Registration Dossier

Administrative data

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:
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.