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Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: Combined repeated dose & carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
Combined repeated dose & carcinogenicity study on rats is presented
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)

- Age at study initiation: (P) x wks; (F1) x wks :
5 to 6 weeks

- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g : No data available

- Fasting period before study: No data available

- Housing: Animal were housed in Polycarbonate (Lab Products, Inc., Seaford, DE), changed weekly (male rat) or twice weekly, bedded on irradiated Sani-Chips (P.J. Murphy Forest Products Corp., Montville, NY), changed weekly (male rat) or twice weekly. Spun-bonded polyester. Cage Filters (Snow Filtration Co., Cincinnati, OH) were changed every 2 weeks and Stainless steel Racks (Lab Products, Seaford, DE) changed and rotated every 2 weeks and animals were identified by tail tattoo in a controlled environment.

- Diet (e.g. ad libitum): Irradiated NTP-2000 wafer feed (Zeigler Brothers, Inc., Gardners, PA), changed weekly, available ad libitum.

- Water (e.g. ad libitum): Tap water (Columbus municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum.

- Acclimation period: 11 days for males and 12 days for females

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2° ± 3° C

- Humidity (%):50% ± 15%

- Air changes (per hr): 10/hour

- Photoperiod (hrs dark / hrs light): Room fluorescent light were available for 12 hours/day
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dose preperation were prepared by adding the appropriate amount of N, N-dimethyl-p-toluidine to 2.5 ml of corn oil to achieve the desired concentration of 0, 62.5, 125, 250, 500, and 1,000 mg/kg.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available

- Mixing appropriate amounts with (Type of food): No data available

- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available

- Concentration in vehicle: 0, 62.5, 125, 250, 500, and 1,000 mg/kg/bw/day

- Amount of vehicle (if gavage): 2.5 ml of corn oil.

- Lot/batch no. (if required): H3124A, Obtained in multiple lots from Spectrum Chemicals and Laboratory Products (Gardena, CA).

- Purity: No data available
Details on mating procedure:
no data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Periodic analyses of the dose formulations were con-ducted by the study laboratory using GC/FID. During the 3-month studies, the dose formulations were ana-lyzed at the beginning, midpoint, and end of the studies; animal room samples of these dose formulations were also analyzed. Of the dose formulations analyzed and used, all 13 for rats were within 10% of the target concentrations; all 13 animal room samples for rats were within 10% of the target concentrations.
Duration of treatment / exposure:
14 weeks (3 month)
Frequency of treatment:
5 days/week
Details on study schedule:
Details on study schedule
- F1 parental animals not mated until [...] weeks after selected from the F1 litters.: No data available

- Selection of parents from F1 generation when pups were [...] days of age.: No data available

- Age at mating of the mated animals in the study: [...] weeks : No data available
Remarks:
Doses / Concentrations:
0, 62.5, 125, 250, 500, and 1,000 mg/kg/bw/day
Basis:
no data
No. of animals per sex per dose:
Total: 140
Control: 10 male,10 female
62.5 mg/kg: 10 male,10 female
125 mg/kg: 10 male,10 female
250 mg/kg: 10 male,10 female
500 mg/kg: 10 male,10 female
1000 mg/kg: 10 male,10 female
Clinical pathology study: 10 male and 10 female rats
Control animals:
yes, concurrent vehicle
Details on study design:
Details on study design
- Dose selection rationale: The doses for the N,N-dimethyl-p-toluidine 3-month studies were selected based on these LD50 values to deliver 0, 62.5, 125, 250, 500, and 1,000 mg/kg in rats
- Rationale for animal assignment (if not random): Animals were distributed randomly into groups of approximately equal initial mean body weights.

Parental animals: Observations and examinations:
Following parameters were examined in parental animal:

- Body weight (On initially, on the first Friday after dosing started, weekly thereafter, and at the end of the studies.)

-Clinical sign (On initially, on the first Friday after dosing started, weekly thereafter, and at the end of the studies.)
Oestrous cyclicity (parental animals):
At the end of the 3-month studies, samples were collected for vaginal cytology evaluations on core study mice administered 0, 15, 30, or 60 mg/kg For 12 consecutive days prior to scheduled terminal kill, the vaginal vaults of the females were moistened with saline, if necessary, and samples of vaginal fluid and cells were stained. Relative numbers of leukocytes, nucleated epithelial cells, and large squamous epithelial cells were determined and used to ascer-tain estrous cycle stage (i.e., diestrus, proestrus, estrus, and metestrus).
Sperm parameters (parental animals):
At the end of the 3-month studies, samples were collected for sperm motility evaluations on core study mice administered 0, 15, 30, or 60 mg/kg For 12 consecutive days prior to scheduled terminal kill. Male animals were evaluated for sperm count and motility. The left testis and left epididymis were isolated and weighed. The tail of the epididymis (cauda epididymis) was then removed from the epi-didymal body (corpus epididymis) and weighed.
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
Survival Analyses:Analysis of survival was estimated by the product-limit procedure of Kaplan and Meier.Statistical analyses for possible dose related effects on survival were analyzed by useing Cox’s method for testing two groups for equality and Tarone’s life table test to identify dose related trends. All reported P values for the survival analyses are two sided. Analysis of Neoplasm and Nonneoplastic Lesion Incidences: The Poly-k test was used to analyzed neoplasm and nonneoplastic lesion. A value of k=3 was usedin the analysis of site-specific lesions. Continuity corrected Poly-3 tests were used in the analysis of lesion incidence and reported P values are one sided. Thesignificance of lower incidences or decreasing trends in lesions is represented as 1–P with the letter N added (e.g., P=0.99 is presented as P=0.01N). Body weight were analyszed by multiple comparison procedures of Dunnett and Williams.
Hematology, clinical chemistry, spermatid and epididymal spermatozoal were analyzed by using the nonparametric multiple comparison methods of Shirley and Dunn. Jonckheere’s test was used to analyszed by the significance of the dose related trends and to determine whether a trend sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose related trend (Dunnett’s or Dunn’s test).
Females in each dosed group were compared to the control group using the Fisher exact test. Tests for extended periods of estrus, diestrus, metestrus and proestrus as well as skipped estrus and skipped diestrus were constructed based on a Markov chain model proposed by Girard and Sager. For each dose group,a transition probability matrix was estimated for transitions among the proestrus, estrus, metestrus and diestrus stages with provision for extended stays within each stage as well as for skipping estrus or diestrus within a cycle.
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined
Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
not examined
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Mortality:
All 1,000 mg/kg male and female rats and one 500 mg/kg male rat died on 3 day of study.

Clinical signs:
Cyanosis, abnormal breathing and lethargy were observed in 250, 500, and 1,000 mg/kg dose group.


BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Final mean body weights and mean body weight gains of surviving males and females of 62.5, 125, 250, 500 mg/kg were significantly less than those of the vehicle controls

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): No data availabe

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Proportion of cycling females were decreased and estrous cycle lenght were incersaed in 125 and 250 mg/kg dose group females. Females in 125 and 250 mg/kg groups spent a significantly higher proportion of time in extended diestrus compared to the vehicle control group.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Spermatic measurements were increased in 125 mg/kg and Epididymal spermatozoa measurements were decreased in 250 mg/kg as compare to vehicle control.


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No data availabe

ORGAN WEIGHTS (PARENTAL ANIMALS)
Relative body weight of heart were decreased in mela and increased in female and absolute body weight of heart were increased in male and female of 62.5, 125,250 and 500 mg/kg. Absolute body weight of right kidney were increased in 125 and 500 mg/kg male and 62.5, 125,250 and 500 mg/kg female. Relative body weight of male and female increased in 62.5, 125,250 and 500 mg/kg.Absolute and relative body weight of liver were increased in male and female rat of 62.5, 125,250 and 500 mg/kg.Absolute right testis weight of 125,250 and 500 mg/kg males was significantly decreased than vehicle controls, but the relative right testis weights of 62.5, 125,250 and 500 mg/kg were significantly increased than vehicle controls.Absolute body weight of thymus were decreased in male and female rat and relative body weight of male rat decreased in 62.5, 125,250 and 500 mg/kg and in female relative organ weight were decreased in 62.5,125 and 500 mg/kg and incerased in 250 mg/kg dose group as compare to vehical control.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Hepatocellular injury, serum activities of alanine aminotransferase and sorbitol dehydrogenase, demonstrated doserelated increases in 62.5,125 and 500 mg/kg dose groups of males and females.
Hepatic function/injury and cholestasis were increased in 500 mg/kg dose animals

HISTOPATHOLOGY (PARENTAL ANIMALS)
In liver, significant increased in hepatocellular hypertrophy were observed in males and females at 125, 250 and 500 mg/kg. In males and females, significant increased in pigmentation were observed in the 62.5, 125, 250, and 500 mg/kg dose groups. Significantly increased in hepatocyte necrosis were observed in 62.5, 250 and 500 mg/kg females as compared to the vehicle control.

In nose increases in olfactory epithelium degeneration were observed in 62.5, 125, 250 and 500 mg/kg males and females. In the 250 and 500 mg/kg males and females, there were significantly increased in olfactory epithelium metaplasia were observed. Respiratory epithelium hyperplasia were significantly increased in males and females were observed at 125, 250 and 500 mg/kg. There were significantly increased in respiratory epithelium squamous metaplasia in 62.5, 125, 250 and 500 mg/kg males and in females at 125, 250 and 500 mg/kg. In males and females, significant increased in hyperplasia of the glands underlying the olfactory epithelium (Bowman’s glands) were obsered in 125, 250, and 500 mg/kg.

In kidney, significantly increased in pigmentation were obsered in males and females at 62.5, 125, 250, and 500 mg/kg. Papillary necrosis in 125, 250 and 500 mg/kg males and 250 mg/kg females were significantly increased than vehicle controls. In males, significantly increased in mineralization were observed in 125, 250 and 500 mg/kg dose groups. In females, significant increased nephropathy were observed in 125, 250 and 500 mg/kg dose groups.

In spleen, significant increased were observed in congestion in 62.5, 125, 250 and 500 mg/kgdose groups of males and 125, 250 and 500 mg/kg females were observed. Lymphoid follicle atrophy were observed in males 250 and 500 mg/kg and females 500 mg/kg and capsular fibrosis in 125, 250 and 500 mg/kg males and females; severities of lesions were increased with dose. Significant increased in mesothelial hypertrophy in 125 mg/kg males and 250 and 500 mg/kg males and females. Hematopoietic cell proliferation and pigmentation in 62.5, 125, 250 and 500 mg/kg dose groups were increased compared to vehicle control.

In bone marrow, hyperplasia in 62.5, 125, 250 and 500 mg/kg dose groups of male and female rats were significantly incerased than vehicle controls.

In mesenteric lymph node, significant increased incidences of atrophy in 500 mg/kg females.

In forestomach, inflammation was significantly increased in 500 mg/kg males.

OTHER FINDINGS (PARENTAL ANIMALS)
Hematology :
Decreased were observed in level of hematocrit, hemoglobin, erythrocytes and MCHC in male and female at 62.5, 125, 250 and 500 mg/kg dose.
Incerased level of reticulocytes, nucleated erythrocytes,MCV,MCH, methemoglobin, methamoglobin hemoglobin and Heize bodies were observed in male and female at 62.5, 125, 250 and 500 mg/kg dose group.
Decreases in leukocyte counts were observed in 250 and 500 mg/kg in male and female.
Dose descriptor:
LOAEL
Effect level:
125 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Effects observed in Reproductive parmeters, Body weight, Survival rates, Organ weight, hematology and histopathology.
Clinical signs:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Reproductive effects observed:
not specified
Conclusions:
The Low observed adverse effect level (LOAEL) of N,N-Dimethyl-p-Toluidine in rats was considered to be 125 mg/kg
Executive summary:

In a reproductive toxicity study, male and femaleF344/Nrats were exposed to N,N-Dimethyl-p-Toluidine in corn oil vehicle by oral gavage in the concentrations of 0, 62.5, 125,150, 500 and 1000 mg/kg for 5 days/week for 14 weeks .The results showed toxic changes were observed in liver, kidney, spleen, nose and bone marrow. Effects on organ weight and hematology of male and female were observed. Effect on reproductive performance in estrous cycle was also observed in female treated with N, N-Dimethyl-p-Toluidine. Therefore , the LOAEL was considered to be 125 mg/kg respectively

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
125 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
K2 level data from NTP study report
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Based on studies of target substance CAS NO 99-97-8 reviewed for toxicity to reproduction from reliable sources having Klimisch rating 2and considering the WoE approcach.

The results are summarized as follows

 

Sr. No

End point

Value

Species

Effects

Remarks

1

LOAEL (Maternal)

 

 

125 mg/kg

Rat

Effects observed in Reproductive parmeters, Body weight, Survival rates, Organ weight, hematology and histopathology.

Data from study report on target chemical

 

2

NOAEL

(Maternal)

 

 

 

 

 

 

 

 

LOAEL (Maternal)

 

 

 

15 mg/Kg bw /d

 

 

 

 

 

 

 

 

 

30 mg/Kg bw /d

 

 

 

 

mouse

No effect observed on reproductive performance in estrous cycle in female and no significant differences in any of the reproductive organ weights or sperm parameters

 

 

Effects observed on Hematology, histopathology

Data from study report on target chemical

3

NOAEL (maternal)

83.3 mg/kg bw/day

Rat

No reproductive effects observed

Predicted data of target chemical

 

Based on the studies summarized in the above table it can be observed that The NOAEL values was found to be in the range of 15-83.3 mg/kg bw/day and LOAEL values varies from 30 -125 mg/Kg . The effects observed on these doses was listed as follows

 

·        Toxic changes were observed in liver, kidney, spleen, nose and bone marrow. Effects on organ weight and hematology of male and female were observed. Effect on reproductive performance in estrous cycle.

·        Changes in body weight and clinical signs were observed. In addition, significant histopathological changes were observed in liver, lungs, nose and thymus. Effects on organ weight and hematology of male and female were observed. No effect observed on reproductive performance in estrous cycle in female and no significant differences in any of the reproductive organ weights or sperm parameters in males observed

·        No reproductive effects observed

Thus based on above values it can be concluded that substance CAS NO 99-97-8 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the lowest observed adverse effective dose value (LOAEL) is 125 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 99-97-8 is considered to be not toxic to maternal toxicity as well as developmental effects belwo the mentioned dose level. The LOAEL of 30 mg/kg bw is not related to reproductive effects thus can be not considered for classification of this substance as repro tox substance. Also CAS NO 99-97-8 does not indicates any mechanistic trigger towards the toxicity based on absence of noncyclic structure that would raise concern of CAS NO 99-97-8 on toxicity to human reproduction. Thus CAS NO 99-97-8 is considered to be not toxic to reproductive effects for the above mentioned dose levels.


Justification for selection of Effect on fertility via oral route:
In a reproductive toxicity study, male and femaleF344/Nrats were exposed to N,N-Dimethyl-p-Toluidine in corn oil vehicle by oral gavage in the concentrations of 0, 62.5, 125,150, 500 and 1000 mg/kg for 5 days/week for 14 weeks .The results showed toxic changes were observed in liver, kidney, spleen, nose and bone marrow. Effects on organ weight and hematology of male and female were observed. Effect on reproductive performance in estrous cycle was also observed in female treated with N, N-Dimethyl-p-Toluidine. Therefore , the LOAEL was considered to be 125 mg/kg respectively

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:
other: estimated data
Principles of method if other than guideline:
Data is from QSAR toolbox version 3.1
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Duration of treatment / exposure:
10 days
Remarks:
Doses / Concentrations:
0, 75, 150, 300 mg/kg bw/day
Basis:
no data
Dose descriptor:
NOAEL
Effect level:
61.875 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified





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

((("a" and ( not "b") )  or ("c" and ( not "d") )  or ("e" and ( not "f") )  )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isothiocyanates OR Acylation >> P450 Mediated Activation to Acyl Halides OR Acylation >> P450 Mediated Activation to Acyl Halides >> 1,1-Dihaloalkanes OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-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 >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinones OR No alert found OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> N-methylol derivates OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Carbenium Ion Formation >> Hydrazine OR SN1 >> Carbenium Ion Formation >> N-Nitroso (alkylation) OR SN1 >> Carbenium Ion Formation >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic nitroso OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic nitro OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Phenoxy polarised alkenes OR SN2 >> Nitrosation-SN2 OR SN2 >> Nitrosation-SN2 >> Nitroso-SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Coumarins OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides OR SN2 >> SN2 at an sp3 Carbon atom >> Alkyl carbamates by DNA binding by OECD

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Acylation >> Direct Acylation Involving a Leaving group >> Sulphonyl halides OR Acylation >> Isocyanates and Related Chemicals OR Acylation >> Isocyanates and Related Chemicals >> Isothiocyanates OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - aldehydes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - cyano OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Polarised Alkenes >> Polarised alkene - nitro OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Benzoquinones OR Michael addition >> Quinones and Quinone-type Chemicals >> Pyranones (and related nitrogen chemicals) OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-diimine OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls OR SN2 OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> Epoxides and Related Chemicals OR SN2 >> Epoxides and Related Chemicals >> Epoxides OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides OR SN2 >> SN2 reaction at a sulphur atom >> Thiols OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) OR SN2 >> SN2 reaction at sp3 carbon atom >> Phosphonates 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: "e"

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

Domain logical expression index: "f"

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: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.234

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.93

Conclusions:
The NOAEL for N,N-dimethyl-p-toluidine was estimated to be 185.875 mg/kg bw/day for rats for 10 days , this subacute value when converted to subchronic value is equivalent to 61.875 mg/kg bw/day for rats for 90 days duration using the toolbox version 3.2
Executive summary:

The NOAEL for N,N-dimethyl-p-toluidine was estimated to be 185.875 mg/kg bw/day for rats for 10 days, this subacute value when converted to subchronic value is equivalent to 61.875 mg/kg bw/day 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

121-69-7

NOAEL

365mg/kg bw/day

mice

365mg/kg bw/day

14 days

no adverse effects on survival or weight gain of the dams, or birth weight, weight gain, or viability of the F1 generation through the first three postpartum day

 

27311-52-0

NOAEL

90.0 mg/kg bw/day

Rat

60, 80, 120 mg/kg/d

10 days

no teratogenic effect observed

 

123-30-8

NOEL

100 mg/kg bw/day

Rat

0, 40, 200, 500 mg/kg

40 - 60 days

Decreased food consumption, and brown urine in females. No developmental effects observed

 

84852-15-3

NOAEL

188 mg/kg bw/day

Rat

0, 75, 150, 300 mg/kg bw/day

10 days

No significant effects were observed on no. of resorption, no of fetus, fetal body weight, sex ratio

 

 

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

CAS no.

End point

Species

Value

Duration

121-69-7

NOAEL

Rat

212.90mg/kg bw/day

90 days

27311-52-0

NOAEL

Rat

30 mg/kg bw/day

90 days

123-30-8

NOEL

Rat

33.3 mg/kg bw/day

90 days

84852-15-3

NOAEL

Rat

62.66 mg/kg bw/day

90 days

 

 

Based on the above values it can be concluded that the estimated value for substance N,N-dimethyl-p-toluidine corresponds to NOEL value for the species rat with duration of 90 days. Thus the calculated NOEL values for 90 days may vary in the range of 30 – 212.90 mg/kg bw /day. Thus the predicted NOEL value is (calculated to be) 61.875 mg/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
61.875 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from OECD QSAR tool box.
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

Based on the various studies available with Klimish rating 2 and 4 for the target and read across substances and 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

61.875 mg/ kg bw/ d

Rat

Oral

No significant effects were observed on no. of resorption, no of fetus, fetal body weight, sex ratio

Predicted data for target chemical

2

LOAEL (maternal and

developmental)

365 mg/kg bw/day

mouse

oral

lowered offspring viability ratio

Data from publication for CAS: 121-69-7

3

LOEL

(maternal)

 

 

 

 

 

 

LOAEL (fetotoxicity)

100 mg/kg bw/day

 

 

 

 

 

 

500 mg/kg bw/day

 

Rat

Oral

 

 

 

 

 

Decreased body weight gain and food consumption; Gross necropsy revealed discolored lungs in some dams at all dose levels.

 

The treatment was fetotoxic (reduced fetal weight gain)

Data from publication for CAS: 91-66-7

 

 

 

 

Based on the studies summarized in the above table with oral routes it can be observed that a NOAEL value was found to be 61.875 mg/Kg bw/ d and the LOAEL value was found to be in the range of 100-500 mg/kg bw/day. The effects observed on these doses was listed as follows

 

·        No significant effects were observed on no. of resorption, no of fetus, fetal body weight, sex ratio.

·        lowered offspring viability ratio

·        Decreased body weight gain and food consumption; Gross necropsy revealed discolored lungs in some dams at all dose levels

·        The treatment was fetotoxic (reduced fetal weight gain)

Thus based on above discussion it can be concluded that substance CAS NO 99-97-8 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 61.875 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 99-97-8 is considered to be not toxic to maternal toxicity as well as developmental effects for the above mentioned dose. Also CAS NO 99-97-8does not indicates any mechanistic trigger towards the toxicity based on absence of noncyclic structure that would raise concern of CAS NO 99-97-8 on toxicity to human reproduction & developmental effects. Thus CAS NO 99-97-8 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 N,N-dimethyl-p-toluidine was estimated to be 185.875 mg/kg bw/day for rats for 10 days , this subacute value when converted to subchronic value is equivalent to 61.875 mg/kg bw/day for rats for 90 days duration using the toolbox version 3.2

Justification for classification or non-classification

N,N-dimethyl-p-toluidine has a harmonized classification within the CLP regulation. It is neither classified as reproductive toxic nor as teratogenic. The studies in the above sections also support the harmonized classification.