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Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductive toxicity study  of 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 415.5 mg/kg bw. When male and female Osborne-Mendel Han rats were exposed with2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1)orally.

Since no experimental data are currently available of reproductive toxicity and only a QSAR prediction for the target compound 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1)conclusions and classifications are solely based on its read across chemicals Salicylic acid (69-72-7), Methyl salicylate(119-36-8) and sodium salicylate (54-21-7).As seen by the available QSAR prediction for the target chemical and the experimental results from its read across it is concluded that the target compound 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) is suspected to be toxic and thus should be classified in Category 2 for reproductive toxicity.

 

 

 

 

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.3, 2018
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Specific details on test material used for the study:
Name of test material : 2-hydroxy-p-toluic acid (m cresotic acid)
Molecular formula :C8H8O3
Molecular weight :152.148 g/mol
Smiles notation :Cc1ccc(c(c1)O)C(=O)O
InChl :1S/C8H8O3/c1-5-2-3-6(8(10)11)7(9)4-5/h2-4,9H,1H3,(H,10,11)
Substance Type: Organic
Physical State: Solid
Species:
rat
Strain:
Osborne-Mendel
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
No data available
Frequency of treatment:
No data available
Details on study schedule:
No data available
Dose / conc.:
415.5 mg/kg bw/day (nominal)
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
No data available
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not examined
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
415.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: overall no effects on reproductive performance
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
415.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Remarks on result:
other: overall no effects on developmental parameters
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and "k" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as m,p - Cresols by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid moiety AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Class 2 (less inert compounds) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.58

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.94

Conclusions:
In reproductive toxicity study, NOAEL was estimated to be 415.5 mg/kg bw. When male and female Osborne-Mendel Han rats were exposed with 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) orally.
Executive summary:

The reproductive toxicity study  of 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 415.5 mg/kg bw. When male and female Osborne-Mendel Han rats were exposed with2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1)orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
415.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2018)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity

In different studies, 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments i.e. most commonly in rats for 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) .The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductive toxicity study of 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 415.5 mg/kg bw. When male and female Osborne-Mendel Han rats were exposed with2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1)orally.

It is supported by experimental study conducted by COSMETIC INGREDIENT REVIEW (International Journal of Toxicology 2003.) on structurally similar read across substance with Salicylic acid(69-72-7)Reproductive toxicity study of Salicylic acid (69-72-7)was performed on female wistar rats.80 rats were divided as 20 rats /dose group.Test material mixed with0.5% solution of sodium carboxymethyl cellulosewere administered in dose concentration 0,75, 150, or 300 mg/kgfrom day 8 through day 14 by oral gavage route.The control group was given 5 ml/kg of vehicle. On day 20 of gestation, 15 of the animals of each group were killed; the remaining 5 were allowed to deliver. The offspring, which were weaned on day 21, were observed daily and weighed every 3 days. Offspring were killed and autopsied on the 56thday for examinations of visceral and skeletal abnormalities Maternal body weight gain was inhibited for animals of the 300-mg/kg group. Salivation and/or piloerection were observed in this group. Feed and water consumption decreased during the administration of 300 mg/kg Salicylic Acid. Three animals of this group died within a few days of the initiation of dosing. Decreased uterine weight was observed in animals of the 150- and 300-mg/kg dose groups as compared to controls; these groups had 25.7% and 100% fetal mortality, respectively. Litter size and neonatal body weight, body length, and tail length were significantly decreased in the 150-mg/kg dose group. The incidences of external, internal, and skeletal anomalies in offspring autopsied at the 56th day were 1.8%, 0%, and 2.5%, respectively, for the 75-mg/kg group and 27.8%, 12.7%, and 65.7%, respectively, for the 150-mg/kg group.The offspring from animals of 150-mg/kg Salicylic Acid group had decreased body length and tail length compared to controls. The thyroid weight of male offspring from the 75-mg/kg group was significantly increased and the adrenal gland weight of male offspring from the 150-mg/kg group was significantly decreased compared to controls. The incidences of external organ, internal organ, and skeletal anomalies in offspring were 0%, 5.0%, and 0%, respectively, for the 75-mg/kg group and 13.7%, 17.2%, and 79.2%, respectively, for the 150- mg/kg group. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 75 mg/kg/day, and the dose-level of 75 mg/kg/day was considered to be the LOAEL for embryo-foetal toxicity. When female wistar rats were treated with Salicylic acid(69-72-7)orally.

 It is supported by experimental study conducted by Environmental Health Research and Testing, Inc (National Toxicology Program, Research Triangle Park, NC. NTP85-022 - PB85-l64283, 1984, page no 1- 165) on structurally similar read across substance Methyl salicylate(119-36-8).The reproductive toxicity study of Methyl salicylate (119-36-8) was performed on male and female  CD-1 mice. Based on dose-range finding study dose levels of0, 100,250,500mg/kg were selected. The vehicle control group (40 male and 40 female) and three dose groups (20 male and 20 female).Eleven-week old male and female CD-l mice were exposed to the chemical during a7-day premating period, after which they were randomly paired (one male: one female) within each dose group. Cohabitation was continued for100days. All animals will be weighed once a week from day 0 (first day of treatment) to day127 New-born litters were evaluated and immediately sacrificed. Eleven animals died, 3 in the control, 2 each in the 100mg/kg and 250mg/kg dose groups, and 4 in the 500mg/kg dose group. The cause of death varied from case to case but it was neither chemical nor dose related. No distinct treatment related symptoms of toxicity were observed during routine health surveillance. Test material in dose level 0,100,250,500 mg/kg bw had no apparent effect on male or female body weights .The fertility index in the control and various treatment groups varied between 95 to 100% all breeding pairs except 1 in the 100mg /kg group delivered at least one litter .There was a significant decrease (p<0.05) in the mean number of litters at the 0.5 g/kg MS level .The average number of pups per litter, the proportion of pups born alive, and mean live pup weight values were also significantly reduced (p<0.05) in the 500mg /kg group compared to the corresponding control. There was no significant effect on any of these parameters in the remaining two dose groups. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 250 mg/kg/day, and the dose-level of 500 mg/kg/day was considered to be the LOAEL for reproductive toxicity. When male and female CD 1 mice were treated with Methyl salicylate (119-36-8) orally.

 It is supported by experimental study conducted by Environmental Health Research and Testing, (National Toxicology Program, NTP-84-156, 1984) on structurally similar read across substance Methyl salicylate(119-36-8). The reproductive toxicity study of Methyl salicylate(119-36-8) was performed onmale and female  CD-1 mice. 11 weeks of age animals were used in study. Based on dose-range finding study dose levels of 0.0, 25.0, 50.0, and 100.0 mg /kg/day were selected. Test material soluble in corn oil and administered by gavage daily during the 7-day premating, 98-day cohabitation, and 21-day segregation periods. The vehicle control group (40 male and 40 female) and three dose groups (20 male and 20 female), For the first week, animals will be housed five per cage by sex. Subsequently, the females and males from the same dose group will be randomly paired and cohabited. The adult animals will be weight weekly. The test material had no influence on the number of litters produced per pair, the number of live pups per litter, the proportion of pups born alive or sex (males/total) of pups born alive .Female live pup weight adjusted for the total number of pups per litter, however, was significantly greater p<0.05) for the breeding pairs given 100.0 mg /kg/day than for those receiving 50.0 mg /kg/day. Further, combined (both sexes) live pup weight adjusted for the total number of pups per litter was significantly greater (p<0.05) for breeding pairs receiving 100.0 mg /kg/day than for those given 25.0 or 50.0 mg /kg/day .Since there were no other indications of toxicity during continuous breeding, these differences might be due to chance alone. It also should be noted that one parental male and female in the control group, one parental female in the 25.0 mg /kg/day group, two parental females and three parental males in the 50.0 mg /kg/day group, and three parental males in the 100.0 mg /kg/day group died prior to the conclusion of the continuous breeding phase .The random distribution of deaths across treatment groups suggested that they were not treatment-related.Due to the lack of an effect of test material on fertility and reproductive performance in the parental mice (F0 generation), it was decided to assess fertility and reproductive performance in the F1 offspring. The litters of the 0.0 and 100.0 mg MS/kg/day. groups were weaned at 21 days of age, and one or two females and male pups from each surviving litter were randomly selected .Each weanling was housed individually and maintained on the same treatment as their parents. At 90±10 days of age, a male and female from different litters within treatment groups were cohabited from 1 to 7 days, depending upon when a copulatory plug was detected. The pairs were separated and the females were allowed to deliver their litters. Continuous exposure of CD-1 mice to test material in utero, via the mother's milk and by gavage (100.0 mg /kg/day) from weaning at 21 days of age to sacrifice at 127±8 days of age was found to have no statistically significant effects on mating behaviour , fertility rate or reproductive performance The 0.0 and 100.0 mg/kg/day F1 parental mice were necropsied .Sperm assessment indicated no significant differences in the %motile sperm, sperm concentration or %abnormal sperm in the cauda epididymis between male mice exposed to 0.0 or 100.0mg /kg/day .In addition, there were no significant differences in body weights or organ weights between the male mice in these two groups .Body weight and liver and pituitary weights also were unaffected by treatment of female mice .In contrast, brain weight was significantly increased (p<0.05)and reproductive tract weight significantly decreased (p<0.05) in female mice given 100.0 mg /kg/day versus control female mice .The reproductive tract weights of the two females in the control group that did not deliver pups were unexpectedly heavier on average than those from the 17 control females that did deliver pups. This was in contrast to the findings for the females treated with100.0 mg MS/kg/day. That is, the six females in this group that did not give birth had lighter reproductive tracts on average than did their eleven post gravid cohorts .This difference, along with the fact that the control group had a greater proportion of females with postgravid reproductive tracts than did the treated group (17/19 versus 11/17, respectively), might well explain the significantly heavier reproductive tracts in the control group as compared to those in the treated group. Thus, since the difference between the two groups appeared to be due to biological variation, it was not considered to be of toxicological significance. Finally, no-treatment-related gross or histopathologic lesions were noted for the pituitary, testis, epididymis, prostate or seminal vesicles in male mice, or for the pituitary, ovary, oviduct, uterus or vagina in female mice. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity for F0 and F1 generation was considered to be 100 mg/kg/day. When male and female  CD-l mice were treated with Methyl salicylate(119-36-8)orally.

 It is supported by experimental study conducted by D.P. Davis, G.P. Daston, M.R. Odio, R.G. York, A.L. Krausa, (Toxicology Letters 84 (1996) 135-141) on structurally similar read across substance sodium salicylate(54-21-7).Reproductive toxicity study of sodium salicylate(54-21-7) was performed on female Sprague Dawley rats. 86 rats were divided into 2 treatment group.25 female rats in treatment group 1 while 16 in treatment group 2 .Test material mixed with0.5% aqueous methyl cellulose were administers in dose concentration 0, 20, 80 or 200 mg/kg bw day from days 15 through 21 of gestation by oral gavage route twice daily. One-half of the dose was given to the animals in the morning and the second half 6-8 h later. Dosing volume was 10 ml/kg per dosing occasion. For mating purposes, one female and one male (from breeding stock) were housed together. The occurrence of copulation was determined by daily inspection for a copulatory plug. The day at which evidence of mating was detected was designated gestation day 0, and the female was placed in an individual cage. The animals were observed twice daily throughout the study for mortality and signs of overt toxicity. Individual body weights were recorded on gestation days 0, 6, 15, 16, 17, 18, 19, 20 and 21. Beginning on day 21, Pups were examined for external abnormalities as soon as possible following delivery. The number of viable and nonviable pups was recorded for each female. Al11p ups were sexed and weighed individually on lactation day 0. All surviving F,, females and F, pups were euthanized by carbon dioxide inhalation at lactation day 1. On gestation day 25, those females which failed to deliver were euthanized. The uterus and ovaries of all dams were exposed by an abdominal incision and grossly examined to determine the number of implantation sites present. No observations of adverse effects until the onset of parturition. As well, there were no apparent compound-related effects on gestational body weight gain in any of the treatment groups. One death occurred in the vehicle-treated group on gestation day 20. However, post-mortum examination revealed no abnormalities or signs of overt clinical toxicity. Both onset of labour and its duration were disrupted in the animals receiving the highest dose. Increased fetotoxicity and periparturn death also appeared to occur among foetuses from females treated with 200 mg/kg/day sodium salicylate but this was not statistically significant of sodium salicylate (200 mg/kg) ,Labour times in these groups ranged from 1-14 h with a mean duration of 3.6 h for the SA-treated For comparison, labor times in control animals ranged from less than 1 h to 3 h with a mean labour time of 1.5 h. There were no observed differences in mean litter size, pup size, or sex ratio, associated with sodium salicylate. Since those pups which did survive delivery had no visible abnormalities or other signs of overt toxicity. Maternal perinatal death was significantly increased in animals treated with both 200 mg/kg/ day sodium salicylate Four animals in each of these treatment groups died or were euthanized because of extreme distress during parturition. Clinical signs of maternal physical distress during parturition included labored breathing, decreased activity, and blood staining in the abdominal, nasal, and oral areas. Notably, each of these seven animals failed to deliver some or all of their pups. Increased maternal mortality was also evidenced as a significant decrease in the gestational index (defined as the percentage of pregnant females producing live pups) for these same treatment groups. No evidence of increased maternal distress or peripatum mortality was noted in animals from either the mid-dose (80 mg/kg/day) or low-dose (20 mg/kg/day) sodium salicylate. Hence No Observed Effect Level (NOEL) was considered to be 80 mg/kg/day, and LOAEL dose-level of 200 mg/kg/day was considered to be for reproductive toxicity. When female Sprague Dawley rats were treated with sodium salicylate (54-21-7)orally.

 Since no experimental data are currently available of reproductive toxicity and only a QSAR prediction for the target compound 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1)conclusions and classifications are solely based on its read across chemicals Salicylic acid (69-72-7), Methyl salicylate(119-36-8) and sodium salicylate (54-21-7).As seen by the available QSAR prediction for the target chemical and the experimental results from its read across it is concluded that the target compound 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) is suspected to be toxic and thus should be classified in Category 2 for reproductive toxicity.

 

 

 

 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Since no experimental data are currently available of reproductive toxicity and only a QSAR prediction for the target compound 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1)conclusions and classifications are solely based on its read across chemicals Salicylic acid (69-72-7), Methyl salicylate(119-36-8) and sodium salicylate (54-21-7).As seen by the available QSAR prediction for the target chemical and the experimental results from its read across it is concluded that the target compound 2-hydroxy-p-toluic acid (m cresotic acid) (50-85-1) is suspected to be toxic and thus should be classified in Category 2 for reproductive toxicity.