3-diethylaminophenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

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 adequate and reliable documentation / justification

Justification for type of information:

QSAR report is attached. prediction is done using OECD QSAR toolbox

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:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

Exposure period: 27 w

Premating exposure period (males): 10 weeks

Premating exposure period (females): 10 weeks

Frequency of treatment:

once per day , 5 d/w
F1 generation producing F2: once per day, 7 days per week

No. of animals per sex per dose:

25 animals/sex/group

Reproductive function: oestrous cycle:

not specified

Dose descriptor:

NOAEL

Effect level:

398 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no treatement related effects were observed

Remarks on result:

other: No adverse effect

Relevant for humans:

not specified

Remarks on result:

not measured/tested

Reproductive effects observed:

no

Relevant for humans:

not specified

Conclusions:

The NOAEL value for 3-diethylaminophenol is estimated to be 199 mg/kg bw/day for rat in 37 weeks , this chronic value when converted to subchronic value using same species is equivalent to 398 mg/kg bw/day

Executive summary:

The NOAEL for 3-diethylaminophenol is estimated to be 199mg/kg bw/dayfor rat in37 weeks, this chronic value when converted to subchronic value using same species is equivalent to 398mg/kg bw/day 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
95-48-7	NOAEL	218 mg/kg bw/day	Rat	0, 30, 175, 450mg/kg/day	37 weeks	There were no treatment related reproductive effects obseved
106-44-5	NOAEL	218 mg/kg bw/day	Rat	0, 30, 175, 450mg/kg/day	29 weeks	No reproductive parameters were affected in either of the two generations
108-39-4	NOAEL	218 mg/kg bw/day	Rat	0, 30, 175, 450mg/kg/day	29 weeks	Effects on reproduction function or on morphology of reproductive tissues were not detected
89-83-8	NOEL	200 mg/kg bw/day	Rat	0 , 8, 40, 200mg/kg/day actual ingested	males: 43 days females: from 14 days before mating to day 3 of lactation	marginaly reduced birth weight at 200 mg/kg bw was related to higher litter size
123-31-9	NOAEL	141 mg/kg bw/day	Rat	0, 15, 50 and 150 mg/kg bw/d nominal conc.	chronic	no adverse reproductive effects observed
88-60-8	NOAEL	12.5 mg/kg bw/day	Rat	0, 2.5, 12.5, 60 mg/kg/day nominal conc	Male: for 42 days; Female: for 40-48 days from 14 days prior to mating to the 3 day of lactation	No adverse effect on maternal toxicity

 

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	Species	Duration
95-48-7	NOAEL	436 mg/kg bw/day	Rat	90 days
106-44-5	NOAEL	436 mg/kg bw /day	Rat	90 days
108-39-4	NOAEL	436 mg/kg bw/day	Rat	90 days
89-83-8	NOEL	66.66 mg/kg bw /dayactual ingested	Rat	90 days
123-31-9	NOAEL	282 mg/kg bw /day nominal conc	Rat	90 days
88-60-8	NOAEL	4.16 mg/kg bw /day nominal conc	Rat	90 days

 

Thus the calculated NOEL of analogues for 90 days for the species rat is within the range of 4.16-436 mg/kg bw /day. Thus the predicted NOEL value is (calculated to be)276.803mg/kg bw/d 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

398 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K2 data from QSAR model considered relaible by OECD

Additional information

Toxicity to Reproduction :

Based on the various studies available with Klimish rating 2 for target CAS NO 91-68-9 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	Route	effects	remarks
1	NOAEL	398 mg/ kg bw/ d	Rat	Oral	There were no treatment related reproductive effects obseved	Predicted data for target chemical
2	NOAEL	500 mg/kg bw/day	Rat	oral	No adverse effect observed	Data from publication for CAS: 108-46-3
3	LOAEL	50000 mg	Human	Oral	unconsciousness, drowsiness, and respiratory failure that required mechanical ventilation along with tonic-clonic seizures and hypothermia. In addition, the laboratory findings were leucocytosis, high bilirubin levels, severe metabolic acidosis, and green-colored urine.	Data from publication for CAS: 108-46-3

 

 

Based on the studies summarized in the above table it can be observed that NOAEL values was found to be in the range of 398 -500 mg/Kg bw/ d and LOAEL was found to be 50000 mg based on the data from prediction for target as well as publication of read across substance. The predicted NOAEL values is estimated to be 398 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

 

·        There were no treatment related reproductive effects obseved.

·        No adverse effect observed

·        unconsciousness, drowsiness, and respiratory failure that required mechanical ventilation along with tonic-clonic seizures and hypothermia. In addition, the laboratory findings were leucocytosis, high bilirubin levels, severe metabolic acidosis, and green-colored urine.

Thus based on above values it can be concluded that substance CAS NO 91-68-9 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 398 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 91-68-9 is considered to be not toxic to reproduction at this dose level .

Also CAS NO 91-68-9 does not indicates any mechanistic trigger towards the toxicity to reproduction based on absence of noncyclic structure that would raise concern of CAS NO 91-68-9 on toxicity to human reproduction. Thus CAS NO 91-68-9 is considered to be not toxic to reproductive effects for the above mentioned dose levels.

Short description of key information:

The substance 3-diethylaminophenol  was not found to be reproductive toxicant.

Justification for selection of Effect on fertility via oral route:

The NOAEL value for 3-diethylaminophenol is estimated to be 199 mg/kg bw/day for rat in 37 weeks , this chronic value when converted to subchronic value using same species is equivalent to 398 mg/kg bw/day  

Effects on developmental toxicity

Description of key information

The substance 3-diethylaminophenol  was not found to be developmental toxicant.

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:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Dose descriptor:

NOAEL

Effect level:

44 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not measured/tested

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

The NOAEL for 3-diethylaminophenol is estimated to be 132 mg/kg bw/day for rat in 10 days , this subacute value when converted to subchronic value using same species is equivalent to 44 mg/kg bw/day

Executive summary:

The NOAEL for 3-diethylaminophenol is estimated to be132mg/kg bw/dayfor rat in10 days, this subacute value when converted to subchronic value using same species is equivalent to 44mg/kg bw/day 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
95-48-7	NOAEL	101mg/kg bw/day	Rat	0, 30, 175, 450mg/kg/day	37 weeks	There were no treatment related developmental effects observed
106-44-5	NOAEL	114 mg/kg bw/day	Rat	0, 30, 175, 450mg/kg/day	Day 6-15 of gestation	No developmental effects observed
108-39-4	NOAEL	155mg/kg bw/day	Rat	0, 30, 175, 450mg/kg/day	Day 6-15 of gestation	No fetotoxicityor malformations observed
108-95-2	NOAEL	90.0 mg/kg bw/day	Rats	0, 60, 120, 360 mg/kg bw/day	Day 6-15 of gestation	no effects observed on fetal development
89-83-8	NOEL	200 mg/kg bw/day	Rat	0 , 8, 40, 200mg/kg/day actual ingested	males: 43 days females: from 14 days before mating to day 3 of lactation	No developmental effects observed
123-31-9	NOEL	75.0 mg/kg bw/day	Rabbit	0, 25, 75 or 150 mg/kg bwnominal conc.	gestation days 6 - 18	no developmental alteration observed
108-46-3	NOAEL	277mg/kg bw/day	Rat	0,125, 250, 500 mg/kg bw	6-15 days of gestation	No embryotoxic, fetotoxic or teratogenic effects observed

 

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	Species	Duration
95-48-7	NOAEL	202 mg/kg bw/day	Rat	90 days
106-44-5	NOAEL	38 mg/kg bw /day	Rat	90 days
108-39-4	NOAEL	51.66 mg/kg bw/day	Rat	90 days
108-95-2	NOEL	30 mg/kg bw /day actual ingested	Rat	90 days
89-83-8	NOAEL	66.66 mg/kg bw /day nominal conc	Rat	90 days
123-31-9	NOEL	15 mg/kg bw /day nominal conc	Rat	90 days
108-46-3	NOAEL	92.333mg/kg bw /day	Rat	90 days

 

Thus the calculated NOEL of analogues for 90 days for the species rat is within the range of 15-202 mg/kg bw /day. Thus the predicted NOEL value is (calculated to be)70.807mg/kg bw/d 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 developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

44 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K2 data from QSAR model considered relaible by OECD.

Additional information

Developmental toxicity / teratogenicity :

Based on the various studies available with Klimish rating 2 for the read across substances for CAS NO 91-68-9 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	NOAEL	44 mg/ kg bw/ d	Rat	Oral	There were no treatment related reproductive effects obseved	Predicted data for target chemical
2	NOAEL	500 mg/kg bw/day	Rat	oral	No embryotoxic, fetotoxic or teratogenic effects were observed	Data from publication for CAS: 108-46-3
3	LOAEL	50000 mg	Human	Oral	The fetus was considered dead 24 h after delivery	Data from publication for CAS: 108-46-3

 

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 44 - 500 mg/Kg bw/ d and the LOAEL values is 50000 mg. The effects observed on these doses was listed as follows

 

·        There were no treatment related reproductive effects obseved.

 

·        No embryotoxic, fetotoxic or teratogenic effects were observed

 

·         The fetus was considered dead 24 h after delivery

 

Thus based on above discussion it can be concluded that substance CAS NO 91-68-9 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 44 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 91-68-9 is considered to be not toxic to maternal toxicity as well as developmental effects for the above mentioned dose. Also CAS NO 91-68-9 does not indicates any mechanistic trigger towards the toxicity based on absence of noncyclic structure that would raise concern of CAS NO 91-68-9 on toxicity to human reproduction & developmental effects. Thus CAS NO 91-68-9 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 NOAEL for 3-diethylaminophenol  is estimated to be 132 mg/kg bw/day for rat in 10 days , this subacute value when converted to subchronic value using same species is equivalent to  44 mg/kg bw/day

Justification for classification or non-classification

Based on the above studies it can be concluded that the substance 3 -diethylaminophenol is not as reproductive and developmental toxicant.