Sodium p-chloro-m-cresolate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Two-generation reproductive toxicity, oral (OECD 416), rat:

- Reproductive toxicity P0 and P1 generation: NOAEL >= 12000 ppm (equivalent to 1043.0 and 1189.7 mg/kg bw/day for males and females of the P0 generation, respectively; equivalent to 1204.9 and 1263.4 mg/kg bw/day for males and females of the P1 generation, respectively)

- Reproductive toxicity F1 generation: NOAEL = 3000 ppm

- Systemic toxicity P0, F1 and F2a generation: NOAEL = 3000 ppm (equivalent to the mean achieved dose before pairing: 247.8 mg/kg bw/day for P0 males; 298.2 mg/kg bw/day for P0 females)

- Systemic toxicity P1 and F2b generation: NOAEL = 750 ppm (equivalent to 74.5 and 90.4 mg/kg bw/day for P 1males and P1 females, respectively)

Link to relevant study records

Reference

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 document provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

3 000 ppm

Based on:

test mat.

Remarks:

equivalent to 247.8 and 298.2 mg/kg bw/day for males and females, respectively

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

histopathology: non-neoplastic

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

>= 12 000 ppm

Based on:

test mat.

Remarks:

equivalent to 1043.0 and 1189.7 mg/kg bw/day for males and females, respectively

Sex:

male/female

Basis for effect level:

other: highest dose tested

Critical effects observed:

no

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

histopathology: non-neoplastic

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

>= 12 000 ppm

Based on:

test mat.

Remarks:

equivalent to 1204.9 and 1263.4 mg/kg bw/day for males and females, respectively

Sex:

male/female

Basis for effect level:

other: highest dose tested

Critical effects observed:

no

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Generation:

F1

Effect level:

3 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Generation:

F1

Effect level:

3 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

sexual maturation

Critical effects observed:

no

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Generation:

F2a

Effect level:

3 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Generation:

F2b

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

no

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 043 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII - IX, 8.7, 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

 There are no data available regarding toxicity to reproduction of sodium p-chloro-m-cresolate (CAS 15733-22-9). The assessment was therefore based on a two-generation reproduction toxicity 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 influence of the source substance p-chloro-m-cresol on reproductive performance was assessed in a two-generation reproductive toxicity study in Wistar Crl: (WI) WU BR rats performed according to OECD Guideline 416 and in compliance with GLP (Eiben, 2006). For the P0 generation, three groups of 25 male rats received the test substance orally, via the diet, at concentrations of 750, 3000 or 12000 ppm for ten weeks before pairing until termination. Four groups of 25 female rats received the test substance orally, via the diet, at concentrations of 750, 3000 or 12000 ppm for ten weeks before pairing, throughout pairing and gestation and during lactation. A similarly constituted control group received untreated basal diet for the same duration. The F1 offspring were nursed up to an age of four weeks. 25 male and 25 female progeny from each group were designated for the P1 generation for breeding the F2a generation and they continued to receive the relevant diet, as per the P0 generation, throughout the study until termination. A second mating was done on P1 rats to breed the F2b to clarify relatively low viability indices at 0 and 3000 ppm observed in the F2a generation. Both F2 generations were nursed up to an age of four weeks.

During the 10 week pre-mating period the test compound intake at 750, 3000 and 12000 ppm was 638, 247.8 or 1043.0 mg/kg bw/day in males and 80.1, 298.2 or 1189.7 mg/kg bw/day in females of the P0 generation, respectively. The corresponding test compound intake for the P1 generation was 74.5, 288.4 or 1204.9 mg/kg bw/day in males and 904, 364.5 or 1263.4 mg/kg bw/day in females, respectively. During gestation and lactation test compound intake in females of the P0 generation was 54.2, 216.8 or 861.8 and 89.2, 320.7 or 1385.8 mg/kg bw/day, respectively. In P1 females generating and weaning the F2a generation test compound intake was 55.8, 235.3 and 982.3 mg/kg bw/day during gestation as well as 83.0, 345.1 and 1582.8 mg/kg bw/day during lactation. Test compound intake in P1 females generating and weaning the F2b generation was 46.6, 195.1 or 773.4 mg/kg bw/day during gestation and 86.7, 279.7 and 1495.3 mg/kg bw/day during lactation.

Mortality, clinical signs, body weights and food intake as well as reproduction parameters such as mating performance, fertility, gestation, rearing, oestrus cycling and sperm analyses were examined in P0 and P1 rats. Furthermore, litter parameters such as litter size, percentage of males born and pup weight at birth as well as viability and lactation indices, body weight gain and clinical signs were studied in F1, F2a and F2b offspring. Developmental milestones were evaluated in F1 post weanlings and ano-genital distance was measured in F2a pups. Necropsies were done on all rats. Implantation sites in P0 and P1 females were recorded. Selected organs were weighed in adult rats and weanlings (recorded as absolute weight and relative to body weight) and histopathology including ovarian follicle staging (only P1) was performed in a number of organs of P0 and P1 rats.

No changes in clinical signs of parental rats were evident up to 12000 ppm.

In the P0 and P1 males and females administered 12000 ppm, test substance statistically significantly decreased body weights and/or weight gains were noted during the pre-mating period as well as gestation and lactation period (females). At 3000 ppm, statistically significantly decreased mean body weight gain in females weaning the F2b generation was observed during lactation. While no effects on food consumption was observed in the P0 generation, decreased food consumption was observed in P1 females during lactation at 3000 ppm (statistically significant) and pre-mating at 12000 ppm without statistical significance. Additionally, 2/25 females of the P1 generation showed increased water intake during lactation (qualitatively determination). At necropsy smaller ovaries were observed in 2/25 females of the P0 generation at 12000 ppm. Emaciation was noted in 7/25 P1 females. 3/25 and 4/25 P1 females showed dilated stomach and cecum, respectively.

Statistically significant, treatment-related effects on organ weights evident as increased relative liver weight and decreased absolute and relative ovaries weight were noted for P0 females of the highest dose group only. In P1 males, statistically significant treatment-related decreased absolute and relative liver weight was noted at 3000 and 12000 ppm. Absolute and relative seminal vesicle weights were increased at 12000 ppm. In P1 females statistically significantly and treatment-related increased relative kidney, liver and spleen as well as decreased absolute ovaries weight was observed at 12000 ppm.

Histopathology revealed periportal cytoplasmic change in the liver, often coincided with reduced hepatocellular glycogen storage in 12000 ppm males of both parental generations. Simultaneously, periportal fat storage was reduced in favour of a more diffuse pattern. In contrast, adaptive periportal hypertrophy/eosinophilia occurred in P0 females at 12000 ppm and in P1 females increasingly at 3000 ppm and above. Reduced hepatocellular glycogen storage was also observed in these animals. Changes in the fat storage became slightly evident in P1 females at 3000 ppm and above (not statistically significant). These liver changes associated with the observed effects on the liver weight might reflect secondary catabolic effects in course of a significant body weight loss in high dose animals. In the kidneys, papillary necrosis was found in males and females of the P1 generation at 12000 ppm. Simple dilation of the papillary tubules was increased at 12000 ppm in both male parental generations and in the female P1 generation at 3000 ppm and above. These findings are accompanied with increased relative kidney weight in females and are interpreted as adverse. Brownish inclusions in the proximal tubules and dilated cortico-medullary tubules were only found in females and raised at 12000 ppm in both generations. A small number of P1 females also showed dilated cortico-medullary tubules at 3000 ppm. Secondary changes belonging to chronic progressive nephropathy (CPN) either increased (P0 females: basophilic tubules) or decreased (P0/P1 males: hyaline casts/dilated tubules; P1 males: basophilic tubules) under high dose treatment. Further histopathological findings in high dose females of both parental generations included ovarian atrophy, increased metoestrus, decreased dioestrus and atrophy of the vaginal epithelium. Histopathological evaluations of ovarian follicles and corpora lutea revealed a statistically significant decrease in the number of growing follicles and corpora lutea in P1 rats treated with 12000 ppm. These findings are discussed as possible secondary due to weight loss and are correlated with reduced ovary weights and/or smaller ovaries.

The parameters of the reproductive performance such as insemination, fertility, gestation and rearing indices as well as gestation length were not influenced by the treatment with the test substance up to 12000 ppm. There was no test substance-related reduction in viability and lactation indices up to 12000 ppm. At 12000 ppm, depressed pup and litter weights occurred in all generations. At 3000 ppm, slightly reduced body weights were observed for female F2b pups. The occurrence of developmental milestones (balano-preputial separation and vaginal opening) was delayed in 12000 ppm F1 rats. No effect was seen at measurements of the ano-genital distance in F2a pups. At 12000 ppm, F2a pups exhibited respiration sounds and blue discolorations and more autolytic F2a pups were found than in the other groups. The spleen and thymus weights were decreased in nearly all pup generations at 12000 ppm.

Thus, under the conditions of this study, it is considered that 3000 ppm (equivalent to the mean achieved dose before pairing: 247.8 mg/kg bw/day for P0 males; 298.2 mg/kg bw/day for P0 females) represents the NOAEL in this study for the P0 animals and the F1 and F2a offspring. For the P1 adult animals and the F2b offspring the corresponding NOAEL is 750 ppm (equivalent to 74.5 and 90.4 mg/kg bw/day for P1 males and P1 females, respectively). In terms of reproductive effects, no treatment-related findings were observed at any dose level tested in the P0 and P1 generation; therefore, the high dose of 12000 ppm (equivalent to the mean achieved dose before pairing: 1043.0 mg/kg bw/day for P0 males; 1189.7 mg/kg/day for P0 females; 1204.9 mg/kg bw/day for P1 males; 1263.4 mg/kg bw/day for P1 females) is considered to be the NOAEL for reproductive toxicity with regard to the parental generations. For the F1 offspring the NOAEL for reproductive toxicity is considered to be 3000 ppm.

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

A reproduction / developmental toxicity screening test was performed according to OECD Guideline 421 and in compliance with GLP. Male and female Crl:CD(SD) rats (12 animals/sex/dose) were administered p-chloro-m-cresol at 35, 150, and 600 mg/kg bw/day in corn oil via oral gavage. Males were dosed for 42 days, including a 14-day pre-mating and mating period. Females were dosed for 56 days, including a 14-day pre-mating, mating and gestation period, and up until lactation Day 3. Cage side observations were made twice daily. Individual body weight and food consumption were determined throughout the study period. For females, vaginal smears were taken and the stage of oestrous determined from the first day of administration to the day of copulation. The following litter parameters were determined: body weights, the number and sex of pups, stillbirths, live births, post-natal mortality and presence of gross anomalies. All pups were euthanized on lactation Day 4 using carbon dioxide and were subject to a gross necropsy. All surviving males were euthanized by exsanguination under ether anaesthesia on the day after the last administration. All surviving females were euthanized by exsanguination under ether anaesthesia on Day 4 of lactation. A gross necropsy was performed on all parental animals. The following organ weights were recorded at necropsy: brain, thymus, heart, liver, kidneys, spleen and adrenals (all animals); testes and epididymides (males); ovaries (females). Histology was performed on the following organs: ileum, testes and epididymides, including staging a spermatogenesis (males); ovaries, pituitary gland, thymus, spleen, kidneys and ileum (females). For females, the number of corpora lutea and the number of implantation sites was determined.

Decreased locomotor activity, crawling position, lateral position and soiled perigenital fur were observed in both sexes at 600 mg/kg bw/day. Significantly reduced body weights and food consumption were observed in both sexes at 600 mg/kg bw/day. On the basis of these effects, the NOAEL for general toxicity was determined to be 150 mg/kg bw/day in males and females. No effects on reproductive and developmental parameters were observed at 600 mg/kg bw/day. The NOAEL was determined to be 600 mg/kg bw/day, the highest dose tested.

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

 

Effects on developmental toxicity

Description of key information

Teratogenicity study, oral (OECD 414), rat:

developmental toxicity: NOAEL = 100 mg/kg/bw/day

Link to relevant study records

Reference

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 document provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Species:

rat

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Abnormalities:

no effects observed

Developmental effects observed:

yes

Lowest effective dose / conc.:

300 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 2) and consistent study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, 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

 There are no data available regarding developmental toxicity of sodium p-chloro-m-cresolate (CAS 15733-22-9). The assessment was therefore based on a two-generation reproduction toxicity 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 teratogenic potential of the source substance p-chloro-m-cresol was assessed in a developmental toxicity study in Bor:WISW(SPF Cpb) Wistar rats performed according to OECD Guideline 414 and in compliance with GLP (Bartmann, 1991). Female rats were mated overnight with males. Three groups of 25 sperm-positive female rats received the test substance by oral gavage from day 6 to 20 postcoital (p.c.) at doses of 30, 100 or 300 mg/kg bw/day in aqueous solution of 0.5% tylose. A control group of 25 females received the vehicle. On day 20 of gestation animals delivered by caesarean section. Investigations were performed on general tolerance of the test substance by the dams as well as its effect on intra-uterine development. At doses of 30 mg/kg bw/day the test substance was tolerated without any effects. At 100 mg/kg bw/day some animals showed laboured breathing. At 300 mg/kg bw/day all dams exhibited marked clinical signs (rough coat, sunken flanks, bloody muzzle, laboured breathing, reduced mobility, high-stepping gait). Within 1 h after application, several animals of this group showed additional clinical signs of more frequently lying on side, somnolence, abdominal position, spastic convulsions and gasping breathing. Five animals of the high dose group died and one was sacrificed in moribund conditions. After treatment with ≥ 100 mg/kg bw/day body weight gain, feed and water intake as well as excretion of faeces was diminished. Urine excretion was increased in isolated cases at 100 and in several animals at 300 mg/kg bw/day.

Weight and external appearance of placentas, sex ratio of foetuses and development of the skeletal system was not affected up to and including 300 mg/kg bw/day. Gestation and resorption rates, number and weight of foetuses as well as number and kind of malformations were not affected at doses of ≤ 100 mg/kg bw/day. At 300 mg/kg bw/day foetal weight, gestation rate and the number of foetuses were diminished due to an increased resorption rate. The slightly increased number of malformations observed in this group, were considered as spontaneous malformations which were not dose-dependent. The embryotoxic effects observed correlated with the marked maternal toxicity. Thus, under the conditions of this study, the NOAEL of the test substance in terms of maternal toxicity following administration of the test substance to pregnant rats via gavage is 30 mg/kg bw/day. The NOAEL in terms of fetal toxicity is 100 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 toxicity to reproduction 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.