Registration Dossier

Administrative data

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 toto 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:
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 2 -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.

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

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 Jan - 02 Aug 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
purity is not provided
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 1981
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 2001
Deviations:
no
Qualifier:
according to
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 1987
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Wistar (Bor:WISW(SPF Cpb))
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: F.Winkelmann, Borchen, Germany
- Age at study initiation: mature animals
- Weight at study initiation: 186 - 148 g (females), > 300 g (males at the time of mating)
- Housing: several females together in Makrolon Type III cages during acclimation period, individually in Makrolon Type II cages on low-dust wood granules (Ssniff GmbH, Soest, Germany) from Day 0 post-coital (females), individually in Makrolon Type III cages (males)
- Diet: Altromin 1324 standard diet (Altromin, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2
- Humidity (%): 30 - 45
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous tylose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Weighed portions of the test compound volumes corresponding to the intended dosages were prepared and stirred smooth in the mortar using a small amount of tylose suspension. Subsequently, additional tylose suspension was added until final concentration was reached. The application formulations were sealed lighttight and used immediately (on the day of preparation) or stored in the refrigerator at approx. 4° C until use on the following days. The formulations were routinely stirred at room temperature on a magnetic stirrer prior to and during applications.

VEHICLE
- Concentration in vehicle: 3, 10 and 30 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Investigations into homogeneity and stability of the active ingredient in the application vehicle were performed prior to the start of study using GC-FID analysis. Samples were collected at all dose formulations (30, 100 and 300 mg/kg bw/day) from top, the middle and the bottom of the formulation. The investigations showed the active ingredient to be homogeneously distributed in the application vehicle for the formulations of the dose groups 30 and 100 mg/kg bw. The active ingredient content in the formulation for the 300 mg/kg bw group displayed clearly inhomogeneous distribution. The stability of the active ingredient in 0.5% aqueous tylose was demonstrated after 8-day storage. A second check of homogeneity was carried out in the 8th week after termination of treatment. Visible particles were observed in the samples of the 300 mg/kg bw formulation, which, however, did not significantly affect the distribution in the application vehicle. The active ingredient content was within the permitted tolerance range (± 20 deviation from the nominal value) in all samples of all formulations; thus, the active ingredient was homogeneously distributed in the application vehicle.
A content check of the formulations of all concentrations was carried out in the 2nd and 5th week of treatment. The results revealed no significant deviations of the active ingredient content from the nominal value in the formulations for the low and high dose group. The control analysis of the application formulations for the 100 mg/kg bw group showed a slightly reduced content (63 - 74 %) in the 5th week of treatment. As only 1/4 investigations for this group (2 homogeneity analyses, 2 content control analyses) displayed a slightly reduced content, no adverse effect on the study results is to be assumed for the 100 mg/kg bw formulations. Since the second check of homogeneity as well as the control analyses for the highest dose formulations revealed active ingredient contents within the permitted tolerance range. Thus, no adverse effect on the study results because of inhomogeneity of the formulations is to be assumed for the 300 mg/kg bw group as well.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 - 15 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
day 20 of gestation
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The range of doses has been selected based on results obtained in a range-finding study where pregnant rats (5 per group) received the test substance at 300, 500 or 1000 mg/kg bw/day. Due to severe maternal toxicity the investigations of the 500 and the 1000 mg/kg bw/day group were discontinued on day 12 p.c. and day 8 p.c., respectively. Impaired body weight development as well as clinical signs including abdominal position after application, rough coat, staggering gait and stertorous breathing were observed at 300 mg/kg bw/day from day 6 p.c. No indications of external malformations were observed.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (once daily on weekends and bank holidays)
- Cage side observations included: mortality, disturbances in the rats' general condition, appearance, behavior, alterations in the excretory products

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily (once daily on weekends and bank holidays)

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 p.c., daily from day 6 to day 15 p.c. as well as on day 20 p.c .

FOOD CONSUMPTION: Yes
Feed intake was determined for the following days of gestation: day 0 - 6, day 6 - 11, day 11 - 16 and day 16 - 20 p.c .

WATER CONSUMPTION: Yes
- during inspections by visual estimation of the quantities left over

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, placenta, visceral organs, abdominal and thoracic organs
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of live and dead fetuses, sex of live fetuses, weights of live fetuses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
A non-parametric rank sum test (Wilcoxon-Mann-Whitney-U-Test) was used for average body weight gain as well as for the number of fetuses per dam with minor skeletal deviations or malformations. The exact Fisher test (two-sided; p ≤ 0.05 and p ≤ 0.01) was applied for fertility and gestation rate as well as for the number of fetuses or litters with retardations/with 14th rib or with malformations. The F-test and t-test or t-test according to Welch was used for feed consumption and corrected body weight gain, for the number of corpora lutea per dam with implantations or with live fetuses, for the number of implantations per dam with implantations or with live fetuses, for the average number of live fetuses per dam, for the percentage of male or female fetuses per dam, for the average weight of fetuses (male, female or both; also per dam) as well as for the average placental weight. The CHI²-test (correction according to Yates) was applied for pre-implantative losses per dam with implantations and live fetuses, for the sex ratio of male to female fetuses per group, for the number of resorptions per dam with implantations/ with live fetuses as well as for the number of early resorptions per dam with implantations/ with live fetuses.
Historical control data:
Historical control data from studies conducted in-house were referred to in order to allow comparison with concurrent controls. The data were generated between 1983 and 1990 and are presented in the report.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
100 mg/kg bw/day: labored breathing in 2/25 animals on days 8 and 16 p.c.
300 mg/kg bw/day: rough coat, sunken flanks, bloody muzzle, labored breathing, reduced motility, high-stepping gait from day 8 p.c.; lying on side, somnolence, abdominal position, spastic convulasions in several animals from day 6 p.c. for a period of approx. 1 h and/or starting approx. 10 min after test compound application; gasping breathing in 1/25 animal
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
300 mg/kg bw/day: 5/25 animals died; 1/26 animal was sacrificed in moribund conditions
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
100 mg/kg bw/day: statistically significant reduced mean body weight gain during days 6 - 15 p.c.; statistically significant reduced corrected body weight gain during days 0 - 20 p.c.; reduced mean body weight gain during days 0 - 20 p.c. (not statistically significant)
300 mg/kg bw/day: statistically significant reduced mean body weight gain during days 6 - 15 p.c. and 0 - 20 p.c.; statistically significant reduced corrected body weight gain during days 0 - 20 p.c.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
100 mg/kg bw/day: statistically significant reduced food intake during the application period (statistical significance from day 11 - 16 p.c. only)
300 mg/kg bw/day: statistically significant reduced food intake during the application and gestation period
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
100 mg/kg bw/day: reduced in one animal on day 9 p.c. (assessed qualitatively only)
300 mg/kg bw/day: reduced for several animals from day 9 p.c., in some cases lasting for 1 - 6 days (assessed qualitatively only)
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
300 mg/kg bw/day: 3/6 animals that dies or were sacrificed moribund had inflated intestines and bloody vaginas, respectively; individual findings included a thorax filled with serous fluid and suppurative foci in the lung tissue, reddened esophagus, an
apparently small stomach, and spleen reduced in size; no effects were observed in surviving animals
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Urine/ faeces excretion:
100 mg/kg bw/day: increased urine excretion in some isolated cases from day 9 p.c.; reduced amount of faeces over a period of 1 - 5 days in several animals from day 9 p.c.
300 mg/kg bw/day: increased urine excretion in several animals from day 8 p.c. for a period of 1 - 5 days; reduced amount of faeces in several animals from day 8 p.c. (lasting for 1 - 5 days)
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
300 mg/kg bw/day: statistically significant increased mean resorptions/dam due to complete resorption by 2/25 dams
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
effects observed, treatment-related
Description (incidence and severity):
300 mg/kg bw/day: reduced gestation rate due to complete resorptions in 2/18 animals (without 6 animals that died or were sacrificed moribund)
Other effects:
no effects observed
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
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
300 mg/kg bw/day: statistically significant decreased fetal weight
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
300 mg/kg bw/day: slightly increased rate of malformations including cryptorchism, microphthalmia or anophthalmia, multiple malformation, dysplasia of humerus, hernia of diaphragm with lung hypoplasia, heart and lung dystopia
Details on embryotoxic / teratogenic effects:
VISCERAL MALFORMATIONS
The kind of malformations observed in the high dose group had been observed in the control group of this study (cryptorchism) or had occurred as spontaneous malformations in this strain in the same laboratory. Thus, they are not to be regarded as indications of a specific teratogenic effect of the test material
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

Table 1: Maternal effects

Parameter

Controldata

30 mg/kg

100 mg/kg

300 mg/kg

Dose-response
+ / –

historical

study

0 mg/kg

Number of dams examined

-

25

25

25

25

 

Clinical findings

 

 

 

 

 

 

audible breathing sounds

-

0

0

1

4

+

gasping breathing

-

0

0

1

1

+

bloody lip

-

0

1

0

0

-

rough coat

3

0

0

0

7

+

bloody muzzle

1 (nose)

0

0

0

4

+

sunken flanks

1

0

0

0

3

+

reduced motility

-

0

0

0

2

+

abdominal knots

-

0

1

0

0

bloody forelimbs

-

0

0

0

1

high-stepping gait

-

0

0

0

1

+

reduced water intake

7#

0

0

1

12

+

light-brown, hard faeces

4

1

0

0

0

 

small amount of faeces

4

0

0

4

14

+

increased urine excretion

5#

0

0

3

9

+

after application

 

 

 

 

 

 

        gasping breathing

-

0

0

0

1

+

        lying on side

-

0

0

0

7

+

        somnolence

-

0

0

0

13

+

        abdominal position

-

0

0

0

9

+

        spastic convulsion

-

0

0

0

5

+

Mortality of dams

-

0

0

0

6

+

Body weight gain [g]

Mean day 0 – 20

73.0-101.9

98.5

95.8

90.9

66.8*

+

Body weight gain [g]

corrected, day 0 – 20

-

37.6

35.3

31.0

13.7***

+

Mean food consumption
(Day 0-20) [g/rat/day]

-

18.5

18.4

18.0

15.5***

+

Pregnancies

7-24

22

24

22

24

-

Necropsy findings in dams dead before end of test

 

 

 

 

 

 

      reddened oesophagus

-

 

 

 

1

+

     suppurative foci in lung tissue

-

 

 

 

1

+

      fluid in thorax

-

 

 

 

1

+

     thorax filled with serous fluid

-

 

 

 

1

+

      stomach appears smaller

-

 

 

 

1

+

     stomach + intestines extremely distended

-

 

 

 

1

+

      reduced spleen size

-

 

 

 

1

+

      gas-inflated intestines

-

 

 

 

2

+

     bloody vagina

1

 

 

 

3

+

     organs autolytic

-

 

 

 

1

+

Necropsy findings in dams at termination

 

 

 

 

 

 

      Ovariary cysts

1

2

0

0

0

      intestinal worms

56

3

8

7

6

-

Statistically significant difference from controls: *p < 0.05; ** p < 0.005; *** p < 0.001

 

Table 2: Litter response (Caesarean section data)

Parameter

Controldata

30 mg/kg

100 mg/kg

300 mg/kg

Dose-response
+ / –

Historical
(1984-1990)

Study
0 mg/kg

Corpora lutea[mean no./dam]

-

13.0

13.2

12.4

12.6

 

Implantations[mean no./dam]

8.3-12.5

11.4

11.3

11.2

10.6

Resorptions[mean no./dam]a

0.3-2.3

0.6

0.8

0.6

1.8***

+

Resorptions[mean no./dam]b

0.6

0.8

0.6

0.7

-

Foetuses[mean no./dam]

7.6-11.7

10.7

10.5

10.6

9.9

Foetus weight(mean) [g]b

3.17-3.68

3.71

3.69

3.65

3.42**

+

Placenta weight[mean/dam] [g]b

0.55-0.68

0.62

0.65

0.62

0.60

Skeletal changes
[mean foetus no/dam]b

1.44-3.18#

2.09

1.46

2.18

1.38

Malformations
[mean foetus no/dam]b

0.00-0.39

0.14

0.08

0.05

0.38

Sex ratio (m:f)b

-

1:0.8

1:0.9

1:1.22

1:1.03

-

awith implantations
bwith live foetuses
# Skeletal retardations
Statistically significant difference from controls: *p < 0.05; ** p < 0.005; *** p < 0.001

 

Table 3: Examination of the foetuses

Parameter

Controldata

30 mg/kg

100 mg/kg

300 mg/kg

Dose-response
+ / –

historical

Study
0 mg/kg

External Examinations

 

No. of foetuses examined

-

236

253

233

158

 

No. of foetuses malformed

 

        hydronephrosis, hydro-ureter

9

1

0

0

0

        cryptorchism

13

2

1

1

1

        microphthalmia or anophthalmia

23

0

1

0

2

        multiple malformation

1

0

0

0

1

        dysplasia of humerus

4

0

0

0

1

               hernia of diaphragm, with lung hypoplasia, heart and lung dystopia

1

0

0

0

1

Total malformed foetuses

51

3

2

1

6

Conclusions:
The test substance had no effect on intrauterine development.
Executive summary:

The teratogenic potential of the test substance 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. 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.

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:
read-across source
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 2 -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.