1-(6-methoxy-2-naphthyl)ethan-1-one

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.1

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: piloerection, vocalization, pushing the bedding and salivation were recorded

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

other: not specified

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Treatment related:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL,NOEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((("a" or "b" or "c" or "d" or "e" )  and "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl AND Ether AND Fused carbocyclic aromatic AND Ketone AND Naphtalene by Organic functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Ether AND Fused carbocyclic aromatic AND Ketone AND Naphtalene AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as 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 Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Similarity boundary:Target: C(C)(=O)c1cc2c(cc(OC)cc2)cc1
Threshold=50%,
Dice(Atom centered fragments)

Domain logical expression index: "f"

Similarity boundary:Target: C(C)(=O)c1cc2c(cc(OC)cc2)cc1
Threshold=40%,
Dice(Atom centered fragments)

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.05

Conclusions:

The NOAEL for 1-(6-methoxy-2-naphthyl)ethan-1-one was estimated to be 375 mg/kg bw/day (actual dose received) for rats for 53 days , this subacute value when converted to subchronic value is equivalent to 125 mg/kg bw/day (actual dose received) for rats for 90 days duration

Executive summary:

The NOAEL for 1-(6-methoxy-2-naphthyl)ethan-1-one was estimated to be  375 mg/kg bw/day (actual

dose received) for rats for 53days, this subacute value when converted to subchronic value is equivalent to 125 mg/kg bw/day (actual dose received) for rats for 90daysduration using the toolbox version 3.2. The data is estimated to be based on the data summarized below

CAS no.	End point	Value	Species	Doses	Duration	Effects	Remarks
68131-13-5	NOEL	300 mg/kg bw/day (actual dose received)	rat	100, 300, 750 mg/kg bw/day (actual dose received)	53 days	piloerection, vocalization, pushing the bedding and salivation were recorded
99-76-3	NOEL	450 mg/kg bw/day (actual dose received)	rat	40,400,800 mg/kg bw/day (actual dose received)	3 days	no increase in uterus weights or premature vaginal opening

All the values when equalized to 90 days duration by using conversion factor of 3, the values are summarized as follows

CAS no.	End point	Value	Duration
840-65-3	NOEL	100 mg/kg bw/day (actual dose received)	90 days
2216-69-5	NOEL	150 mg/kg bw/day (actual dose received)	90 days

 

Thus the calculated NOEL of analogues for 90 days for the species rat is within the range of 100-150 mg/kg bw/day (actual dose received). Thus the predicted NOEL value is (calculated to be) 125 mg/kg bw/day (actual dose received) with 90 days for rat (harmonized using assessment factors) falls within the domain using Log Kow as the descriptor and justified to be used as NOEL for further DNEL calculation for the purpose of risk assessment. Also it does not impact the classification of the substance thus the predicted value considered to be acceptable.

 

Justified to be used as NOEL for the purpose of weight of evidence

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

125 mg/kg bw/day

Study duration:

subacute

Species:

other: Rat

Quality of whole database:

K2 data obtained from QSAR estimation

Additional information

Based on the various studies available with Klimish rating 2 for target CAS NO 3900-45-6 and for the read across substances based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows

 

Sr. No	End point	Value	Species	Effects	Remarks
1	NOEL (Maternal)	125 mg/Kg bw /d	Rat	piloerection, vocalization, pushing the bedding and salivation were recorded	Predicted data for target chemical
2	NOAEL (Maternal)	238.33 mg/Kg bw /d	Rat	No test substance related adverse effects observed.	Predicted data for target chemical
3	NOAEL male (Maternal)	2 mg/Kg	Rat	No other changes in fertility or reproductive performance were seen	Data from publication for CAS: 22204-53-1
4	NOAEL female (Maternal)	2 mg/Kg	Rat	No other changes in fertility or reproductive performance were seen	Data from publication for CAS: 22204-53-1
5	LOAEL (P)       NOAEL (F1)	30 mg/Kg       15 mg/kg	Rat	increase in number of dead fetuses and resorptions   No visceral or skeletal abnormalities were seen in pups born	Data from publication for CAS: 22204-53-1

 

Based on the studies summarized in the above table it can be observed that NOAEL was found to be in the range of 2 mg/kg -238.33 mg/Kg bw/ d and LOAEL was found to be in 30 mg/kg based on the data from prediction for target as well as publication of read across substance. The predicted NOAEL values is estimated to be 125 mg/Kg bw /d which is well within the range and can be considered for the DNEL calculations. The effects observed on these doses was listed as follows

 

·        piloerection, vocalization, pushing the bedding and salivation were recorded.

·        No test substance related adverse effects observed

·        No other changes in fertility or reproductive performance were seen

·        increase in number of dead fetuses and resorptions

·        No visceral or skeletal abnormalities were seen in pups born 

Thus based on above values it can be concluded that substance CAS NO 3900-45-6 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the no effective dose value (NOAEL) is 2 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 3900-45-6 is considered to be not toxic to reproduction at this dose level .

Justification for selection of Effect on fertility via oral route:

The NOAEL for 1-(6-methoxy-2-naphthyl)ethan-1-one was estimated to be 375 mg/kg bw/day (actual dose received)  for rats for 53 days , this subacute value when converted to subchronic value is equivalent to 125 mg/kg bw/day (actual dose received) for rats  for 90 days duration

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.1

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Duration of treatment / exposure:

90 days

Dose descriptor:

other: not specified

Based on:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Dose descriptor:

LOEL

Effect level:

64.2 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: fetotoxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

The prediction was based on dataset comprised from the following descriptors: NOEL,LOEL
Estimation method: Takes average value from the 5 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 "i" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl AND Ether AND Fused carbocyclic aromatic AND Ketone AND Naphtalene by Organic functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Ether AND Fused carbocyclic aromatic AND Ketone AND Naphtalene AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as 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 Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Similarity boundary:Target: C(C)(=O)c1cc2c(cc(OC)cc2)cc1
Threshold=50%,
Dice(Atom centered fragments)

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.13

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.31

Conclusions:

The LOEL for 1-(6-methoxy-2-naphthyl) ethan-1-one was estimated to be 64.2 mg/kg bw/day for Rattus norvegicus for 90 days

Executive summary:

The LOEL for 1-(6-methoxy-2-naphthyl) ethan-1-one was estimated to be 64.2 mg/kg bw/day for Rattus norvegicus  for 90days, using the toolbox version 3.2. The data is estimated to be based on the data summarized below

CAS no.	End point	Value	Species	Doses	Duration	Effects	Remarks
43121-43-3	LOEL	84.3 mg/kg/day	Rattus norvegicus	-	subchronic	Cleftlip palate
126-07-8	LOEL	617 mg/kg/day	Rat	125, 250, 750, 1250, 1500 mg/kg/day	Gestation day 6-15	effect observed on growth and survival
83-79-4	LOEL	6 mg/kg/day	Rattus norvegicus	-	chronic	fetal weight reduction
50-78-2	LOEL	250 mg/kg/day	rat	-	Gestation day 6-15	Resorption increase

All the values when equalized to 90 days duration by using conversion factor of 3, the values are summarized as follows

CAS no.	End point	Value	Duration
43121-43-3	LOEL	84.3 mg/kg bw/day	90 days
126-07-8	LOEL	205.66 mg/kg bw/day	90 days
83-79-4	LOEL	12 mg/kg bw/day	90 days
50-78-2	LOEL	83.333 mg/kg bw/day	90 days

 

Thus the calculated LOEL of analogues for 90 days for the species rat is within the range of 12-205.66 mg/kg bw/day. Thus the predicted LOEL value is (calculated to be) 96.32 mg/kg bw/day with 90 days for rat (harmonized using assessment factors) falls within the domain using Log Kow as the descriptor and justified to be used as LOEL for further DNEL calculation for the purpose of risk assessment. Also it does not impact the classification of the substance thus the predicted value considered to be acceptable.

 

Justified to be used as LOEL for the purpose of weight of evidence

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

62.4 mg/kg bw/day

Study duration:

subacute

Species:

other: Rattus norvegicus

Quality of whole database:

K2 data obtained from QSAR estimation

Additional information

Based on the various studies available with Klimish rating 2 for the read across substances for CAS NO 3900-45-6 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows

Sr. No	End point	Value	Species	Route	Effects	Remarks
1	LOEL	64.2mg/ kg bw/ d	Rattus norvegicus	Oral	Cleftlip palate	Predicted data for target chemical
2	NOAEL teratogenicity	2 mg/kg	Rabbit	oral	No visceral or skeletal abnormalities were seen in pups born	Data from publication for CAS: 22204-53-1
3	NOAEL teratogenicity	15 mg/kg	Rabbit	oral	No visceral or skeletal abnormalities were seen	Data from publication for CAS: 22204-53-1
4	NOAEL teratogenicity	2 mg/kg	Rabbit	oral	No stilborn observed, no malformation observed in fetus	Data from publication for CAS: 22204-53-1

 

Based on the studies summarized in the above table with oral routes it can be observed that a NOAEL value was found to be in the range of 2 - 15 mg/Kg and the LOEL values is 64.2 mg/kg bw/day. The effects observed on these doses was listed as follows

 

·        Cleftlip palate.

 

·        No visceral or skeletal abnormalities were seen in pups born

 

·         No visceral or skeletal abnormalities were seen

 

·        No stilborn observed, no malformation observed in fetus

 

Thus based on above discussion it can be concluded that substance CAS NO 3900-45-6 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the no effective dose value (NOAEL) is 2 mg/Kg thus based on this value it can be concluded that substance CAS NO 3900-45-6 is considered to be not toxic to developmental effects for the above mentioned dose. Also CAS NO 3900-45-6 does not indicates any mechanistic trigger towards the toxicity based on absence of noncyclic structure that would raise concern of CAS NO 3900-45-6 on toxicity to human reproduction & developmental effects. Thus CAS NO 3900-45-6 is considered to be not toxic to reproductive & developmental effects for the above mentioned dose levels.

Justification for selection of Effect on developmental toxicity: via oral route:

The LOEL for 1-(6-methoxy-2-naphthyl) ethan-1-one was estimated to be 64.2 mg/kg bw/day for  Rattus norvegicus   for 90 days

Justification for classification or non-classification

Based on the above studies and and criteria of classifiction mentioned in new CLP regulation it can be concluded that 1-(6-methoxy-2-naphthyl) ethan-1-one is not reprotoxic or fetotoxic substance.

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