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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

NOAEL was estimated to be 494.70mg/kg bw when male and female Crj: CD (SD) rats were exposed with 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) orally.

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 v3.4 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 v3.4, 2017
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 the test material: 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one
- IUPAC name: 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one
- Molecular formula: C11H12O2
- Molecular weight: 176.214 g/mol
- Substance type: Organic
Species:
rat
Strain:
Crj: CD(SD)
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: drinking water
Type of inhalation exposure (if applicable):
other: NOT_SPECIFIED
Vehicle:
water
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:
F0 parental animals: 90 days before mating
F1 and F2 parental animals: 110 days
Frequency of treatment:
continuously
Details on study schedule:
No data available
Dose / conc.:
494.7 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Total:
treated group:10 males and 20 females;
control groups:15 males and 30 females
Control animals:
yes, concurrent vehicle
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:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
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 specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
494.7 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
reproductive performance
Remarks on result:
other: No adverse effect was observed at given dose level
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:
no effects observed
Gross pathological findings:
not specified
Histopathological findings:
no effects observed
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
494.7 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Remarks on result:
other: No adverse effects was observed in given dose
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 9 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((("a" or "b" )  and ("c" and ( not "d") )  )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and "i" )  and ("j" and ( not "k") )  )  and "l" )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Nucleophilic addition AND Nucleophilic addition >> Addition to carbon-hetero double bonds AND Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.4

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Class 1 (narcosis or baseline toxicity) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes by DNA binding by OASIS v.1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Basesurface narcotics by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No alert found by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated aliphatic alkoxy group by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "m"

Similarity boundary:Target: COc1ccc2CCC(=O)Cc2c1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.07

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.18

Conclusions:
NOAEL was estimated to be 494.70mg/kg bw when male and female Crj: CD (SD) rats were exposed with 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) orally.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0).No effect was observed on reproductive parameter . Hence,NOAEL was estimated to be 494.70mg/kg bw when male and female Crj: CD (SD) rats were exposed with 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
494.7 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)
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, sodium 3-[(4-anilinophenyl)diazenyl] benzenesulfonate (587-98-4) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for sodium 3-[(4-anilinophenyl)diazenyl] benzenesulfonate (587-98-4).

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0).No effect was observed on reproductive parameter . Hence,NOAEL was estimated to be 494.70mg/kg bw when male and female Crj: CD (SD) rats were exposed with 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) orally.

It is supported by experimental study conducted by U.S. Environmental Protection Agency (TSCA Confidential Business Information Center,FYI-10-01671, 2010) on structurally similar read across substance Tricyclodecanedimethanol(26896-48-0), Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screen in test of  tricyclodecanedimethanol was performed on rats according to OECD 422.Test material was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 150, 350 and 600 mg/kg/day.10animals /dose level were used . Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 28 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 42-53 days).Formulation analysis showed that the formulations were prepared accurately and homogenously, and were stable for at least 6 hours at room temperature. The parental parameters investigated in this study i.e. clinical appearance, functional observations, body weights, food consumption, haematology and clinical biochemistry parameters, macroscopic examination, organ weights, and microscopic examination. Also the mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites were observed.

 

No mortality occurred during the study period that was considered to be related to treatment with the test substance. One female at 150 mg/kg/day died during delivery. No cause of death could be determined for this animal. Since no further mortality occurred among this dose group or in the other dose groups, this death was considered to be unrelated to treatment. No clinical signs indicative of treatment-related toxicity were noted during the observation period. Salivation observed among all animals at 350 and 600 mg/kg/day and at lower incidence at 150 mg/kg/day was considered to be a physiological response (eg. to taste of the formulation) rather than a sign of systemic toxicity, considering the nature and minor severity of the effect and its time of occurrence (i.e. after dosing). Rales, and at lower incidence lethargy, shallow or laboured respiration, piloerection, uncoordinated movements and hunched posture were observed among the dose groups without a clear dose-related incidence. The occurrence of these signs was of an intermittent/transient nature (i.e. not related to the duration of treatment) and were therefore not considered to be toxicologically relevant. A single female at 350 mg/kg was noted with a swelling of the left and right axillary regions for a few days during the post-coitum and lactation periods. Upon macroscopic examination this animal was found with a hard, gray-white nodule in the subcutis of the axillary region which was determined to be an adenocarcinoma of the mammary gland at histopathological examination. This was not considered to be treatment-related. Other incidental findings consisted of a wound, scabbing and alopecia of various body parts. The incidence of these findings occurred within the background range of findings encountered for rats of this age and strain, which are housed and treated under the conditions of this study. No toxicological relevance was therefore ascribed to these observations.  

No toxicologically relevant changes in body weights and body weight gain were noted. The slightly lower mean body weights and body weight gain of males at 600 mg/kg/day during the premating and mating period (achieving a level of statistical significance on several occasions) remained within the range considered normal for rats of this age and strain, and thus were not toxicologically relevant. Other statistically significant changes in body weight (gain) occurred in the absence of a dose- and time-related trend, and were of a very slight nature. These changes consisted of a lower body weight of females at 350 mg/kg/day on Day 1 of lactation, and a higher body weight gain of females and 150 and 600 mg/kg/day on Day 4 of the Post-coitum phase. No toxicological relevance was ascribed to these changes. One female at 350 mg/kg/day showed a notable weight loss on Day 7 of the Post-coitum phase as (14%). As the incidence of this finding was unrelated to the dose, this was considered to be without toxicological relevance.  No treatment-related changes in food consumption before or after allowance for body weight were noted. The statistically significant higher absolute and relative food consumption of females at 600 mg/kg/day over Days 0-4 of the Post-coitum phase was slight in nature and was absent during the remainder of the Post-coitum and Lactation period. No toxicological relevance was ascribed to these changes. Two females at 350 mg/kg/day showed a severely reduced food intake during the Post-coitum phase on Days 7-11 and 4-7 respectively. As these were incidental occurrences, no toxicological relevance was ascribed to these changes.  No toxicologically relevant changes occurred in haematological parameters of treated rats. Any statistically significant changes in haematological parameters were considered to be of no toxicological relevance as these occurred in the absence of a dose-related trend and/or remained within the range considered normal for rats of this age and strain. These changes consisted of lower mean corpuscular haemoglobin concentrations (MCHC) for males at 150, 350 and 600 mg/kg/day, and higher reticulocyte counts and lower haemoglobin levels for females at 350 mg/kg/day. Any notably high or low individual haematological values occurred in the absence of a dose-related incidence, and were considered to be of no toxicological relevance. These individual variations included higher relative neutrophil counts and lower lymphocyte counts in male no. 23 (Group 3) and female no. 53 (Group 2), and higher red cell distribution width (RDW) in male no. 35 (Group 4).   The statistically significant higher sodium levels for males at 350 mg/kg and chloride levels for males at 150 and 600 mg/kg/day were considered to be of no toxicological relevance as they occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain. These changes were generally slight in nature (i.e. within the normal range or slightly exceeding the range), and occurred in the absence of any corroborative morphological changes indicative of organ dysfunction. Therefore, the changes in clinical biochemistry parameters were not considered to be toxicologically relevant.  Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.  No toxicologically relevant changes in motor activity were observed. Locomotor activity for females at 350 and 600 mg/kg/day appeared higher than controls. The higher counts for both the high and low sensors for these females were largely driven by one female in each of the two groups with notably high sensor counts (nos. 65 and 73, respectively). When the data were re-calculated excluding the sensor counts for these females, high sensor values were similar to control values, whilst low sensor values still appeared higher for females at 350 and 600 mg/kg/day, being statistically significant for females at 600 mg/kg/day. However, the means remained within the range considered normal for rats of this age and strain, and clinical signs did not support these variations. Therefore, no toxicological relevance was ascribed to these variations.   No treatment-related effects on reproductive parameters were noted. The mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites were unaffected by treatment. Also No toxicologically significant changes were noted in organ weights and organ to body weight ratios. The statistically significant higher kidney to body weight ratio of males at 600 mg/kg/day was considered to be without toxicological relevance since the mean remained within the normal range for rats of this age and strain, no dose-related increase in absolute kidney weights was observed among male dose groups, and no histopathological correlates were found. The higher testes to body weight of males at 600 mg/kg/day occurred due to a lower terminal body weight since absolute weights were similar to control levels. The statistically significant lower liver to body weight ratios of males and adrenal to body weight ratios of females at 150 mg/kg/day occurred in the absence of a dose-related trend, and were therefore considered to not be toxicologically relevant. Other organ weights and organ to body weight ratios among the dose groups were similar to control levels.  Macroscopic observations at necropsy did not reveal any alterations that were considered to be toxicologically relevant. One female at 350 mg/kg/day, showed a gray-white hard nodule of the left axillary region subcutis. This finding corresponded to a swelling of the axillary region noted during the in-life phase, and to an adenocarcinoma of the mammary gland which was not considered to be treatment related. The female that died spontaneously at 150 mg/kg/day was noted with yellowish contents of the gastro-intestinal tract, several reddish foci on the thymus, red discolouration of the mandibular lymph nodes, and cloudiness of both eyes. No relationship with treatment was established for these findings. Incidental findings included alopecia and/or scabbing of various body parts, reddish foci on the lungs, stomach and/or thymus, reddish or red-brown discoloration of the liver, thymus, reddish discoloration of the mesenteric lymph node, irregular surface of the fore stomach, a red-brown or tan focus on the clitoral gland, and accentuated lobular pattern of the liver. The incidence of these findings was within the background range of findings that are encountered among rats of this age and strain, did not show a dose-related incidence trend. These necropsy findings were therefore considered to be of no toxicological significance. No macroscopic abnormalities were noted among surviving females at 150 mg/kg/day.  There were no treatment-related microscopic findings. One female at 600 mg/kg had minimal fore stomach inflammation, hyperplasia and hyperkeratosis and slight fore stomach edema. In the absence of any other fore stomach lesions in the animals at this dose level, and considering that this finding sometimes occurs in this type of study, it was not considered to be treatment-related. One female at 350 mg/kg had a mammary gland adenocarcinoma which correlated to the gray-white nodule finding recorded upon macroscopic examination. Although mammary gland adenocarcinoma is a rare finding at this age, mammary gland lesions are one of the most commonly occurring natural neoplastic lesions in this rat strain. As such, this finding was regarded as not treatment-related. All other microscopic findings recorded were considered to be within the normal range of background pathology encountered in Wistar-Han rats of this age and strain. No abnormalities were seen in the reproductive organs of suspected non-fertile animals which could account for infertility and the assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impaired spermatogenesis.

 No toxicologically relevant effects on developmental parameters were observed. The gestation index and duration of gestation were unaffected by treatment. No deficiencies in maternal care were observed. Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No signs of difficult or prolonged parturition were noted among the pregnant females, with the exception of a single female at 150 mg/kg that died during delivery. No cause of death could be established for this female. The number of dead and living pups at first litter check, sex ratio, postnatal loss, viability index, and early postnatal pup development (mortality, clinical signs, body weight and external macroscopy) were unaffected by treatment.  Three pups of the control group, one pup at 150 mg/kg/day, two pups at 350 mg/kg/day and one pup at 600 mg/kg/day were found dead or missing during the first days of lactation. No relationship with treatment was established for these deaths. All pups of the female that died during delivery were found dead, and one early resorption was found. Incidental clinical symptoms of pups consisted of small size and pale appearance. No relationship with treatment was established for these observations and they were considered to be of no toxicological significance. There were no differences in body weights between control and treated pups at any dose level.  Incidental macroscopic findings of pups that survived until their scheduled necropsies included small size, a bent tail and black discoloration of the 5th digit of the hindleg. Incidental macroscopic findings of pups that were found dead at the first litter check or in the days prior to the scheduled necropsy included absence of milk in the stomach and autolysis. No relationship with treatment was established for these findings and they were considered to be of no toxicological significance.

 

 No macroscopic or microscopic abnormalities were seen in the reproductive organs of the test animals indicative of reproductive toxicity of test substance. The assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impaired spermatogenesis. The mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites were unaffected by treatment.No toxicologically relevant effects on developmental parameters were observed. The gestation index and duration of gestation were unaffected by treatment. Overall, no reproductive/developmental toxicity was observed at any dose level. Hence, No Observed Adverse Effect Level (NOAEL) was considered to be 600 mg/kg/day, As it did not cause either parental toxicity nor reproductive or developmental toxicity up to the highest dose tested (600 mg/kg bw/day),When rats were treated

with Tricyclodecanedimethanol(26896-48-0)orally.

 

 It is supported by experimental study conducted by Dr. Paul Kotin and Dr. Hans Falk, NIH, Dr. A. J. Pallotta and Dr. E. Ross Hart, BRL (National Cancer Institute Division of Cancer Cause &Prevention Carcinogenesis Program Bethesda, Maryland, 1968) on structurally similar read across substance Tricyclodecanedimethanol(26896-48-0), In a reproductive toxicity study, B6AKF1 female mice were treated with (4-methoxyphenyl) acetic acid in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6AKF1 female mice by using (4-methoxyphenyl) acetic acid for 18 months.

So, based on the above mentioned studies for target substance 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) and to its read across substance, it was considered that no adverse effects on sexual function and fertility was observed. Therefore, according to CLP criteria, the substance 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) cannot be classified as reproductive toxicant.

 

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

Therefore, according to CLP criteria, the substance 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (4133-34-0) cannot be classified as reproductive toxicant.