4'-cyanoacetophenone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL was estimated to be 947 mg/kg bw when rats were orally exposed with 4'-Cyanoacetophenone.

Thus, as per criteria of CLP regulation, 4'-Cyanoacetophenone can be Not classified 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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: 4'-Cyanoacetophenone
InChI:1S/C9H7NO/c1-7(11)9-4-2-8(6-10)3-5-9/h2-5H,1H3
SMILES:CC(=O)c1ccc(C#N)cc1
Molecular Formula: C9H7NO
Molecular Weight: 145.16 g/mole

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Remarks on MMAD:

not specified

Vehicle:

polyethylene glycol

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

46 days

Frequency of treatment:

Daily

Dose / conc.:

947 mg/kg bw/day

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

not specified

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

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 specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

947 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect observed

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:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

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:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: 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 8 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aromatic compound OR Carbonyl compound OR Ketone OR Nitrile by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acetylenic Carbon [#C] OR Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aromatic Carbon [C] OR Carbonyl, aliphatic attach [-C(=O)-] OR Carbonyl, olefinic attach [-C(=O)-] OR Carbonyl, one aromatic attach [-C(=O)-] OR Cyano, aromatic attach [-C#N] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Ketone OR Nitrile OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aryl OR Ketone OR Nitrile by Organic Functional groups ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Quinones OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon 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 >> Polycyclic Aromatic Hydrocarbon Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 ketones by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Alkyl and vinyl nitriles< C6 atoms- sub category 25 (c, d) OR Inorganic chemical OR Known precedent reproductive and developmental toxic potential OR Metal atoms were identified OR Not covered by current version of the decision tree by DART scheme v.1.0

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert by Repeated dose (HESS)

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 amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonyl compound AND Ketone AND Nitrile by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonyl compound AND Ketone AND Nitrile by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Acetylenic Carbon [#C] AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Carbonyl, olefinic attach [-C(=O)-] AND Carbonyl, one aromatic attach [-C(=O)-] AND Cyano, aromatic attach [-C#N] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.306

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.76

Conclusions:

The NOAEL was estimated to be 947 mg/kg bw when rats were orally exposed with 4'-Cyanoacetophenone.

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 for 4'-Cyanoacetophenone. The NOAEL was estimated to be 947 mg/kg bw when rats were orally exposed with 4'-Cyanoacetophenone.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

947 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimsch 2 and from OECD QSAR toolbox

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, 4'-Cyanoacetophenone has been investigated for reproductive toxicity to a greater or lesser extent. Studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 4'-Cyanoacetophenone along with the study available on structurally similar read across substance Cyclohexene (CAS no 110-83-8), 1,2,3-Benzotriazole (CAS no 95-14-7) and Acetophenone (CAS no 98-86-2). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 4'-Cyanoacetophenone. The NOAEL was estimated to be 947 mg/kg bw when rats were orally exposed with 4'-Cyanoacetophenone.

In another experimental study conducted by  Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation (J-CHECK, 2010) on structurally similar read across substance Cyclohexene (CAS no 110-83-8), Crj:CD(SD)IGS male and female rats were treated with Cyclohexenein the concentration of 0, 50, 150 and 500 mg/kg/day orally by gavage in corn oil for 48 consecutive days in male and 53 days in female respectively as per OECD 422. Nasal secretions in 2 cases, loose stools in 1 cases of male and depilation and crusts in 2 cases were observed at 50 mg/kg bw, salivation in 3 cases, nasal secretions in 1 cases, loose stools in 2 cases, crust 1 cases in male rats at 150 mg/kg bw. Most salivation observed was a transient change from immediately after administration to about 5 minutes after administration. In female rats, salivation in 2 cases, lacrimation before mating, mating, pregnancy and nursing period, depilation and crusts in 2 cases were observed at 150 mg/kg bw. Salivation was a transient change from immediately after administration to about 5 minutes after administration in the 150 mg / kg group. Salivation in 12 cases, lacrimation in 2 cases, loose stools in 2 cases, crust in 4 cases, trauma 1 case in male at 500 mg/kg bw and salivation in continued from 30 to 60 minutes after administration. In female, lacrimation in all 12 cases, nasal secretions and ocular secretion in 1 case, depilation and crusts in 2 cases were observed. Several animals continuing up to 6 hours after administration were also observed at 500 mg/kg bw. A dead case was males in the 50 mg / kg group and one case was observed on the 33th day. However, this animal was accidental death that was mistakenly caught in a breeding cage and died, and it was not related to administration of the test substance. No significant change in body weight was observed in treated rats as compared to control. In male rat, significant increase in food consumption were observed during the administration of 43 to 48 days at 500 mg/kg bw, but it was a slight change and was not judged as the influence of administration of the test substance. There was no difference in the cumulative food consumption between 1 and 15 days after administration and the control group in any of the test substance administration groups. In females, no significant difference was observed between the control group and the test substance administered group. In male rats, significant increase in reticulocyte rate, significantly shorter in activated partial thromboplastin time in the blood clotting ability was observed at 500 mg/kg. In female, significant increase in large unstained cell ratio and significantly prolonged prothrombin time were observed at 500 mg/kg, but it was a minor change and was not judged as the influence of administration of the test substance. No changes were observed at 50 and 150 mg/kg bw treated male and female rats as compared to control. In males, increase in A / G ratios and total bile acids level at 500 mg/kg, but not significant as compared to control. Low neutral fat Value were observed. Total bilirubin level was significantly increased at 500 mg/kg but, it was a minor change and was not judged as the influence of administration of the test substance. In female rats, significant decrease in ALT value was observed at 500 mg/kg. Significant increase in total bile acids value although there was no significant or statistically significant difference in all test substance administered groups. Slight Yellow urine were observed in 3, 2, 1 and 0 cases in the control group, 50, 150 and 500 mg / kg group, respectively. No significant differences were found between the control group and the test substance-administered group in other treated groups. Similarly, no significant effect on reproductive parameters of treated rats were observed as compared to control such as estrous cycle, copulation index, fertility index, gestation length, numbers of corpora lutea or implantations, implantation index, gestation index, delivery index, purturition or maternal behavior, numbers of offspring or live offspring, the sex ratio and live birth index. Scar of the liver and red spots of the brain of dead were observed at 50 mg / kg in male rat. No gross pathological and histopathological changes were observed in P treated male and female rats as compared to control. In addition, No effect on 4-day survival rate and body weight of treated pups were observed as compared to control. When treated with 150 mg/kg bw, pelvic dilation were observed in one male pup during the nursing period. At necropsy on 4th day of nursing, thymus neck residues were 1 in 150 males and 500 mg / kg male group, 1 in each case in liver white spots of 500 males and 50 mg / kg females, 1 kidney 4, 3, 2 and 1 cases respectively in the 4, 3 and 1 cases, 50, 150 and 500 mg / kg group in the 50, 150 and 500 mg / kg male groups, respectively. Tubular expansion was 1, 3, 5 and 4 cases respectively in 4, 3 and 1 cases, 50, 150 and 500 mg / kg group in males, control group in females, 50, 150 and 500 mg / kg group, respectively Crust was found in 150 mg / kg group of male and female, respectively 3 cases, gangrene of the tail was 1 in case of female in control group, 1 case in female with mucosa, ankle and liver whitening in 500 mg / kg group and skin Crust was observed in one case in a 500 mg / kg group males of F1. Therefore, No adverse effect level (NOAEL) was considered to be 5.1 mg/kg for males and 5.7 mg/kg for females when FDRL male and female rats were treated with Beta-Naphthyl ethyl ether orally in feed for 90 days. No adverse effect level(NOAEL) was considered to be 500 mg/kg for P and F1 generation when Crj:CD(SD)IGS male and female rats were treated with Cyclohexene orally by gavage for 48 consecutive days in male and 53 days in female respectively.

Further supported by experimental study conducted by  Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation (J-CHECK, 2010) on structurally similar read across substance 1,2,3-Benzotriazole (CAS no 95-14-7), Crj:CD (SD) male and female rats were treated with 1,2,3-Benzotriazole in the concentration of 0 (vehicle), 0, 30, 100, 300 mg/kg/day orally by gavage for male 42 days and for female 42 – 45 days (from 14 days before mating to day 4 of lactation). Soil of perigenitalia were observed in male and female rats and loss of fur was observed in the female rats, Reduced body weight and food consumption were observed in the females during the pregnant and lactation periods and no effect on male rats were observed at 300 mg/kg/day. No changes in reflex/reaction, grip strength and locomotor activity were observed in any dosed group of male and female rats. No abnormal changes were observed in urinalysis of treated male and female rats. Similarly, increased MCV and decreased MCHC in male rats and increased MCV continued until the end of the recovery period at 300 mg/kg bw and In female rats, No significant change in hematological parameters was observed in any dosed females at the end of the administration period, while the levels of MCV and MCH in the recovery females at 300 mg/kg were increased as compared to recovery control. Increase in Plasma levels of AST, ALT, A/G ratio and potassium and decrease in level of total protein were observed in male rats and increase in ALT and phospholipid levels of female rats were observed at 300 mg/kg bw. In addition, no reproductive toxic effect were observed in treated male and female rats such as estrous cycle, copulation, fertility, delivery and lactation of treated rats were observed as compared to control. Increase in relative liver weight were observed in female rats at 300 mg/kg bw. No effect were observed in male rats at 30, 100, 300 mg/kg/day. Kidney lesion characterized by regeneration of proximal tubules was observed in the females rat at 100 mg/kg bw. These pathological findings were not observed in the satellite females given 300 mg/kg. No changes were observed in male rats as compared to control. No effect on viability of pups on day of lactation and clinical sign were observed in pups as compared to control. Decrease in body weight were observed in male and female pups on days 0 and 4 of lactation at 300 mg/kg bw. No external abnormalities or macroscopic findings were observed in any pup as compared to control. Therefore, NOAEL was considered to be 300 mg/kg/day for P and F1 generation when Crj:CD (SD) male and female rats treated with 1,2,3-Benzotriazole orally by gavage for 42 days.

Again supported by experimental study summarized by Flavor and Extract Manufacturers' Association of the United States (Flavor and Extract Manufacturers' Association of the United States, Volume I, October 1978) on structurally similar read across substance Acetophenone (CAS no 98-86-2), Shermanmale and female rats were treated withacetophenonein the concentration of0, 1.2 to 102 mg/kg bw (intermediate doses not specified) orally bygavagefor 30 days. No clinical sign and change in body weight were observed in treated male and female arts. In addition, No histopathological liver, kidney, spleen or testis of any rat as compared to control. Therefore, NOAEL was considered to be 102 mg/kg/day for P generation whenShermanmale rats treated withacetophenoneorally bygavage for 30 days.

Thus, based on the above studies and predictions on 4'-Cyanoacetophenone and its read across substances, it can be concluded that NOAEL value is 947 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide can be Not classified 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

Based on the above studies and predictions on 4'-Cyanoacetophenone and its read across substances, it can be concluded that NOAEL value is 947 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide can be Not classified for reproductive toxicity.