females that either died or were sacrificed intercurrently. However, there were no statistically significant increases in pituitary adenomas in females when the number of observed pituitary adenomas from all animals scheduled for terminal sacrifice in each group was compared to the control group. The incidences of these tumours were within the historical control range. A statistically significant increase in pituitary adenomas was also observed in males at 2000 ppm, but not at 400 or 10000 ppm. Again, the incidences of these tumours were within the historical control range. No relation to treatment is assumed for increased pituitary adenoma rate since all incidences were within the historical control ranges and no dose-dependency was observed in males. Furthermore, males treated with 2000 and 10000 ppm exhibited slightly more cases of Leydig cell tumors (interstitial cell tumors) of the testes compared with the control group. Since the frequency of this tumor in both groups did not differ in a statistically significant manner from that in the control group and was also within the range of historical tumor incidences, no treatment-related effect is derived from the incidences in these groups. Thus, no indication of carcinogenic effects of the test compound at doses up to and including 10000 ppm was noted. Under the conditions of this study the NOAEL in terms of carcinogenic potential was the high dose of 10000 ppm for males and females (equivalent to 558.9 and 743.5 mg/kg bw/day in males and females, respectively) following a 24-month period of dietary administration with the test substance.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No 1907/2006, information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to sodium p-chloro-m-cresolate, data will be generated from data of the reference source substance to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

                                                                   

The available data on carcinogenicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification. This is in line with the existing harmonised classification of the source substance according to Annex VI of Regulation (EC) 1272/2008 as well as with the Opinion of the Committee for Risk Assessment (RAC), adopted 10 March 2016.