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Administrative data

Description of key information

Subchronic repeated dose toxicity, oral (similar to OECD 408), rat: NOAEL >= 1500 ppm (equivalent to 120 and 167 mg/kg bw/day in males and females, respectively)

Subchronic repeated dose toxicity, dermal (similar to OECD 411), rat: NOAEL >= 500 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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 document provided in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOAEL
Effect level:
>= 1 500 ppm
Based on:
test mat.
Remarks:
equivalent to 120 and 170 mg/kg bw/day in males and females, respectively
Sex:
male/female
Basis for effect level:
other: highest dose tested
Critical effects observed:
no
Conclusions:
The available oral subchronic toxicity study in rats with the source substance (CAS 59-50-7) revealed a NOAEL ≥ 120 mg/kg bw/day, the highest dose level used in this study. Applying the read-across approach, similar results are expected for the target substance (CAS 15733-22-9).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
120 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
50 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.
System:
immune system
Organ:
thymus

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:
sub-chronic 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 document provided in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested
Critical effects observed:
no
Conclusions:
The available dermal subchronic toxicity in rats with the source substance (CAS 59-50-7) revealed a NOAEL ≥ 500 mg/kg bw/day, the highest dose level used in this study. Applying the read-across approach, similar results are expected for the target substance (CAS 15733-22-9).
Endpoint conclusion
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 information comprises adequate, reliable (Klimisch score 1) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

 There are no data available regarding repeated dose toxicity of sodium p-chloro-m-cresolate (CAS 15733-22-9). The assessment was therefore based on studies 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). With regard to repeated dose toxicity of the source substance, short-term, subchronic and chronic toxicity studies via the oral route, a short-term toxicity study via the inhalation route and a subchronic as well as short-term toxicity studies via the dermal route are available. Summaries of these studies are provided below. The subchronic studies via the oral and the dermal route which are used for the derivation of the DNEL (please refer to the section "Toxicological information") are provided as robust study summaries.


 


CAS 59-50-7


Oral:


90-day subchronic toxicity feeding study in the rat


The potential toxicity of the source substance p-chloro-m-cresol was assessed in a 90-day subchronic toxicity feeding study in the Wistar rat performed according to US EPA Guideline 82-1 and similar to OECD Guideline 408 as well as in compliance with GLP (Eiben, 1988). 20 male and female rats per sex and dose group received the test substance at concentrations of 0, 150, 500 and 1500 ppm in the diet for 3 continuous months. Observations for clinical signs and mortality were made twice daily (once daily on weekends and holidays). Individual body weights, food consumption as well as detailed physical examinations for clinical signs of toxicity were determined / performed once each week on all animals. Blood samples were collected for haematological and clinical chemistry examination from all surviving animals after 4 weeks and at study termination. Urine specimens were collected in 16 h intervals at several timepoints during the study period in each case a few days before blood sampling. All animals found dead or were moribund and sacrificed during the study period were dissected and the organs / tissues were subjected to thorough gross pathological examination. All surviving animals were sacrificed at termination and a gross pathological examination was performed. Organ weights of the heart, testicles, liver, lung, spleen, kidneys, adrenals and thymus were determined. Histopathological examinations were performed with the tissues from 10 males and females of the control and high dose group. Appearance, general behaviour, mortality and food intake were unaffected in any dose group. Two females (1/20 at 150 ppm, 1/20 at 500 ppm) died in connection with blood sampling. Autopsy of these animals did not indicate a relation between the treatment and death. Body weight gain was retarded in mid- and high-dose males while no effect on the body weights of females was noted. Since observations on the male body weight were of slight degree the effect is considered non-adverse. Urinalysis and haematological examinations revealed no treatment-related effects. With respect to clinical biochemistry, at the 1 month blood sampling, significantly decreased alkaline phosphatase activity was noted in males at 500 and 1500 ppm. Since this effect was not apparent at study termination and in the absence of corresponding histopathological finding, decreased enzyme activity was not considered adverse. Clinical chemistry examination provided no further treatment-related effects. No treatment-related effects or abnormalities were found during gross pathological and histopathological examinations. Decreased absolute liver weights in males at 1500 ppm as well as increased relative liver weights in females at 500 and 1500 ppm were not associated with any indications of an effect on the liver or its functioning as evident in the clinical chemistry, gross pathological and histopathological examinations. Additionally, variations of the liver weights were of slight nature. Thus, differences in liver weights were not considered adverse. Further isolated findings on kidney, heart or lung weights were most likely to be random findings without toxicological relevance. Thus, under the conditions of the study, the NOAEL over a 3-month period of dietary administration with the test substance to the rat was ≥ 1500 ppm in both sexes (equivalent to 120 and 167 mg/kg bw/day in males and females, respectively).


 


105 week/2 year chronic toxicity feeding study in the rat


The chronic toxicity of the source substance p-chloro-m-cresol was 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. Statistically significant decreased body weights of females treated with 400 and 2000 ppm are related to an incidental and unusual development of body weight gain in control females. Additionally, since no effects on body weight development were recorded, the differences in body weights at 400 and 2000 ppm were not considered treatment-related. However, 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. Statistically significant decreased cholesterol and triglyceride content in both sexes at 10000 ppm were in the range of historical control data and possibly related to growth effects. Thus, these effects are not considered toxicologically relevant. 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. Relative ovarian weights were increased in females of the high dose group. This effect was not associated with gross pathological or histopathology findings. 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. Additionally, no indication of carcinogenic effects of the test compound at doses up to and including 10000 ppm was noted. Thus, under the conditions of the study, the NOAEL in terms of systemic toxicity over a 24 -month period of dietary administration with the test substance to the rat was 2000 ppm in both sexes (equivalent to 103.1 and 134.3 mg/kg bw/day in males and females, respectively).


 


28-day subacute toxicity feeding study in the rat


The potential toxicity of the source substance p-chloro-m-cresol was assessed in a 28-day subacute toxicity feeding study in the Wistar rat performed according to OECD Guideline 407 (1981; Leser, 1989). The study was a dose-range finder for the determination of a maximum tolerable dosage as a basis for the dose stipulation for a chronic study. 6 rats per sex and dose group received the test substance formulated with 1% peanut oil at concentrations of 0, 2500, 5000 and 10000 ppm in the diet for 4 continuous weeks. All rats were observed at least twice daily (once daily on weekends and holidays) for evidence of treatment-related clinical signs or mortality. Body weights and feed consumption were measured once weekly. Fasted blood samples for haematological and clinical biochemistry determinations were obtained from all rats prior to necropsy. Urine specimens were collected in 16-h intervals. A complete necropsy examination was conducted on all surviving rats at study termination. Weights of the brain, heart, testis (paired), liver, lung, spleen, kidneys (paired), adrenals (paired), ovaries (paired), and thymus were recorded and organ/body weight ratios were calculated. No mortalities occurred and no indications of dose-related findings on the physical condition or general behaviour were noted. The average food and water consumption was not affected in all animals. The body weight gain of males of the highest dose group (10000 ppm) was reduced compared to control animals. No effect on the body weight gain was observed in females treated with 10000 ppm of the test substance or in any animal of the other dose groups. Haematology, clinical biochemistry and urinalysis revealed no treatment-related effects. No test-substance related organic lesions or pathological influence on metabolic functions were found. Thus, under the conditions of the study, the NOAEL over a 4 week period of dietary administration with the test substance to the rat was 5000 ppm in males (equivalent to 385 mg/kg bw/day) and 10000 ppm in females (equivalent to 920 mg/kg bw/day).


 


Additional repeated dose toxicity data on p-chloro-m-cresol, CAS 59-50-7 (Ministry of Health, Labour and Welfare, Japan):


A 28-day repeated-dose toxicity study was performed according to “Guideline for 28-Day Repeated Dose Toxicity Test in Mammalian Species, Chemical Substances Control Law of Japan” (equivalent to OECD guideline 407) and in compliance with GLP. Male and female Crl:CD(SD) rats (five animals/sex/dose) were administered with p-chloro-m-cresol at doses of 15, 60, 250, and 1000 mg/kg bw/day in olive oil via oral gavage. In addition, a 14-day recovery period with five animals/sex/dose was included for the vehicle control and 1000 mg/kg bw/day groups. Cage side observations were conducted four times per day during the administration period and once per day during the recovery period. A detailed clinical observation was conducted prior to the start of administration and weekly thereafter. Body weights and food consumption were recorded on a weekly basis. A neurobehavioral assessment was performed on Week 4 of the administration period and Week 2 of the recovery period, consisting of an examination of sensory activity (hearing reaction, eye sight reaction, sense of touch reaction, pain reaction, pupil reflex, righting reflex), grip strength and motor activity. Urinalysis was performed on Week 4 of the administration period and Week 2 of the recovery period. An assessment of haematological and clinical chemistry parameters was conducted for all animals, fasted overnight prior to necropsy. All animals were subject to a gross necropsy and the following organ weights recorded: brain, pituitary, thyroid, adrenals, spleen, heart, liver, kidneys, thymus, testes, epididymides and ovaries. Histopathological examinations were performed on the tissues of all surviving animals from the vehicle control and 1000 mg/kg bw/day groups, as well as on the liver and forestomach of animals from the 60 and 250 mg/kg bw/day groups.


At 1000 mg/kg bw/day, one female died during the administration period, clinical examination of this animal revealed tremors, decreased locomotor activity, ptosis, prone/side position, soiled perineal region and salivation. Histopathological examination of this animal revealed severe hyperplasia of the squamous tissue in the forestomach, slight congestive oedema and inflammation in the lung, slight haemorrhage in the thymus and slight atrophy in the spleen. Tremors, decreased locomotor activity, ptosis and prone position were observed in all surviving males and females at 1000 mg/kg bw/day. Soiled perineal region was also observed in all females at 1000 mg/kg bw/day. Transient prone position in three males and decreased locomotor activity in two males was observed at 250 mg/kg bw/day. Transient salivation was observed in all males and females at doses ≥ 250 mg/kg bw/day. This finding was thought to be due to the irritancy of the test substance. Body weight, body weight gain and food consumption were decreased in males at 1000 mg/kg bw/day. Clinical chemistry examinations revealed increased alanine aminotransferase levels in females at 1000 mg/kg bw/day. Relative liver weights were higher in males and females at 1000 mg/kg bw/day. Gross pathological examination revealed slight thickening of the forestomach mucosa in males at 1000 mg/kg bw/day. Histopathological examination revealed hypertrophy of centrilobular hepatocytes in the livers of males and females at 1000 mg/kg bw/day, and hyperplasia of the squamous tissue in the forestomach of both sexes at doses ≥ 250 mg/kg bw/day.


After the 14-day recovery period, all findings were reversible, with the exception of hyperplasia of the squamous tissue in the forestomach, which was still evident in one male and one female at 1000 mg/kg bw/day.


On the basis of these effects, a NOAEL for repeated-dose toxicity was determined to be 60 mg/kg bw/day in male and female rats, based on the local irritant effects seen in the forestomach. No specific conclusions were made in relation to a NOAEL for systemic toxicity, however, no significant effects suggestive of systemic toxicity were apparent up to and including a dose level of 250 mg/kg bw/day. The effects seen at 1000 mg/kg bw/day in relation to clinical signs, and decreased body weight, body weight gain and food consumption may be secondary to the local irritant effects in the forestomach and/or a consequence of administration of a large single daily gavage dose of the test substance. For both sexes, no adverse clinical signs were recorded during the recovery period, and body weight, body weight gain and food consumption were comparable with the control group. At 1000 mg/kg bw/day, the increased levels of alanine aminotransferase in females, and the increased liver weights and corresponding hypertrophy of centrilobular hepatocytes in both sexes may be indicative of an adaptive response to the administration of the test substance, given the findings were of minimal severity and fully reversible after the 14-day recovery period.


The endpoint summary for this study has been prepared from the available information on the Japan CHEmicals Collaborative Knowledge database (J-CHECK) for 4-Chloro-m-cresol (CAS 59-50-7):https://dra4.nihs.go.jp/mhlw_data/jsp/FileListPageENG.jsp?parameter_csno=59-50-7


 


Inhalation:


14-day subacute inhalation toxicity study in the rat


The potential toxicity of the source substance p-chloro-m-cresol was assessed in a 14-day subacute inhalation toxicity study in the Wistar rat performed according to OECD Guideline 412 and in compliance with GLP (Rajsekhar, 2011). Exposure of control and dose groups to the test substance as dry aerosol (dust) was performed on a daily basis for 6 h/day continuously over a period of 14 days under nose-only conditions. Three groups of 5 animals per sex and dose were exposed to 0.05, 0.25 and 0.51 mg/L air (mean actual chamber concentration). Another 5 animals per sex allocated to the control group were exposed to air only. Additionally, two satellite groups consisting of 5 females and 5 males per group were exposed to the high concentration (high concentration satellite group) as well as to air alone (satellite control group) and were allowed to recover over a period of 14 days after the 14 day treatment period. Aerosol concentrations were measured gravimetrically. The particle size distribution of the test aerosol was determined regularly during the exposure period. All animals were observed daily for mortality and clinical signs. Body weights were taken on day 1 and twice weekly thereafter. Feed consumption and water consumption were recorded daily. Blood collections for haematology and clinical biochemistry examinations as well as urinalysis were conducted on day 15 (main groups) and on day 29 (satellite groups). A complete gross pathology including weighing of selected organs was performed after the treatment period. Histopathology of selected organs was performed on all groups. Special attention was attributed to irritating effects of the respiratory tract organs along with associated lymphnodes. The MMAD (Mass Median Aerodynamic Diameter) was in the range of 2.30 – 2.57 µm with a Geometric Standard Deviation (GSD) of 1.97 – 2.66. No mortalities occurred during the study period. Clinical signs were observed at 0.51 mg/L (main and satellite group) and included lacrimation, nasal irritation, dullness, nostril discharge, change of body coat, facial swelling, reddened nostrils, edematous forelimbs, forelimbs with red encrustations and gasping. With regard to the satellite group, these effects were reversible after 1 or 2 days (males or females) of recovery. Significantly decreased body weights were observed on different days in males and females of the mid and high concentration group as well as in the high concentration satellite group. The effect was reversible within 21 days in satellite females only. Body weight findings correlate to decreased feed consumption noted in the same dose groups at the end of the first and second week. Feed consumption effects were reversible in both the sexes of the recovery group. Furthermore, water consumption was significantly decreased in males at 0.25 and 0.51 mg/L (main and satellite group) as well as in females at 0.05, 0.25 and 0.51 mg/L (main group only) at the end of the second week. Females of the highest concentration satellite group showed a significant decrease in water consumption at the end of the first week. Water consumption effects were reversible in both the sexes of the recovery group. No effects on haematological and urinalysis parameters were noted. Significantly decreased glucose levels of females (main group) and males (satellite group) noted on day 15 as well as a tendency towards decreased glucose levels across the groups of both sexes might be related to the reduction in the feed consumption. Mean absolute and relative thymus weights were decreased in males at all treatment concentrations. In females, there was a dose-related tendency towards decreased thymus weights without attaining statistical significance. These findings were accompanied by reduced size during gross pathological examination (2/5 males and 2/5 females at 0.51 mg/L and 1/5 female at 0.25 mg/L) as well as histopathologically by atrophy at 0.25 and 0.51 mg/L (1/5 mid dose females and 2/5 males and 2/5 females of the high dose group, respectively). Thus the low-dosed animals (0.05 mg/L) were not adversely affected, as the weight decrease in this group had no concomitant histopathological findings. The changes were fully reversible. Further findings at gross pathological examination included emaciation, reddened nostrils and (swollen) forelimbs with red encrustations on the digits in several males and females of the high dose group. Further treatment-related finding during histopathology consisted of minimal to moderate mucous cell hyperplasia of the respiratory epithelium of the nasopharyngeal tissues (1/5 male and 2/5 females at 0.25 mg/L and in 4/5 males and 4/5 females at 0.51 mg/L) suggesting a slight irritation at the upper respiratory system. Further, minimal inflammatory cell foci in the trachea (1/5 males and 1/5 females of the high dose group) were found. Thus, under the conditions of the study, the NOAEC over a 14 day period of inhalation exposure with the test substance in the rat was 0.05 mg/L of air in both sexes.


 


Dermal:


90-day subchronic dermal toxicity study in the rat


The potential toxicity of the source substance p-chloro-m-cresol was assessed in a 90-day subchronic dermal toxicity study in the Wistar rat performed according to EU method B.28 and similar to OECD Guideline 411 as well as in compliance with GLP (Leser, 1991). 10 male and female rats per sex and dose group received the test substance at concentrations of 0, 20, 100 and 500 mg/kg bw/day for 13 continuous weeks. The applications were performed 5 days per week for a duration of 6 h each. 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 recorded once per week. A detailed physical examination of all animals was performed before treatment and then weekly thereafter. Blood samples for haematology and clinical chemistry examination were collected in week 5 or 6 and week 13. Urine specimens were collected in 16 h intervals in week 5 or 6 and 13 after blood sampling. On treatment days 20 and 60 the thickness of the skin was determined on all animals. All surviving animals were sacrificed at termination and a gross pathological examination was performed. Organ weights of the brain, heart, testis (paired), liver, lung, spleen, kidneys (paired) and adrenals (paired) were determined. Histopathological examinations were performed with the tissues of all animals of the control and high dose group. In addition, ophthalmoscopic examinations were performed on all animals of the control and high dose group 3 days before the first treatment and on day 80. No mortalities occurred and no treatment-related clinical symptoms were noted during the study period. Body weight gain, food consumption and water intake, haematological and clinical chemistry examinations as well as urine analyses revealed no treatment-related effects. Absolute and relative organ weights, gross pathological and histopathological examinations showed no evidence of organ damage. Thus, under the conditions of the study, the NOAEL over a 3-month period of dermal administration with the test substance to the rat was ≥ 500 mg/kg bw/day in both sexes.


 


28-day subacute dermal toxicity study in the rat


The potential toxicity of the source substance p-chloro-m-cresol was assessed in a 4-week subacute dermal toxicity study in the Wistar rat (Leser, 1993). The study was used as a dose finding study for a dermal subchronic toxicity study. 6 male and female rats per dose group received the test substance formulated in polyethyleneglycol 400 at concentrations of 0, 40, 200 and 1000 mg/kg bw/day for 4 continuous weeks. The applications were performed 5 days per week for a duration of 6 h each under occlusive conditions. All animals were inspected for mortality and signs of toxicity twice daily (once on weekends and holidays). Detailed clinical observations as well as determinations of body weights, food and water consumption were performed pre-exposure and weekly thereafter. Gross pathological examinations were performed on all animals killed moribund or sacrificed at termination. Organ weights of adrenals, brain, heart, liver, lung, spleen and testicles were recorded and relative organ weights were determined. No effects were noted in any animal of the 0, 40 and 200 mg/kg bw/day dose groups. After a few exposures the application sites of all animals of the 1000 mg/kg bw/day dose group showed erythema, oedema, wounds and crustifications, as well as hard and leathery skin sites. The skin thickness of these animals was considerably increased compared to control animals. The intensity of these findings decreased during the fourth treatment week. One animal of the 1000 mg/kg bw/day dose group was killed on day 16 in moribund condition. Gross pathological examination of this animal and another animal of this dose group revealed expanded ureters and blood clots of the urinary bladder. Body weight gain in this group was about 50% reduced compared to controls. Feed consumption was about 14% reduced, water-intake about 12% increased in the highest dose group compared to controls. Thus, under the conditions of the study, the NOAEL over a 4-week period of dermal administration with the test substance to the rat was 200 mg/kg bw/day.


 


15-day subacute dermal toxicity study in the rabbit


The potential toxicity of the source substance p-chloro-m-cresol was assessed in a 15-day subacute dermal toxicity study in the New Zealand White rabbit (Rutter, 1980). 10 male and female rabbits per sex and dose group received the test substance at concentrations of 0, 10, 40 and 160 mg/kg bw/day for 3 continuous weeks. The applications were performed 5 days per week for a duration of 6 h each under occlusive conditions. The area of exposure of four animals of each sex from each group was abraded with minor incisions during the first five applications. Thereafter, exposure was performed according to the other animals. All animals were observed daily for mortality and signs of toxicity, food and water intake as well as dermal effects. Dermal irritation was graded and scored each morning before application according to the Draize Scoring System. Body weights were recorded during Days 1, 4, 8, 11, 15, 18, 21, and prior to terminal sacrifice of each animal. Food consumption was recorded during Days 3, 5, 8 (Week 1), 10, 12, 15 (Week 2), 17, 19, and 22 (Week 3). Blood samples for haematological and clinical biochemistry examinations were collected of 5 animals per sex and dose group prior to initiation of treatment and at study termination. Gross pathological examinations were performed on all animals killed moribund or sacrificed at termination. Organ weights of adrenals, heart, liver, pituitary, thyroid (with parathyroid), kidneys and gonads were recorded and relative organ weights were determined. Skin (treated and untreated), liver, kidneys, brain, pituitary, heart, thyroid, parathyroid, adrenals, testes or ovaries, and unusual lesions were evaluated histopathologically. No treatment-related mortality and clinical signs as well as effects on the body weight and food consumption were noted. In addition, haematolgy and clinical biochemistry revealed no treatment-related differences from the control. Significantly higher absolute and relative pituitary weights were noted for all treated female groups compared to control without any apparent relationship to treatment with the test substance. Slight to well-defined erythema as well as (very) slight edema was observed in all dose groups in both sexes. A few and numerous instances of moderate to severe erythema were evident in the mid dose group and in the high dose group, respectively. A pronounced frequency of blanching, raw areas, necrosis, and brown scab-like areas were noted at 40 and 160 mg/kg bw/day. These findings were confirmed by dermal observations during terminal necropsies (light, dark brown, or dark red scab(s); dark brown and/or crusty area(s); necrotic or raw areas hair loss; epidermal thickening, scaling or sloughing). Histopathologial examinations further correlate to gross pathological findings: Epidermal and dermal necrosis with destruction of adnexal structures was noted in the mid- and high-dose rabbits with somewhat less severe dermal irritation in the low-dose rabbits. Additionally, diffuse pleocellular inflammation infiltrate, acanthosis, hyperkeratosis, necrotic cell debris on the epidermis and subepidermal congestion was recorded. Thus, under the conditions of the study, although there were local effects, there was no consistent evidence of treatment-related systemic effects of the test substance when applied repeatedly to the skin of rabbits. The corresponding NOAEL over a 3-week period of dermal administration with the test substance to the rabbit was ≥ 160 mg/kg bw/day.

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 oral, inhalation and dermal repeated dose toxicity do not meet the criteria for classification according to Regulation (EC) No 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.