N-acetylsulphanilyl chloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Data source

Reference

Reference 1

Reference Type:

other: study report

Title:

Unnamed

Year:

2003

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD TG No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

Principles of method if other than guideline:

According to OECD TG No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4-Methylbenzenesulfonyl chloride

Cas Number:

98-59-9

Molecular formula:

C7H7ClO2S

IUPAC Name:

4-Methylbenzenesulfonyl chloride

Test material form:

not specified

Details on test material:

Name: p-Toluenesulfonyl chloride
CAS No.: 98-59-9
Molecular Formula: C7-H7-Cl-O2-S
Molecular Weight: 190.6493 g/mol
SMILES: Cc1ccc(cc1)S(=O)(=O)Cl

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation:9 weeks old
- Weight at study initiation: - 363.1 g for males and 198.5 - 229.3 g for females

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

unchanged (no vehicle)

Details on exposure:

No Data Available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Details on mating procedure:

No Data Available

Duration of treatment / exposure:

34, 36 - 45, and 51 days for male, copulated female and not copulated female animal

Frequency of treatment:

Daily

Duration of test:

34-51, covering the full duration of pregnancy

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 150, 350 and 750 mg/kg/day
Basis:

No. of animals per sex per dose:

60 animals for each sex

Control animals:

yes, concurrent no treatment

Details on study design:

No Data Available

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Weekly

BODY WEIGHT: Yes
- Time schedule for examinations:once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of the gestation period, date of delivery, and 4 days of the lactation day

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
once a week except mating period

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day #
- Organs examined:

OTHER:

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:

Fetal examinations:

There were no abnormalities in the treatment groups but in the control groups, a case
of runt and 2 cases of blunt-tipped tail were observed. On the day 4 of lactation, 2 cases of blunt-tipped tail were observed but no abnormalities in the treatment groups

Statistics:

Statistical decision tree, but in case of recovery group, either two-side Student’s t-test or two-side Aspin-Welch t-test was used. In case of categorical data, two-sided Fisher’s exact test was used

Indices:

Reproductive indices:
- Copulation index
- number of implantations
- number of corpus luteum
- Number of females pregnant
Offspring viability indices:
- Number of life pups
- post natal loss
- pre and post-implantation loss

Historical control data:

Tissues were fixed to do histopathologic tests such
as testes, epididymides, ovaries, accessory sex organs for all animals,
brain (including cerebrum, cerebellum and pons), spinal cord, stomach,
small and large intestines (including peyer’s patches), liver, kidneys,
adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary
bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or
tibial), bone marrow

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, non-treatment-related

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY
No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18
In the control groups, there were no specific clinical symptoms during test period.
150 mg: Intermittent (blood-like) salivation and staining around mouth (3/18 males, 6/18 females), and in females at delivery: difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection.
350 mg: Intermittent (blood-like) salivation and staining around mouth were observed after day 15 and (blood-like) staining around nose (7/12 males, 4/12 females). Iintermittent soft stool and staining around anorectal region were observed for the most male animals and in 2 females. One female showed difficult delivery, lacrimation, and irregular respiration from day 4.
750 mg: soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawing position, hypoactivity, and abdominal swelling.
In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

BODY WEIGHT AND WEIGHT GAIN
From start of dosing BW gain at 750 mg/kg group a bit lower resulting to a lower BW of 8% in males and 5.5% in females compared to controls during first week of recovery which partly recovered during the second week of the recovery period.

FOOD CONSUMPTION:
Only during the first week food consumption some somewhat lower in the 750 mg group.

HAEMATOLOGY
No major changes were seen compared to control, although the reported that dose related decrease in RBC and HCT and an increase in platelet counts were observed in males.

CLINICAL CHEMISTRY
In males and females BUN is decreased compared to control at 750 mg/kg but not in the recovery groups. Total cholesterol was decreased in the recovery groups. In females chloride is decreased at 750 mg/kg.

NEUROBEHAVIOUR
No significant effects were found.

ORGAN WEIGHTS
No effects were seen in sex-organ weights. Weight of the spleen was increased in treatment groups compared to controls for both males and females, although in females not relative weight. No differences in spleen weights were seen in recovery groups. In males the absolute, but not the relative, weight of the heart was decreased in the 750 mg/kg group. In the female recovery group the weights for adrenal and the brain were increased.

GROSS PATHOLOGY
No information provided.

HISTOPATHOLOGY:
dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: not specified

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Number of pups born, viability and sex ratio: No significant difference was observed between the treatment groups and the control group at the time of the delivery and on the day 4 of the lactation.
External examination of pups (group) showed no developmental abnormalities

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

external malformations

skeletal malformations

visceral malformations

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Overall developmental toxicity

Developmental effects observed:

no

Treatment related:

no

Any other information on results incl. tables

Body weights of pups (group)

Group	Sex	Pup BW at birth		At lactation day 4
		Male	Female	Male	Female
0	Mean	6.25	5.75	8.57	8.03
	SD	0.6	0.66	1.26	1.18
	N	67	69	66	69
150	Mean	5.99	5.62	8.56	7.98
	SD	0.56	0.46	1.34	1.27
	N	62	70	63	66
350	Mean	6.37	5.73	9.71	8.59
	SD	0.9	0.8	2.17	1.57
	N	59	48	55	44
750	Mean	5.98	5.59	8.7	8.21
	SD	0.6	0.51	0.87	0.74
	N	48	51	46	49

 

External examination of pups (group)

Group	No. of animals	At birth			No. of animals	Lactation day 4
		No.of pups examined	No.of pups	Obser-vations		No.of pups examined	No.of pups	Obser-vations
0	11	143	140	NGF	11	136	134	NGF
			2	BT			2	BT
			1	Runt
150	11	143	144	NGF	11	129	129	NGF
350	10	116	116	NGF	9	100	100	NGF
750	9	105	105	NGF	8	95	95	NGF

NGF: No Gross findings

BT: Blunt-tipped Tail

Applicant's summary and conclusion

Conclusions:

The No observed adversed effect level NOAEL value of 4-Methylbenzenesulfonyl chloride on rat was observed at a dose level of 750 mg/kg/day.

Executive summary:

The toxicity of Tosyl chloride has been evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and in compliance to GLP. Tosyl chloride was dose by gavage to groups of 12 Sprague-Dawley rats/sex/dose level at levels of 0, 150, 350 and 750 mg/kg/day for 35 days and 36 - 51 days for male and female rats, respectively. A separate group of 6 animals/sex were added for a 14-day recovery group to the control and the high dose groups. No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18. Some clinical signs were observed at the dose level of 150 mg/kg/day in both male and females such as intermittent (blood-like) salivation and staining around mouth. Effects were more severe at 350 mg/kg and at 750 mg/kg reported clinical signs were soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. A decreased BW gain was observed in the 750 mg group resulting to a lower BW that was maximal 8% lower in males and 5.5% in females compared to controls. Food consumption was a bit lower during the first week in the 750 mg group. Histopathology showed dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg.In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

Thus from above findings we can conclude that NOAEL for developmental effects was stated to be above the highest tested dose (750 mg/kg/day)