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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Repeated dose toxicity: via oral route;

NOAEL was considered to be in a dose range of 100- 125 mg/kg when male and female rats were exposed to test chemical  for chronic study.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance of N-methylformanilide (93-61-8) which is reported as 0.02077671 mmHg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical of N-methylformanilide is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for N-methylformanilide (93-61-8) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that N-methylformanilide shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that N-methylformanilide shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral, other
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
data from handbook or collection of data
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: As mention below
Principles of method if other than guideline:
Weight of evidence prepared from various publication mention below
1,A chronic toxicity study was conducted in Osborn-Mendel rats to evaluate the toxic effects of cinnamaldehyde.
2,A repeated dose toxicity study was conducted for test chemical in F344/N rat male and female rats for 90 days by oral feed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 1,Osborne-Mendel 2,F344/N rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
1,Details on test animal
TEST ANIMALS
- Source: No data available
- Age at study initiation: Weanling rats
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed individually in wire cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimatization period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

2,Details on oral exposure
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):
The dose formulations were prepared at least every 3 weeks by mixing microencapsulated trans-cinnamaldehyde with nonirradiated NTP-2000 feed during the 3-month studies.

- Mixing appropriate amounts with (Type of food): Placebo and/or loaded microcapsules were combined with feed to a concentration of 10% (3-month studies) in the diet. A premix was prepared by hand and then blended with additional feed in a Patterson-Kelly twin-shell blender for 15 minutes, without the use of the intensifier bar.

- Storage temperature of food: Formulations were stored in plastic buckets at room temperature (3-month studies) for up to 5 weeks.
Route of administration:
oral: feed
Vehicle:
other: Feed
Details on oral exposure:
Details on oral exposure
PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Details not specified.
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Feed
- Concentration in vehicle: 0, 1000, 2500 or 10000 ppm (0, 5, 125 or 500 mg/Kg bw)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
1,16 weeks
2 ,105 or 106 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 10000, 2500 or 1000 ppm (0, 500, 125 or 5 mg/Kg bw)
Basis:
no data
Remarks:
0, 1000, 2100, or 4100 ppm delivered average daily doses of approximately 50, 100, or 200 mg/kg body weight to males and females.
No. of animals per sex per dose:
1,Total: 80 animals
0 ppm: 10 males, 10 females
1000 ppm: 10 males, 10 females
2500 ppm: 10 males, 10 females
10000 ppm: 10 males, 10 females

2,Total number of animals 400 animals
0mg/kg= (50 males and 50 females)
50mg/kg= (50 males and 50 females)
100mg/kg= (50 males and 50 females)
200mg/kg= (50 males and 50 females)

Control animals:
yes, concurrent vehicle
Details on study design:
Details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available
Observations and examinations performed and frequency:
1,Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Weekly
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 3, 6, 12 and 22 months
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: On all animals included in the study.
- Parameters examined: White cell counts, red cell counts, haemoglobins and haematocrits.

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters examined: No data available

URINALYSIS: No data available - Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters examined No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

2,CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical findings were recorded on day 8 and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: animals were weighed at the beginning, weekly and at the end of the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: weekly

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified


OPHTHALMOSCOPIC EXAMINATION: Not specified


HAEMATOLOGY: Yes
- Time schedule for collection of blood:
Blood was collected from the retroorbital sinus of clinical pathology study rats on study days 5 and 22 and from all core study rats surviving to the end of the studies for hematology analyses. Blood samples for
hematology analyses were placed in microcollection
tubes containing potassium EDTA.

- Anaesthetic used for blood collection: Yes , carbon dioxide anesthesia

- How many animals: All animals
- Parameters checked in table [No.?] were examined.; Parameters hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration;
and leukocyte count and differentials were observed.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was collected from the retroorbital sinus
- How many animals: All animals
- Parameters checked in table [No.?] were examined. Parameters urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids were determined



URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected during a 24-hour period from five male and five female rats from each core study group at the end of the study.
- Metabolism cages used for collection of urine: Yes
- Parameters checked in table [No.?] were examined. Parameters evaluated included creatinine and hippuric acid concentrations and volume.
Sacrifice and pathology:
1,GROSS PATHOLOGY: Yes
Tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed.

HISTOPATHOLOGY: Yes
Liver, kidneys, spleen, heart, testes, abdominal and thoracic viscera, and one hind leg, for bone, bone marrow and muscle were preserved, embedded, sectioned and stained with haematoxylin-eosin prior to microscopic examination.

2,Sacrifice and pathology
GROSS PATHOLOGY: Yes, Necropsies were performed on all core study animals by using Carbon dioxide asphyxiation. Organs weighed were heart, right kidney, liver, lung, right testis, and thymus.

HISTOPATHOLOGY: Yes, Tissues for microscopic examination were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 μm, and stained with hematoxylin and eosin. Histopathology was performed on untreated controls, vehicle controls and treated group 4000 and 3100 mg/kg/day of male and female rats respectively. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart with aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland (except male mice), nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. In addition, the stomach (forestomach) was also observed.
Statistics:
No data available
Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical findings related to toxicity related to test chemical exposure in any group 50, 100, or 200 mg/kg body weight of treated animals compare to control.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Mortality of 200 mg/kg males was greater than that of the vehicle control group; mortality in other exposed groups of males and of exposed females was similar to that of the vehicle control groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weights in 200mg/kg males were significantly less than those of the vehicle controls throughout the study however in 200mg/kg females body weight were significantly less after week 18 as compared to control treated group.

Mean body weights of 100mg/kg males were less after
week 94 compared to control treated group
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
Feed consumption by 100mg/kg and 200mg/kg males and 200mg/kg females was less than that by the vehicle controls at the beginning and end of the study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Description (incidence and severity):
2,Hippuric acid excretion in urine expressed as the hippuric acid to creatinine ratio was proportional to dose indicating that neither absorption, metabolism, nor excretion was saturated in either male or female rats exposed to dosed feed containing 50 ,100and 200mg/kg of test chemical.
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Slight hepatic cell swelling was noted and slight hyperkeratosis of squamous portion of the stomach at a dose of 500 mg/Kg bw
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
The incidences of adenoma of the preputial gland (vehicle control, 5/50; 50mg/kg, 1/49; 100mg/kg, 2/50; 200 mg/kg, 0/50) and prostate gland (4/50, 0/49, 0/49, 0/50) in 200 mg/kg males were significantly decreased compared to those in the vehicle controls

The incidence of mononuclear cell leukemia in 200mg/kg males was significantly decreased (18/50, 15/50, 21/50, 9/50), was considered unrelated test chemical exposure.
Details on results:
The No observed Adverse Effect Level (NOAEL) for the test compound cinnamaic aldehyde in Osborne-Mendel rats is found to be 125 mg/Kg bw.
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Test material given through feed. No effects observed
Dose descriptor:
NOAEL
Effect level:
100 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect were observed at this dose
Remarks on result:
other: No toxic effect were observed
Critical effects observed:
not specified
Conclusions:
NOAEL was considered to be in a dose range of 100- 125 mg/kg when male and female rats were exposed to test chemical for chronic study..
Executive summary:

The data available for the test chemical was reviewed to determine the toxic nature of N-methylformanilide (93-61-8) repeated exposure by oral route. The study is as mentioned below:

Repeated dose toxicity: via oral route;

In a chronic toxicity oral study, test substance was evaluated in male and female Osborne-Mendel rats where the test chemical was administered by diet at concentration of 0, 1000, 2500 or 10000 ppm (0, 5, 125 or 500 mg/kg body weight). No effects were noted when the rats were exposed to 2500 ppm (125 mg/kg body weight) while treatment with 10000 ppm (500 mg/kg body weight) resulted in slight hepatic cell swelling and slight hyperkeratosis of squamous portion of the stomach. Therefore, NOAEL was considered to be 125 mg/kg body weight when test chemical were administered by diet to male and female Osborne-Mendel rats for 16 weeks.

The present study aimed to performed chronic study (2 years) of the test chemical inF344/N male and female rats. In this chronic study the vehicle control treated and dietary doses equivalent to 50, 100 and 200mg/kg/bw/day was exposed to male and female F344/N rats. The exposure of test chemical to the animals was performed for105 (Male) and 106 (females) weeks. The animals were observed throughout the study duration for mortality, change in body weight, food consumption, clinical signs and urinalysis, gross and histopathology at the end of the study.Mortality of 200 mg/kg males was greater than that of the vehicle control group but not significantly however mortality in other exposed groups of males and of exposed females was similar to that of the vehicle control groups. No clinical signs of toxicity observed in any animals exposed to test chemical. In the body weight study mean body weights of 200mg/kg males were less than those of the vehicle controls throughout the study however in 200mg/kg females body weight were significantly less after week 18 as compared to control treated group.Mean body weights of 100mg/kg males were less afterweek 94 compared to control treated group. At the beginning and end of the study feed consumption by 100mg/kg and 200mg/kg males and 200mg/kg females was less than that by the vehicle controls.In urinalysis Hippuric acid excretion in urine expressed as the hippuric acid to creatinine ratio was proportional to dose indicating that neither absorption, metabolism, nor excretion was saturated in either male or female rats exposed to dosed feed containing 50mg/kg to 200mg/kg of test chemical. No visible lesions were observed in gross pathology However in histopathology The incidences of adenoma of the preputial gland (vehicle control, 5/50; 50mg/kg, 1/49; 100mg/kg, 2/50; 200 mg/kg, 0/50) and prostate gland (4/50, 0/49, 0/49, 0/50) in 200 mg/kg males were significantly decreased compared to those in the vehicle controls. The incidence of mononuclear cell leukemia in 200mg/kg males was significantly decreased (18/50, 15/50, 21/50, 9/50), was considered not related to test chemical exposure. Thus the NOAELfor chronic study (2 years)in F344/N male and female rats of test chemicalwas considered to be 100mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Weight of evidence prepared from various publication

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The data available for the test chemical was reviewed to determine the toxic nature of N-methylformanilide (93-61-8) repeated exposure by oral route. The study is as mentioned below:

Repeated dose toxicity: via oral route;

In a chronic toxicity oral study, test substance was evaluated in male and female Osborne-Mendel rats where the test chemical was administered by diet at concentration of 0, 1000, 2500 or 10000 ppm (0, 5, 125 or 500 mg/kg body weight). No effects were noted when the rats were exposed to 2500 ppm (125 mg/kg body weight) while treatment with 10000 ppm (500 mg/kg body weight) resulted in slight hepatic cell swelling and slight hyperkeratosis of squamous portion of the stomach. Therefore, NOAEL was considered to be 125 mg/kg body weight when test chemical were administered by diet to male and female Osborne-Mendel rats for 16 weeks.

The present study aimed to performed chronic study (2 years) of the test chemical inF344/N male and female rats. In this chronic study the vehicle control treated and dietary doses equivalent to 50, 100 and 200mg/kg/bw/day was exposed to male and female F344/N rats. The exposure of test chemical to the animals was performed for105 (Male) and 106 (females) weeks. The animals were observed throughout the study duration for mortality, change in body weight, food consumption, clinical signs and urinalysis, gross and histopathology at the end of the study.Mortality of 200 mg/kg males was greater than that of the vehicle control group but not significantly however mortality in other exposed groups of males and of exposed females was similar to that of the vehicle control groups. No clinical signs of toxicity observed in any animals exposed to test chemical. In the body weight study mean body weights of 200mg/kg males were less than those of the vehicle controls throughout the study however in 200mg/kg females body weight were significantly less after week 18 as compared to control treated group.Mean body weights of 100mg/kg males were less afterweek 94 compared to control treated group. At the beginning and end of the study feed consumption by 100mg/kg and 200mg/kg males and 200mg/kg females was less than that by the vehicle controls.In urinalysis Hippuric acid excretion in urine expressed as the hippuric acid to creatinine ratio was proportional to dose indicating that neither absorption, metabolism, nor excretion was saturated in either male or female rats exposed to dosed feed containing 50mg/kg to 200mg/kg of test chemical. No visible lesions were observed in gross pathology However in histopathology The incidences of adenoma of the preputial gland (vehicle control, 5/50; 50mg/kg, 1/49; 100mg/kg, 2/50; 200 mg/kg, 0/50) and prostate gland (4/50, 0/49, 0/49, 0/50) in 200 mg/kg males were significantly decreased compared to those in the vehicle controls. The incidence of mononuclear cell leukemia in 200mg/kg males was significantly decreased (18/50, 15/50, 21/50, 9/50), was considered not related to test chemical exposure. Thus the NOAELfor chronic study (2 years)in F344/N male and female rats of test chemicalwas considered to be 100mg/kg.

 

 

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance of N-methylformanilide (93-61-8) which is reported as 0.02077671 mmHg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical of N-methylformanilide is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for N-methylformanilide (93-61-8) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that N-methylformanilide shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that N-methylformanilide shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Based on the data available for the test chemical N-methylformanilide (93-61-8) not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the test chemical N-methylformanilide (93-61-8) not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.