5-nitrovanillin

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive 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)

Guideline:

other: OECD Guideline 415 (One-Generation Reproduction Toxicity Study);OECD Guideline 452 (Chronic Toxicity Studies);OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test);OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Principles of method if other than guideline:

Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor

GLP compliance:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: unspecified

Duration of treatment / exposure:

Subchronic

Control animals:

not specified

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Dose descriptor:

NOAEL

Effect level:

23.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects were observed

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

Remarks on result:

not measured/tested

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: NOEL,"NOAEL reproductive toxicity","NOAEL (single application)",NOAEL
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 Aldehydes (Acute toxicity) AND Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aldehydes (Mono) AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism by ROS formation AND Radical >> Radical mechanism by ROS formation >> Nitro Compounds AND SN1 AND SN1 >> Nitrenium ion formation AND SN1 >> Nitrenium ion formation >> Nitro Compounds by DNA binding by OASIS v.1.1

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation AND Schiff base formation >> Schiff base formation with carbonyl compounds AND Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes by Protein binding by OASIS v1.1

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Nitrophenols/ Halophenols (Energy metabolism dysfuntion) Rank B by Repeated dose (HESS)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.927

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.14

Conclusions:

The NOAEL value of 5-Nitrovanillin on rat was found to be 23.3 mg/kg bw/day (nominal) for Subchronic duration.

Executive summary:

WoE Summary for Cas:6635-20-7

 

The NOAEL value of 5-Nitrovanillin is estimated to be 47.3 mg/kg bw/day (nominal) for sub acute duration on rat (23.3mg/kg bw/day (nominal) for 90 days) using the toolbox .

The data is estimated to be based on the data summarized below

Sr no.	CAS no	End point	Value	Species	Doses	Duration	Effects	Remarks
1	1671-49-4	NOAEL	15 mg/kg bw/day (nominal)	Rat	0 (control), 2, 15, 100 mg/kg/day	10 weeks	no effects were observed
2	119313-12-1	NOAEL reproductive toxicity	79.6mg/kg bw/day (nominal))	Dog	0.57, 3.9, 35 mg/kg bw/d	chronic	No effects on body weight; food consumption and compound intake organ weights; histopathology

 

The above table consist of various reproductive toxicity studies available for the read across substances for CAS: 6635-20-7.Based on the above results it can be observed that NOAEL values are in the range of 15 – 79.6 mg/kg bw/day(nominal) the no effects observed on the above doses are listed as follows.

 

·        body weight; food consumption and compound intake organ weights; histopathology

Thus based on above discussion it can be concluded that estimated value 47.3 mg/kg/day(actual dose recived) (23.3mg/kg bw/day (nominal) for 90 days)) for the substance (CAS: 6635-20-7) and it is close to the 15 mg/kg bw/day (nominal).

 

CAS no	End point	Value	Species	Duaration
1671-49-4	NOAEL	7.5 mg/kg bw/day (nominal)	Rat	90 days
25321-14-6	NOAEl	55.7mg/kg bw/day (nominal)	Rat	90 days

 

 

 

 

 

Thus the calculated NOAEL of analogues for 90 days for the species rat is within the range of 7.5 – 55.6 mg/kg bw /day(nominal). Thus the predicted NOAEL value is (calculated to be) 31.6 mg/kg/day(nominal) 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 NOAEL 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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

23.3 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Model considered reliable by OECD.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

WoE Summary of 6635-20-7 for toxicity to reproduction 

Based on the various studies available with Klimish rating 2 for the target as well as read across substances for CAS: 6635-20-7. The results is summarized as follows:

Sr. No	End point	Value	Species	Route	Effects	Remarks
1	NOAEL	23.3 mg/kg bw/day(nominal)	Male/female Rat	Oral	No effects were observed.	Predicted data forCAS: 6635-20-7
2	NOAEL	>50 mg/kg bw/day	Male /Female mouse	intraperitonial	No effects on number of live fetuses, fetal body weight,fetal mortality and incidence of external and skeletal abnormalities.	Data from publication for RA CAS: 121-33-5

 

Based on the studies summarized with various routes in the above table it can be observed that NOAEL values is found to be in the range of 23.3- 50 mg/Kg bw/ d .The no effects observed on the higher doses was listed as follows:

·         Effects on number of live fetuses, fetal body weight, fetal mortality and incidence of external and skeletal abnormalities.

Thus based on above discussion it can be concluded that substance CAS: 6635-20-7 has no observed adversed effect value (NOAEL) as 23.3 mg/kg bw/d via oral route .thus based on these values it is considered that CAS: 6635-230-7 does not have any reproductive toxic effect below the mentioned dose levels Also there are no known evidence of adverse effect on reproduction to Human of CAS: 6635-20-7.

Justification for selection of Effect on fertility via oral route:

. The no observed adversed effect level (NOAEL) in Rat  male/female; as predicted by the QSAR model was found to be 23.3 mg/kg/day(nominal) for a 90 days exposure period

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)

Guideline:

other: Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor

Principles of method if other than guideline:

Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor

GLP compliance:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: unspecified

Duration of treatment / exposure:

Subchronic

Dose descriptor:

NOEL

Effect level:

85 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Dose descriptor:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

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

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

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" )  and ("j" and "k" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aldehydes (Mono) AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism by ROS formation AND Radical >> Radical mechanism by ROS formation >> Nitro Compounds AND SN1 AND SN1 >> Nitrenium ion formation AND SN1 >> Nitrenium ion formation >> Nitro Compounds by DNA binding by OASIS v.1.1

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation AND Schiff base formation >> Schiff base formation with carbonyl compounds AND Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes by Protein binding by OASIS v1.1

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Nitrophenols/ Halophenols (Energy metabolism dysfuntion) Rank B by Repeated dose (HESS)

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Di-substituted alpha, beta-unsaturated aldehydes OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> Thiophosphates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives

Domain logical expression index: "i"

Similarity boundary:Target: c1(OC)c(O)c(N(=O)=O)cc(C=O)c1
Threshold=40%,
Dice(Atom centered fragments)

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.55

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.64

Conclusions:

The NOEL no observed effect level of 5-Nitrovanilin on rat was predicted to be 85 mg/kg bw/day for 90 days

Executive summary:

WoE Summary for Cas: 6635-20-7

 

The NOEL value of 5,nitrovanillain isestimated to be 255 mg/kg bw/day for sub-acute duration (85 mg/kg bw/day for 90 days) of rat using the toolbox version 3.2.

The data is estimated to be based on the data summarized below

Sr no.	CAS no	End point	Value	Species	Doses	Duration	Effects	Remarks
1	6358-09-4	NOEL	350 mg/kg bw/day	Rat	6,87.5,175,350 mg/kg/day	15 days	-no effects
2	5307-14-2	NOEL	160 mg/kg/day	Mouse	17,64,32,128,160 mg/kg/day	14 days	no adverse effects

The above table consist of various developmental toxicity studies available for the read across substances for CAS: 6635-20-7.Based on the above results it can be observed that NOEL values are in the range of 160 – 350 mg/kg bw./day for rat . The no effects observed on the above doses .

Thus based on above discussion it can be concluded that toxicity of the target chemical 255 mg/kg bw/day (85 mg/kg bw/day for 90 days) is predicted from category members using read-across based on above values and it is close to ( 350 mg/kg/day) for sub-acute duration of rat from nearest neighbors compared by prediction descriptors.

 

Sr no.	CAS no	End point	Value	Species	Duration	Remarks
1	6358-09-4	NOEL	116 mg/kg bw/day	Rat	90 days
2	5307-14-2	NOEL	93.27 mg/kg/day	Rat	90 days

 

Thus the calculated NOEL of analogues for 90 days for the species rat is within the range of 93 .27 – 116 mg/kg bw /day. Thus the predicted NOEL value is (calculated to be)104 .6mg/kg bw/dwith 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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

85 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Model considered realiable by OECD

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

WoE Summary of 6635 -20 -7 for developmental toxicity

Based on the various studies available with Klimish rating 2 & 4 for the target as well as for read across cas. The results is summarized as follows

Sr.No	Endpoint	Effect Type	Effect values	Species	Route of Administration	Effects	Sources
1	NOEL	Developmental toxicity	85 mg/kg bw/day	Rat	Oral	No effects were observed	Predicted data for target Cas :6635-20-7
2	NOAEL                     NOEL	Maternal toxicity                     teratogenicity	250 mg/kgbw/day                   500 mg/kgbw/day	Rat	Oral	only effects reported with only few details: death, clinical signs and change in body weight and feed consumption     no adverse effects were observed	Experimental data for RA Cas:121-33-5
3	NOAEL	Developmental toxicity	>50 mg/kg bw/day	mouse	Oral	No effects were observed	Experimental data for RA Cas:121-33-5
3	no NOAEL identified	Teratogenicty	Negative effects	chicken embryo	Through injection	No teratogenic effects observed	Experimental data for RA Cas:121-33-5

 

Based on the studies summarized in the above table with oral route it can be observed that the NOEL & NOAEL values varies from 50-500mg/Kg bw/ d. The no effects observed on the these doses was listed as follows

·        only effects reported with only few details: death, clinical signs and change in body weight and feed consumption

 

Thus based on above discussion it can be concluded that substance CAS: 6635-20-7 has no effective dose value (NOEL) as 85 mg/kg bw/day thus based on this value it can be concluded that substance CAS: 6635-20-7 is considered to be not toxic to Developmental toxicity as well as developmental effects below the above mentioned dose. Also there are no known evidence of adverse effect on reproduction to Human of CAS: 6635-20-7.

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

The NOEL no observed effect level of 5-Nitrovanilin on rat was predicted to be 85 mg/kg bw/day for 90 days

Justification for classification or non-classification

In the absence of available studies pertaining to the reproduction toxicity and developmental toxicity, the predicted values do not suggest 5 -nitrovanillin to be a reproductive and developmental toxicant