Printing Date
2017-01-04 16:26:52 JST
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Name
4-chlorobenzoyl chloride
Legal entity owner
National Institute of Health Sciences / Tokyo / Japan
Substance: 4-chlorobenzoyl chloride
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dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:25:23 JST
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0 Related Information
0.1 Templates
0.2 Categories
0.3 Mixtures
1 General Information
1.1 Identification
Substance identification
Chemical name
4-chlorobenzoyl chloride
Legal entity
Reference substance
 
EC number
EC name
204-515-3
4-chlorobenzoyl chloride
CAS number
CAS name
122-01-0
 
IUPAC name
 
 
1.2 Composition
1.3 Identifiers
1.4 Analytical information
1.5 Joint submission
1.6 Sponsors
1.7 Suppliers
1.8 Recipients
1.9 Product and process oriented research and development
2 Classification & Labelling and PBT assessment
2.1 GHS
2.2 DSD - DPD
3 Manufacture, use and exposure
3.1 Technological process
Technological process
3.2 Estimated quantities
3.3 Sites
3.4 Information on mixtures
3.5 Life Cycle description
3.6 Uses advised against
3.7 Exposure Scenarios, exposure and risk assessment
3.7.2 Environmental assessment for aggregated sources
3.7.3 Generic exposure potential
3.8 Biocidal information
3.10 Application for authorisation of uses
7 Toxicological information
7.2 Acute Toxicity
7.2.1 Acute toxicity: oral
Endpoint study record: Acute toxicity: oral.001
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IUC5-a979f21c-55c9-4b3c-9783-184bbe71d749
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dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:17:31 JST
Remarks
   
   
Administrative Data
Purpose flag
key study
Study result type
experimental result
   
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
OECD Test Guideline study under GLP condition
Data source
Reference
Reference type
Author
Year
Title
Bibliographic source
Testing laboratory
Report no.
Owner company
Company study no.
Report date
study report
MHW (Ministry of Health and Welfare), Japan
2007
Single Dose Oral Toxicity Test of 4-chlorobenzoyl chloride in Rats
Japan Existing Chemical Data Base (JECDB)
Biosafety Research Center, Foods, Drugs and Pesticides (An-Pyo Center)
       
Data access
data published
Materials and methods
Test type
acute toxic class method
Limit test
yes
Test guideline
Qualifier
Guideline
Deviations
according to
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
no
GLP compliance
yes
Test materials
Identity of test material same as for substance defined in section 1 (if not read-across)
yes
Test material identity
Identifier
Identity
CAS number
1220-01-0
Details on test material
- Name of test material (as cited in study report): 4-chlorobenzoyl chloride
- Molecular weight: 175.01
- Physical state: Colorless liquid
- Analytical purity: 99.79%
- Melting point/ boiling point: 12—14°C/222°C
-Solubility: Very soluble in acetone (656 mg/mL), methanol, ethanol, ether, ketone, and toluene, and insoluble in water
- Vapor pressure: 110°C /20 mmHg
- Specific gravity: 1.377/20°C
- Odor: Very irritating odor
- Supplier: Iharanikkei Chemical Industry Co., Ltd
- Lot/batch No.: I5001
- Storage condition of test material: Room temperature
Test animals
Species
rat
Strain
Crj: CD(SD)
Sex
female
Details on test animals and environmental conditions
TEST ANIMALS- Source: Charles River Japan Inc.
- Age at the time of purchase: 7 weeks old
- Weight at dosing: Females, 190 - 198 g
- Fasting period before study: Approximately 16 hrs
- Housing: One animal/cage- Diet (e.g. ad libitum): Ad libitum except fasting period for 16 hrs before administration to 3 hrs after administration
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 7 - 8 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.6 - 23.6
- Humidity (%): 45.6 - 62.2
- Ventilation (per hr): Approximately > 12 times
- Photoperiod (hrs light / hrs dark): 12/12
Administration / exposure
Route of administration
oral: gavage
Vehicle
corn oil
Details on oral exposure
VEHICLE
- Concentration in vehicle: 40 w/v%
- Lot no.: V4F1900 produced by Nacalai Tesque, INC..
MAXIMUM DOSE VOLUME APPLIED: 5 ml/kg bw
Doses
2000 mg/kg bw
No. of animals per sex per dose
First time of administration: 3 females (animal ID No. 3, 7, 10) /dose
Second time of administration: 3 females (animal ID No. 6, 8, 9)/dose
Control animals
no
Details on study design
- Duration of observation period following administration: 14 days
- Frequency of observations: Day 1 (day of administration): within 30 minutes and 1, 2, 3, 4, 5 and 6 hrs after administration. After day 2: once a day
- Frequency of weighing: Days 1 (before administration), 7, and 14
- Necropsy of survivors performed: Yes
The LD50 value was estimated to be around 820 mg / kg from information of the test substance. Therefore, the starting administration dose was set as 2000 mg/kg bw. No clinical changes were observed in the first administration, therefore the second dose was also set as 2000 mg/kg bw
Statistics
No
Results and discussions
Effect levels
Sex
Endpoint
Effect level
Based on
95% CL
Remarks
female
LD50
> 2000 mg/kg bw
act. ingr.
   
Mortality
No deaths were observed in first and second times.
Clinical signs
No changes related to the test substance were observed in first and second times.
Body weight
No changes related to the test substance were observed in first and second times.
Gross pathology
No changes related to the test substance were observed in first and second times.
Other findings
- Organ weights: No data
- Histopathology: No data
- Potential target organs: Not identified
- Other observations: No data
Applicant's summary and conclusion
Conclusions
The LD50 value was more than 2000 mg/kg bw for female rats.
7.5 Repeated dose toxicity
7.5.1 Repeated dose toxicity: oral
Endpoint study record: Repeated dose toxicity: oral.001
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IUC5-2c9bcc31-9c27-489b-aab9-4ae7f1fdf45c
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0
Author
 
dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:26:31 JST
Remarks
   
   
Administrative Data
Purpose flag
key study
Study result type
experimental result
   
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
OECD Test Guideline study under GLP condition
Data source
Reference
Reference type
Author
Year
Title
Bibliographic source
Testing laboratory
Report no.
Owner company
Company study no.
Report date
study report
MHW (Ministry of Health and Welfare), Japan
2011
A combined repeated-dose/reproductive-developmental toxicity study of 4-chlorobenzoyl chloride by oral administration in rats.
Japan Existing Chemical Data Base (JECDB)
BoZo Research Center Inc.
       
Data access
data published
Cross-reference to same study
7.8.1 Toxicity to reproduction: Toxicity to reproduction.001
7.8.2 Developmental toxicity/teratogenicity: Developmental toxicity/teratogenicity.001
Materials and methods
Test type
combined repeated dose and reproduction / developmental screening
Limit test
no
Test guideline
Qualifier
Guideline
Deviations
according to
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
no
GLP compliance
yes
Test materials
Identity of test material same as for substance defined in section 1 (if not read-across)
yes
Test material identity
Identifier
Identity
CAS number
122-01-0
Details on test material
- Name of test material (as cited in study report): 4-chlorobenzoyl chloride
- Molecular weight: 175.01
- Physical state: Colorless liquid to white crystal mass
- Analytical purity: 99.6%
- Melting point/ boiling point: 12°C (solid point)/220-222°C
-Flash point: 118°C
- Solubility: Very soluble in acetone (656 mg/mL), methanol, ethanol, ether, ketone, and toluene, and insoluble in water
- Vapor pressure: 110°C /20 mmHg
- Specific gravity: 1.377/20°C
- Odor: Very irritating odor
- Supplier: Iharanikkei Chemical Industry Co., Ltd
- Lot/batch No.: KSSFK
- Storage condition of test material: Room temperature
Test animals
Species
rat
Strain
Crj: CD(SD)
Sex
male/female
Details on test animals and environmental conditions
TEST ANIMALS
- Source: Atsugi Breeding Center, Charles River Laboratories Japan, Inc.
- Age at study initiation:10 weeks of age
- Weight at study initiation: 395-476 g for males and 225-282 g for females
- Housing: bracket-type metallic wire-mesh cages (W 250 × D 350 × H 170 mm)- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:19 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21 to 24°C
- Humidity (%):40 to 56%
- Air changes (per hr):10 to 15 times per hour
- Photoperiod (hrs dark / hrs light):12-hour lighting per day
Administration / exposure
Route of administration
oral: gavage
Vehicle
corn oil
Details on oral exposure
PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in corn oil for injection.
VEHICLE
- Justification for use and choice of vehicle: No data
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): V0M3906 produced by Nacalai Tesque, INC.
- Dosing volume: 5 mL/kg bw
- Stability (test solutions): At least 7 days
- Storage condition of test solution: Stored in a refrigerator
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
Test suspensions at each concentration to be used for males in week 1 and six week of administration were analyzed by the HPLC method at Bozo Research Center Inc. Results showed that the concentration of the test article in each suspension was 98.0 to 104.0% of the nominal concentration and both values were within the acceptable range (concentration: percentage of the nominal concentration, 100 ± 10%; C.V.: 10% or below)
Duration of treatment / exposure
(P) Males: 42 days including 14 days pre-mating, mating, and thereafter 14 days (P)Females: 42–48 days including 14 days pre-mating, mating and gestation periods and the days until day 4 of lactation
Frequency of treatment
Daily: 7 times / week
Doses/concentrations
0 (vehicle), 20, 100 and 500 mg/kg bw/day
Basis
actual ingested
No. of animals per sex per dose
12 animals/sex/dose (main dose group)
Five out of 12 males at 0 and 500 mg/kg bw/day were used as a recovery assessment group. In addition, 10 females/dose were administered 0 and 500 mg/kg bw/day for 42 days without mating and examined after the administration period or after a 14 day recovery period.
Control animals
yes, concurrent vehicle
Details on study design
- Dose selection rationale: A preliminary study was conducted to determine the doses to be employed. Male and female rats were receiving 0, 250, 500, and 1000 mg/kg bw/day of the substance was administered for 14 days. As a result, no death, and no effects of food consumption and hematology were observed in all treated groups. Loose stool, salivation, pale stool (females), slight depression of body weights, increase in T-CHO, decrease in BUN (males) and increase in liver weight (females) were observed in both sexes receiving 1000 mg/kg. In addition, raised lesion in the forestomach in both sexes and dark red colored lesion in the glandular in males were observed in the 1000 mg/kg bw/day group. Raised focus in the forestomach in both sexes and dark red colored lesion in the glandular in males were observed in the 500 mg/kg bw/day group. Raised focus in the forestomach in females was observed in the 250 mg/kg bw/day group. Therefore, the highest dose was set at 500 mg/kg bw/day, the concentration in which the expression of apparent toxicity is expected, and the middle and low dose were set at 100 and 20 mg/kg bw/day using a common ratio of 5.
Positive control
no
Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
Males and females: once before the start of administration, 3 times/day during the administration period, and once during the recovery period
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Males: once before the start of administration, during the administration and recovery periods
Females: once before the start of administration, days 1, 7, 14 and 20 of gestation, and day 4 of lactation
BODY WEIGHT: Yes
- Time schedule for examinations:
Males in the main groups were weighed on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39 and 42 of administration and on the day of necropsy, and males and females in the recovery groups were weighed on days 1, 4, 8, 11 and 14 of recovery and on the day of necropsy in addition to the measurement days for males in the main groups.
Females in the main groups were weighed on days 1, 4, 8, 11 and 15 of administration (uncopulated animals were weighed on day 18 and 22 of administration as well), days 0, 4, 7, 11, 14, 17 and 20 of gestation, days 0 and 4 of lactation and the day of necropsy.
FOOD CONSUMPTION : Yes
- Food consumption (g/day/rat) for each animal determined from the difference of the of the previous day's feeding amount: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
males in the main groups on days 1, 4, 8, 11, 15, 32, 36, 39 and 42 of administration; males and females in the recovery groups on days 1, 4, 8, 11 and 14 of recovery in addition to the measurement days for males in the main groups; and females in the main groups on days 1, 4, 8, 11 and 15 of administration, days 1, 4, 7, 11, 14, 17 and 20 of gestation and days 2 and 4 of lactation.
FOOD INTAKE: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On the day after the final day of administration and on the final day of the recovery period
- Anaesthetic used for blood collection: Yes (identity)
- Animals fasted: Yes
- How many animals:5 animals/sex/group
- Parameters examined red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte percentage, platelet count, white blood cell count, differential white blood cell count, absolute number of each white blood cell, prothrombin time, activated partial thromboplastin time, fibrinogen
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On the day after the final day of administration and on the final day of the recovery period
- Animals fasted: Yes
- How many animals: 5 animals/sex/group
- Parameters checked: ALP, total cholesterol, triglyceride, phospholipids, total bilirubin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, A/G ratio, AST (GOT), ALT (GPT), LDH, γ-GTP
URINALYSIS: Yes
- Time schedule for collection of urine: final week of administration (days 39 to 40 of administration) and in the final week of recovery (days 11 to 12 of recovery)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes ,
A urine collector to collect four-hour urine samples under fasting but ad libitum drinking conditions, followed by collection of 20-hour urine samples under ad libitum feeding and drinking conditions.
- Parameters checked: pH, protein, ketones. glucose, occult blood, bilirubin, urobilinogen, color, sediment, urine volume (4-hour volume), osmotic pressure, urine volume (20-hour volume), water intake (24-hour volume)
BLOOD HORMONE: Yes
- Time schedule for collection of serum: Same as clinical chemistry
- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (THS) of thyroid hormone
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Manipulative test and measurements of grip strength and motor activity were conducted on 5 animals per group with the following frequencies: males in the main groups were examined in the final week of administration (day 37 of administration), females in the main groups on day 4 of lactation (day 42 to day 44 of administration) after necropsy of F1 pups, and males and females in the recovery groups in the final week of administration (day 37 of administration) and in the final week of recovery (day 9 of recovery).
- Dose groups that were examined: All animals were examined for detailed clinical signs once before the start of administration. Thereafter, males in the main groups were examined once weekly during the administration period, whereas females were observed once weekly during the pre-mating administration period and mating period as well as on designated days during the gestation and lactation periods (days 1, 7, 14 and 20 of gestation, and day 4 of lactation). Animals in the recovery groups were examined once weekly during the administration and recovery periods.
- Battery of functions tested:
1) Open field observation. Arousal, gait, posture, tremor, convulsion, rearing count, defecation (defecation count, urination), stereotypy (grooming, circling, etc.), abnormal behavior (self-biting, backward walking, etc.)
2) Manipulative Test. Auditory response, approach response, touch response, tail pinch response, pupillary reflex, aerial righting reflex, landing foot splay
3) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb was measured by CPU gauge MODEL-9502A (AIKOH Engineering Co., Ltd.).
4) Measurement of Motor Activity.Following measurement of grip strength, motor activity was measured by a motor activity sensor for experimental animals NS-AS01 (NeuroScience, Inc). The measurement was conducted for 1 hour, and measured values at 10-minute intervals and from 0 to 60 minutes were collected.
Sacrifice and pathology
GROSS PATHOLOGY AND ORGAN WEIGHTS: Brain, puitality, thyroids(including parathyroids), thymus, heart, liver, spleen, kidneys, adrenals, seminal, prostate, testes, epididymis, ovaries, uterus
HISTOPATHOLOGY: Cerebrum, cerebellum (including pontocerebellar), sciatic nerve, spinal cord (thoracic), eye, optic nerve, Harder gland, pituitary, thyroid, parathyroid, adrenal glands, thymus, spleen, submandibular lymph nodes, mesenteric lymph nodes, heart, thoracic aorta, trachea, lung (including bronchial), tongue, larynx, esophagus, stomach, duodenum, jejunum, ileum (including Peyer's patches), cecum, colon, rectum, submandibular gland, sublingual gland, liver, pancreas, kidney, bladder, testis, ovary, epididymis, uterus, vagina, prostate, seminal vesicles (including the coagulating gland), mammary gland (groin), sternum and femur (including bone marrows), femoral skeletal muscle, skin (groin), macroscopic lesions, and parts for identification (auricles)
Statistics
The data were analyzed for homogeneity of variance by the Bartlett test (level of significance: 0.01, two-tailed). If variances were homogeneous, data was analyzed by the Dunnett test, whereas heterogeneous data was analyzed by a Steel test. In the recovery test, these values of two groups were analyzed by F test and Student or Aspin-Welch t-test. Frequency data were analysed by Fisher test. Statistical significance was set at < 5% by two-sided
Results and discussions
Effect levels
Endpoint
Effect level
Based on
Sex
Basis for effect level / Remarks
NOAEL
100 mg/kg bw/day (actual dose received)
act. ingr.
male/female
Effects of lesions in the kidneys and stomach of both sexes and the thymus of females at 500 mg/kg bw/day
Results of examinations
Clinical signs and mortality
yes (No animal died in any group.Clinical signs: Salivation was observed in 1 to 7 males receiving 500 mg/kg bw/day after Day 12 during the dosing period. Salivation was observed in 1 mating female receiving 500 mg/kg bw/day after Day 12, however this sign was not observed after Day 16 of gestation. No clinical signs were observed in both sexes of recovery animals during the recovery period. )
Body weight and weight gain
no effects
Food consumption and compound intake (if feeding study)
no effects
Food efficiency
not examined
Ophthalmoscopic examination
no effects
Haematology
no effects
Clinical chemistry
no effects
Urinalysis
no effects (Significant increases in water consumption and urine volume were observed in males receiving 500 mg/kg bw/day, but it was not considered to be toxicological effects. during the dosing period.)
Neurobehaviour
no effects
Organ weights
yes (see Details on results)
Gross pathology
yes (see Details on results)
Histopathology: non-neoplastic
yes (see Details on results)
Histopathology: neoplastic
not examined
Details on results
DETAILED CLINICAL OBSERVATIONS, MANIPULATIVE TEST, GRIP STRENGTH TEST AND LOCOMOTOR ACTIVITY MEASUREMENT:There were no changes in main males and females and satellite females during the dosing and recovery periods.
ORGAN WEIGHTS: An Increase in relative kidney weight was observed in males receiving 500 mg/kg bw/day at the end of the administration period. Decreases in absolute and relative thymus weights were observed in mating females receiving 500 mg/kg bw/day at the end of the administration. In addition, a decrease in relative thyroid weight and increases in relative wights of the heart and testis were observed in males and decreases in relative weights of the puitality and heart were observed in females at 500 mg/kg bw/day at end of the recovery period; however, these changes were determined to be within physiological variation range.

GROSS PATHOLOGY:
Kidneys: Irregular surface was observed in 1 male receiving 500 mg/kg bw/day.
Stomach: Thickening wall and focus/raised of forestomach was observed in both sexes receiving 500 mg/kg bw/day.

HISTOPATHOLOGY
basophilic changes in the tubular cells of kidneys from males and both mating and non-mating females, and tubular dilatation, granular casts, and fibrosis was observed in male kidneys. Atrophy of the thymus was observed in all mating females, including the control group; however, the incidence was particularly high in the 500 mg/kg bw/day group. Furthermore, histopathological changes were observed in the stomach, including intercellular edema in squamous cells and cell infiltration or hyperplasia of the forestomach mucosa, in males and mating and non-mating females. Forestomach erosion and ulceration were present in one mating female administered 500 mg/kg bw/day. These histopathological changes tended to resolve after the 14 day recovery period.
Any other information on results incl. tables

Figures and Tables (in English) are available in the following full report of the study.

http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF122-01-0d.pdf

Applicant's summary and conclusion
Conclusions
Based on the effects of 4-chlorobenzoyl chloride on the thymus, kidney, and stomach, the no observed adverse effect level (NOAEL) for repeated oral dosing was determined to be 100 mg/kg bw/day in male and female rats.
Executive summary

A combined repeated oral dose toxicity study with the reproduction/developmental toxicity screening test was performed according to the OECD TG 422. Male and female rats (12 animals/sex/dose) were administered 4-chlorobenzoyl chloride at 0, 20, 100, and 500 mg/kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating period and subsequent mating period; whereas females were dosed for 42–48 days, including the 14 day pre-mating, mating, and gestation periods, and the time until day 4 of lactation. Five out of 12 males at 0 and 500 mg/kg bw/day were used as a recovery assessment group. In addition, 10 females/dose were administered 0 and 500 mg/kg bw/day for 42 days without mating and examined after the administration period or after a 14 day recovery period. At 500 mg/kg bw/day, the absolute and relative thymus weights had decreased in the mating group females. Relative kidney weight increased in males at 500 mg/kg bw/day. Histopathological examination revealed basophilic changes in the tubular cells of kidneys from males and both mating and non-mating females, and tubular dilatation, granular casts, and fibrosis was observed in male kidneys. Atrophy of the thymus was observed in all mating females, including the control group; however, the incidence was particularly high in the 500 mg/kg bw/day group. Furthermore, histopathological changes were observed in the stomach, including intercellular edema in squamous cells and cell infiltration or hyperplasia of the forestomach mucosa, in males and mating and non-mating females. Forestomach erosion and ulceration were present in one mating female administered 500 mg/kg bw/day.These histopathological changes tended to resolve after the 14 day recovery period.Based on the effects of 4-chlorobenzoyl chloride on the thymus, kidney, and stomach, the no observed adverse effect level (NOAEL) for repeated oral dosing was determined to be 100 mg/kg bw/day in male and female rats.

7.6 Genetic toxicity
7.6.1 Genetic toxicity in vitro
Endpoint study record: Genetic toxicity in vitro.001
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IUC5-2e59c227-c537-4b93-b700-e6a72a4ec840
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0
Author
 
dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:18:22 JST
Remarks
   
   
Administrative Data
Purpose flag
key study
Study result type
experimental result
   
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
OECD Test Guideline study under GLP condition
Data source
Reference
Reference type
Author
Year
Title
Bibliographic source
Testing laboratory
Report no.
Owner company
Company study no.
Report date
study report
MHW (Ministry of Health and Welfare), Japan
2006
Reverse Mutation Test of 4-chlorobenzoyl chloride on Bacteria.
Japan Existing Chemical Data Base (JECDB)
Biosafety Research Center, Foods, Drugs and Pesticides (Anpyo Center)
       
Data access
data published
Materials and methods
Type of genotoxicity
gene mutation
Type of study
bacterial reverse mutation assay (e.g. Ames test)
Test guideline
Qualifier
Guideline
Deviations
according to
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
no
according to
OECD Guideline 472 (Genetic Toxicology: Escherichia coli, Reverse Mutation Assay)
no
according to
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
no
GLP compliance
yes
Test materials
Test material identity
Identifier
Identity
CAS number
120-01-0
Details on test material
- Name of test material (as cited in study report): 4-chlorobenzoyl chloride- Molecular weight: 175.01
- Physical state: Colorless liquid
- Analytical purity: 99.79%
- Melting point/ boiling point: 12—14°C/222°C
-Solubility: Very soluble in acetone (656 mg/mL), methanol, ethanol, ether, ketone, and toluene, and insoluble in water
- Vapor pressure: 110°C /20 mmHg
- Specific gravity: 1.377/20°C
- Odor: Very irritating odor
- Supplier: Iharanikkei Chemical Industry Co., Ltd
- Lot/batch No.: I5001
- Storage condition of test material: Room temperature
Method
Species/strain
Species/strain
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation
with and without
Metabolic activation system
rat liver, induced by phenobarbital and 5,6-benzoflavone
Species/strain
E. coli WP2 uvr A
Metabolic activation
with and without
Metabolic activation system
rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations
-S9 mix: 7.81, 15.6, 31.3, 62.5, 125, 250, 500 μg/plate (TA100, TA1535, TA98 strains)
, 15.6, 31.3, 62.5, 125, 250, 500, 1000 μg/plate (WP2uvrA strain), and 3.91, 7.81, 15.6, 31.3, 62.5, 125, 250 μg/plate (TA1537 strain)
+S9 mix: 15.6, 31.3, 62.5, 125, 250, 500, 1000 μg/plate (all strains)
Vehicle
- Vehicle(s)/solvent(s) used: Acetone
Controls
Negative controls
no
Solvent / vehicle controls
yes
True negative controls
no
Positive controls
yes
Positive control substance
other: other: -S9 mix: 2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide (TA 100, TA98 and WP2 uvrA), sodium azide (TA1535) and 9-aminoacridine hydrochloride (TA1537). +S9 mix: 2-aminoanthracene (all strains)
Details on test system and conditions
RANGE-FINDING/SCREENING STUDIES:Concentration: 9.19, 20.5, 51.2, 128, 320, 800, 2000, 5000 μg/plate
Cytotoxic conc.: No


METHOD OF APPLICATION: Preincubation
DURATION
- Preincubation period: 20 min at 37 ℃
- Exposure duration:48 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 1
DETERMINATION OF CYTOTOXICITY
- Method: other: growth inhibition
Evaluation criteria
In any strain(s) tested with or without S9 mix, when the mean number of revertant colonies per plate increased twice more than that of the negative control and when the increase was shown to be dose-related and reproducible, the chemical was judged mutagenic.
Statistics
No
Results and discussions
Test results
Species/strain
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation
with and without
Test system
all strains/cell types tested
Genotoxicity
negative
Cytotoxicity
no
Vehicle controls valid
yes
Negative controls valid
not examined
Positive controls valid
yes
Species/strain
E. coli WP2 uvr A
Metabolic activation
with and without
Test system
all strains/cell types tested
Genotoxicity
negative
Cytotoxicity
no
Vehicle controls valid
yes
Negative controls valid
not examined
Positive controls valid
yes
Any other information on results incl. tables

Figures and Tables (in English) are available in the following full report of the study.

http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF122-01-0e.pdf

Applicant's summary and conclusion
Interpretation of results
negative
Conclusions
In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, and TA1537, and Escherichia coli WP2uvrA (OECD TG 471), 4-chlorobenzoyl chloride was negative with or without metabolic activation.
Endpoint study record: Genetic toxicity in vitro.002
UUID
 
IUC5-1cc6257a-ecfb-4760-896a-031e4df5890e
Dossier UUID
 
0
Author
 
dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:18:26 JST
Remarks
   
   
Administrative Data
Purpose flag
key study
Study result type
experimental result
   
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
OECD Test Guideline study under GLP condition
Data source
Reference
Reference type
Author
Year
Title
Bibliographic source
Testing laboratory
Report no.
Owner company
Company study no.
Report date
study report
MHW (Ministry of Health and Welfare), Japan
2006
In Vitro Chromosomal Aberration Test of 4-chlorobenzoyl chloride on Cultured Chinese Hamster Cells.
Japan Existing Chemical Data Base (JECDB)
Biosafety Research Center, Foods, Drugs and Pesticides (Anpyo Center)
       
Data access
data published
Materials and methods
Type of genotoxicity
chromosome aberration
Type of study
in vitro mammalian chromosome aberration test
Test guideline
Qualifier
Guideline
Deviations
according to
OECD Guideline 473 (In vitro Mammalian Chromosome Aberration Test)
no
according to
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
no
GLP compliance
yes
Test materials
Identity of test material same as for substance defined in section 1 (if not read-across)
yes
Test material identity
Identifier
Identity
CAS number
120-01-0
Details on test material
- Name of test material (as cited in study report): 4-chlorobenzoyl chloride
- Molecular weight: 175.01
- Physical state: Colorless liquid
- Analytical purity: 99.79%
- Melting point/ boiling point: 12—14°C/222°C
-Solubility: Very soluble in acetone (656 mg/mL), methanol, ethanol, ether, ketone, and toluene, and insoluble in water
- Vapor pressure: 110°C /20 mmHg
- Specific gravity: 1.377/20°C
- Odor: Very irritating odor
- Supplier: Iharanikkei Chemical Industry Co., Ltd
- Lot/batch No.: I5001
- Storage condition of test material: Room temperature
Method
Target gene
Chromosome
Species/strain
Species/strain
other: Chinese hamster lung(CHL/IU) cells
Metabolic activation
with and without
Metabolic activation system
rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations
-S9 mix (continuous treatment): 0, 74.1, 106, 151, 216, 309, 441 ug/mL-S9 mix (short-term treatment): 0, 106, 151, 216, 309, 441, 630 ug/mL+S9 mix (short-term treatment): 0, 106, 151, 216, 309, 441, 630, 900 ug/mL
Vehicle
- Vehicle(s)/solvent(s) used: Acetone
Controls
Negative controls
no
Solvent / vehicle controls
yes
True negative controls
no
Positive controls
yes
Positive control substance
mitomycin C
cyclophosphamide
Details on test system and conditions
METHOD OF APPLICATION: Exposure duration: [continuous treatment]: 24 hrs [short-term treatment]:6 hrs + 18 hr
SPINDLE INHIBITOR: Colcemid
STAIN: Giemsa stain for 12 min.
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 200 cells / dose
DETERMINATION OF CYTOTOXICITY
- Method: relative total growth
Evaluation criteria
For the evaluation of the frequencies of structural aberrations and of polyploidy induced, the following criteria, which are usually used for chromosomal aberration testing with CHL, were employed.Appearance incidence of cell with chromosomal aberrations:Negative(-): less than 5%Equivocal(±): 5% or more, less than 10%Positive(+): 10% or more
Statistics
Fisher and Chochran-Armitage trend tests (one-sided test, P = 2.5%)
Results and discussions
Test results
Species/strain
other: Chinese hamster lung (CHL/IU) cells
Metabolic activation
with and without
Test system
all strains/cell types tested
Genotoxicity
negative
Cytotoxicity
no
Vehicle controls valid
yes
Negative controls valid
not examined
Positive controls valid
yes
Any other information on results incl. tables

Figures and Tables (in English) are available in the following full report of the study.

http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF122-01-0f.pdf

Applicant's summary and conclusion
Interpretation of results
negative
Conclusions
4-Chlorobenzoyl chloride did not induce chromosomal aberrations in cultured cells.
Executive summary

Anin vitrochromosomal aberration test using CHL/IU cells (OECD TG 473) was negative with or without metabolic activation.

7.8 Toxicity to reproduction
7.8.1 Toxicity to reproduction
Endpoint study record: Toxicity to reproduction.001
UUID
 
IUC5-425c2820-7a3b-4906-ba61-2f2048c78a20
Dossier UUID
 
0
Author
 
dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:18:44 JST
Remarks
   
   
Administrative Data
Purpose flag
key study
Study result type
experimental result
   
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
OECD Test Guideline study under GLP condition
Data source
Reference
Reference type
Author
Year
Title
Bibliographic source
Testing laboratory
Report no.
Owner company
Company study no.
Report date
study report
MHW (Ministry of Health and Welfare), Japan
2011
A combined repeated-dose/reproductive-developmental toxicity study of 4-chlorobenzoyl chloride by oral administration in rats.
Japan Existing Chemical Data Base (JECDB)
BoZo Research Center Inc.
       
Data access
data published
Cross-reference to same study
7.5.Repeated dose toxicity: oral: Repeated dose toxicity: oral.001
Materials and methods
Test type
screening
Limit test
no
Test guideline
Qualifier
Guideline
Deviations
according to
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
no
GLP compliance
yes
Test materials
Identity of test material same as for substance defined in section 1 (if not read-across)
yes
Test material identity
Identifier
Identity
CAS number
120-01-0
Details on test material
- Name of test material (as cited in study report): 4-chlorobenzoyl chloride
- Molecular weight: 175.01
- Physical state: Colorless liquid to white crystal mass
- Analytical purity: 99.6%
- Melting point/ boiling point: 12°C (solid point)/220-222°C
-Flash point: 118°C
- Solubility: Very soluble in acetone (656 mg/mL), methanol, ethanol, ether, ketone, and toluene, and insoluble in water
- Vapor pressure: 110°C /20 mmHg
- Specific gravity: 1.377/20°C
- Odor: Very irritating odor
- Supplier: Iharanikkei Chemical Industry Co., Ltd
- Lot/batch No.: KSSFK
- Storage condition of test material: Room temperature
Test animals
Species
rat
Strain
Crj: CD(SD)
Sex
male/female
Details on test animals and environmental conditions
TEST ANIMALS
- Source: Atsugi Breeding Center, Charles River Laboratories Japan, Inc.
- Age at study initiation:10 weeks of age
- Weight at study initiation: 395-476 g for males and 225-282 g for females
- Housing: bracket-type metallic wire-mesh cages (W 250 × D 350 × H 170 mm)- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:19 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21 to 24°C
- Humidity (%):40 to 56%
- Air changes (per hr):10 to 15 times per hour
- Photoperiod (hrs dark / hrs light):12-hour lighting per day
Administration / exposure
Route of administration
oral: gavage
Vehicle
corn oil
Details on exposure
PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in corn oil for injection.
VEHICLE
- Justification for use and choice of vehicle: No data
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): V0M3906 produced by Nacalai Tesque, INC.
- Dosing volume: 5 mL/kg bw
- Stability (test solutions): At least 7 days
- Storage condition of test solution: Stored in a refrigerator
Details on mating procedure
- M/F ratio per cage:1:1
- Length of cohabitation:up to 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no]
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
Test suspensions at each concentration to be used for males in week 1 and six week of administration were analyzed by the HPLC method at Bozo Research Center Inc. Results showed that the concentration of the test article in each suspension was 98.0 to 104.0% of the nominal concentration and both values were within the acceptable range (concentration: percentage of the nominal concentration, 100 ± 10%; C.V.: 10% or below)
Duration of treatment / exposure
(P) Males: 42 days including 14 days pre-mating, mating, and thereafter 14 days
(P)Females: 42-48 days including 14 days pre-mating, mating and gestation periods and the days until day 4 of lactation
Frequency of treatment
Daily: 7 times / week
Doses / concentrations
0 (vehicle), 20, 100 and 500 mg/kg bw/day
Basis
actual ingested
No. of animals per sex per dose
12 animals/sex/dose
Five out of 12 males at 0 and 500 mg/kg bw/day were used as a recovery assessment group. In addition, 10 females/dose were administered 0 and 500 mg/kg bw/day for 42 days without mating and examined after the administration period or after a 14 day recovery period.
Control animals
yes, concurrent vehicle
Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
Males and females: once before the start of administration, 3 times/day during the administration period, and once during the recovery period
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Males: once before the start of administration, during the administration and recovery periods
Females: once before the start of administration, days 1, 7, 14 and 20 of gestation, and day 4 of lactation
BODY WEIGHT: Yes
- Time schedule for examinations:
Males in the main groups were weighed on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39 and 42 of administration and on the day of necropsy, and males and females in the recovery groups were weighed on days 1, 4, 8, 11 and 14 of recovery and on the day of necropsy in addition to the measurement days for males in the main groups.
Females in the main groups were weighed on days 1, 4, 8, 11 and 15 of administration (uncopulated animals were weighed on day 18 and 22 of administration as well), days 0, 4, 7, 11, 14, 17 and 20 of gestation, days 0 and 4 of lactation and the day of necropsy.
FOOD CONSUMPTION : Yes
- Food consumption (g/day/rat) for each animal determined from the difference of the of the previous day's feeding amount: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
males in the main groups on days 1, 4, 8, 11, 15, 32, 36, 39 and 42 of administration; males and females in the recovery groups on days 1, 4, 8, 11 and 14 of recovery in addition to the measurement days for males in the main groups; and females in the main groups on days 1, 4, 8, 11 and 15 of administration, days 1, 4, 7, 11, 14, 17 and 20 of gestation and days 2 and 4 of lactation.
COMPOUND INTAKE: No
FOOD EFFICIENCY: No
WATER CONSUMPTION: No
Estrous cyclicity (Parental animals)
Vaginal smears were collected from all females in the main groups and microscopically examined every day from the day after the start of administration until the day copulation was confirmed. During the pre-mating administration period, vaginal smear pictures were classified as proestrus, estrus, metestrus or diestrus and examined for the frequency of estrus and interval between estruses (estrous cycle). During the mating period, vaginal smears were examined for the presence of sperm.
Sperm parameters (Parental animals)
Parameters examined in P male parental generations: testes weight, epididymides weight
Litter observations
PARAMETERS EXAMINED:The following parameters were examined in F1 offspring: Number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, and weight gain.
GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.
Postmortem examinations (Parental animals)
SACRIFICE: Male animals: Rats were euthanized by exsanguination under ether anesthesia on the day after the last administration. Maternal animals: Rats were euthanized by exsanguination under ether anesthesia on day 4 of lactation.

GROSS PATHOLOGY AND ORGAN WEIGHTS:Yes Brain, puitality, thyroids(including parathyroids), thymus, heart, liver, spleen, kidneys, adrenals, seminal, prostate, testes, epididymis, ovaries, uterus
HISTOPATHOLOGY: Yes Cerebrum, cerebellum (including pontocerebellar), sciatic nerve, spinal cord (thoracic), eye, optic nerve, Harder gland, pituitary, thyroid, parathyroid, adrenal glands, thymus, spleen, submandibular lymph nodes, mesenteric lymph nodes, heart, thoracic aorta, trachea, lung (including bronchial), tongue, larynx, esophagus, stomach, duodenum, jejunum, ileum (including Peyer's patches), cecum, colon, rectum, submandibular gland, sublingual gland, liver, pancreas, kidney, bladder, testis, ovary, epididymis, uterus, vagina, prostate, seminal vesicles (including the coagulating gland), mammary gland (groin), sternum and femur (including bone marrows), femoral skeletal muscle, skin (groin), macroscopic lesions, and parts for identification (auricles)
Postmortem examinations (Offspring)
SACRIFICE: The F1 pups were euthanized on PND 4 by exsanguination under ether anesthesia.
GROSS NECROPSY: Yes
Statistics
The data were analyzed for homogeneity of variance by the Bartlett test (level of significance: 0.01, two-tailed). If variances were homogeneous, data was analyzed by the Dunnett test, whereas heterogeneous data was analyzed by a Steel test. In the recovery test, these values of two groups were analyzed by F test and Student or Aspin-Welch t-test. Frequency data were analysed by Fisher test. Statistical significance was set at < 5% by two-sided
Reproductive indices
) Each parameter was determined by the following equations:
Copulation index (%) = (No. of copulated animals/No. of co-housed animals) × 100
Fertility index (%) = (No. of pregnant females/No. of copulated females) × 100
Insemination index (%) = (No. of pregnant females/No. of copulated males) × 100
Duration of gestation (days) = day 0 of lactation – day 0 of gestation
Delivery index (%) = (No. of females delivered liveborn pups/No. of pregnant females) × 100
Implantation index (%) = (No. of implantation sites/No. of corpora lutea) × 100
Stillborn index (%) = (No. of stillborn pups/Total No. of pups born) × 100
Liveborn index (%) = (No. of liveborn pups/Total No. of pups born) × 100
External abnormalities (%) = (No. of pups with external abnormalities/No. of liveborn pups) × 100
Sex ratio = No. of males/(No. of males + No. of females)
Viability index (%) = (No. of surviving pus on day 4 after birth/No. of liveborn pups on day 0 after birth) × 100
Offspring viability indices
Number of live pups on day 0 of lactationBirth index (%) = (Number of live pups on day 0/Number of implantation sites) ×100
Live birth index (%) = (Number of live pups on day 0/Number of pups born) ×100
Pups weight on day 0 of lactationSex ratio on day 0 of lactation
Number of live pups on day 4 of lactation
Pups weight on day 4 of lactation
Sex ratio on day 4 of lactation
Viability index = (Number of live pups on day 4 after birth/Number of live pups born) ×100
Results and discussions
Effect levels
Endpoint
Generation
Sex
Effect level
Based on
Basis for effect level / Remarks
NOAEL (reproduction)
P
male/female
500 mg/kg bw/day (actual dose received)
 
no effects on reproduction
NOAEL (development)
F1
male/female
100 mg/kg bw/day (actual dose received)
 
The body weights of pups on postnatal day (PND) 0 and PND 4 were decreased in pups of both sexes following 500 mg/kg bw/day dosing
Results of examinations: parental animals
Clinical signs (parental animals)
yes (see Details on results)
Body weight and food consumption (parental animals)
no effects
Test substance intake (parental animals)
no effects
Reproductive function: estrous cycle (parental animals)
no effects
Reproductive function: sperm measures (parental animals)
not examined
Reproductive performance (parental animals)
no effects
Organ weights (parental animals)
no effects
Gross pathology (parental animals)
no effects (on reproductive organs)
Histopathology (parental animals)
no effects (on reproductive organs)
Details on results (parental animals)
CLINICAL SIGNS AND MORTALITY: Mortality: No animal died in any group.Clinical signs: Salivation was observed in 1 to 7 males receiving 500 mg/kg bw/day after Day 12 during the dosing period. Salivation was observed in 1 mating female receiving 500 mg/kg bw/day after Day 12, however this sign was not observed after Day 16 of gestation. No clinical signs were observed in both sexes of recovery animals during the recovery period.
1) Estrous Cycle
There were no animals showing abnormal estrous cycles, and there were no significant differences in the average length of the estrous cycle between the control group and any treatment groups.
2) Results of Mating
There were no significant differences in the number of elapsed days until copulation, copulation index, insemination index or fertility index between the control group and any treatment groups.
3) Delivery Data and Delivery
With regard to delivery status, all pregnant animals delivered normally between day 21 and day 23 of gestation excluding one dam of 100 mg/kg bw/day group. There were no significant differences in the delivery index, duration of gestation, number of corpora lutea, number of implantation sites, implantation index, stillborn index, number of liveborn pups or liveborn index between the control group and any treatment groups. Significantly increase of delivery index was observed in dam receiving 500 mg/kg bw/day, which showed high value, however this change was determined the incidental effect.
Results of examinations: offspring
Viability (offspring)
no effects
Clinical signs (offspring)
no effects
Body weight (offspring)
yes (The body weights of pups on postnatal day (PND) 0 and PND 4 were decreased in pups of both sexes following 500 mg/kg bw/day dosing)
Sexual maturation (offspring)
not examined
Organ weights (offspring)
not examined
Gross pathology (offspring)
no effects
Histopathology (offspring)
not examined
Applicant's summary and conclusion
Conclusions
The NOAELs for rat reproductive toxicity and developmental toxicity were determined to be 500 mg/kg bw/day and 100 mg/kg bw/day, respectively.
Executive summary

In the combined repeated oral dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422), reproductive parameters were not affected up to 500 mg/kg bw/day. The body weights of pups on postnatal day (PND) 0 and PND 4 were decreased in pups of both sexes following 500 mg/kg bw/day dosing. The NOAELs for rat reproductive toxicity and developmental toxicity were determined to be 500 mg/kg bw/day and 100 mg/kg bw/day, respectively.

14 Information requirements
14.2 Alternative name request
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IUC5-a2a9360b-d978-4902-b119-ef75ccfb7959
Dossier UUID
 
0
Author
 
dra / National Institute of Health Sciences / Tokyo / Japan
Date
 
2017-01-04 16:23:46 JST
Remarks
   
General information
Reference substance name
4-chlorobenzoyl chloride
EC inventory
EC number
204-515-3
CAS number
122-01-0
EC name
4-chlorobenzoyl chloride
Molecular formula
C7H4Cl2O
Reference substance information
CAS information
CAS number
122-01-0
Molecular and structural information
Molecular formula
C7H4Cl2O
UUID
 
IUC4-b036ff75-0f3c-323b-b200-ed5f46cf5101
Dossier UUID
 
0
Author
 
XML Transformation V4.0 Plug-In
Date
 
2011-06-23 11:55:01 JST
Remarks
 
Successfully migrated to IUCLID 5.5 format.
General information
Legal entity name
National Institute of Health Sciences
Identifiers
Other IT system identifiers
Flags
IT system
ID
Remarks
 
LEO
10767
 
 
IUCLID4
16558402024DIV750
 



Contact information
Contact address
Address
1-18-1 kamiyoga
Address
Setagaya-ku
Postal code
158-8501
Town
Tokyo
Country
Japan
Contact persons
Organisation
National Institute of Health Sciences
Department
Division of Risk Assessment
Title
Dr.
First name
Akihiko
Last name
Hirose
Address
1-18-1 Kamiyoga
Address
Setagaya-ku
Postal code
158-8501
Town
Tokyo
Country
Japan