3,5-dimethylbenzoyl chloride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4 November 1992 - 18 November 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japan 59 NohSan Notification No. 4200

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,5-dimethylbenzoyl chloride

EC Number:

413-010-9

EC Name:

3,5-dimethylbenzoyl chloride

Cas Number:

6613-44-1

Molecular formula:

C9H9ClO

IUPAC Name:

3,5-dimethylbenzoyl chloride

Details on test material:

DMBC
Appearance: clear liquid

Test animals

Species:

rat

Strain:

other: Crl:CDBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Kingston, Stone Ridge, NY.
- Age at study initiation: Adult. The males were approximately 55 days old and the females were approximately 65 days old.
- Weight at study initiation: The fasted body weights ranged from 197 - 223 g for males and from 188 - 216 g for females.
- Fasting period before study: Overnight.
- Housing: The animals were housed 1 per cage in suspended stainless steel cages (7 x 13.5 x 8 in., i.e. 18 x 34 x 20 cm) with wire mesh fronts and bottoms. Cages were suspended above absorbent-paper pan liners which were changed 3 times a week.
- Diet (e.g. ad libitum): ad libitum Purina Certified Rodent Chow 5002(C) (Purina Mills Inc., Richmond, IN).
- Water (e.g. ad libitum): Free access to filtered tap water (via automatic watering).
- Acclimation period: Quarantined for approximately one week.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 23 °C
- Humidity (%): 52 - 54 % relative
- Photoperiod (hrs dark / hrs light): The light cycle was automatically controlled, 12 hr on and 12 hr off

IN-LIFE DATES: From: To: 4 November 1992 - 18 November 1992

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Dosed as a dispersion in corn oil at a constant volume of 10 mL/kg.

The animals were dosed within 90 minutes of preparation of the dispersions. After dose administration, samples were collected and submitted for analytical verification of the target concentration.

Chemical analysis confirmed that the active ingredient concentrations of the dosing solutions were within 97.7 % of the target concentration.

Doses:

500, 2000 and 5000 mg/kg bw.

No. of animals per sex per dose:

6 animals per sex per dose.

Control animals:

no

Details on study design:

The test substance was administered as a single gavage dose.

Observations and Determinations:
All animals were observed for signs of ill health, or reaction to treatment at 1, 2, 4 and 5 h after dosing and once daily thereafter for 14 days. Body weights were recorded on day 0 (prior to dosing) and on days 7 and 14. Body weights were determined for found-dead animals when they survived beyond the day of treatment.

Decedents were necropsied as death occurred. Surviving rats were killed on day 14 and necropsied.
Necropsy consisted of a gross examination of organs in situ.

Statistics:

The mortality incidences of males and females were compared with a categorical data modelling procedure using SAS CATMOD (SAS Institute Inc. SAS Users' Guide: Statistics, Version 5 Edition, p, 171 - 253. Cary, NC: SAS Institute Inc., 1985). The criterion of statistical significance was 0.05. If the results indicated a significant difference between the mortality responses for males and females, the LD50 was calculated separately by sex; otherwise the LD50 was calculated on the pooled mortality incidences at each dose.

The binomal test was used to estimate the LD50 (Stephan, C.E., "Methods for Calculating an LD50", Aquatic Toxicology and Hazard Evaluation, ASTM STP 634, F.L. Mayer and J.L. Hamelink, Eds., American Society for Testing and Materials, 1977, pp. 65 - 84). Note that this test uses the highest dose with no mortality and the lowest dose with total mortality as the associated confidence limits but does not provide a dose-response slope estimate.

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

3 162 mg/kg bw

Based on:

test mat.

95% CL:

2 000 - 5 000

Mortality:

Dose-related mortality was observed in this study (Tables 1A and 1B). The total mortality incidences (no. deaths/no. treated) for males and females in this study were as follows:
Dose (mg/kg)
500 2000 5000,
Males 0/6 0/6 1/6
Females 0/6 0/6 6/6

Since there was a statistically significant sex-related difference in mortality, the LD50 was calculated separately for males and females.

In the 5000 mg/kg group, all females were dead within 4 days of dose administration while the male decedent was dead within 2 days.

Clinical signs:

other: Clinical signs observed in this study are presented in Tables 1A and 1B. Clinical signs indicative of neurotoxicity (e.g., passive, ataxia, tremors, hyperreflexia, convulsions (opisthotonos) and twitching of the extremities) were observed in males and/or

Gross pathology:

Necropsy of the decedents revealed primarily gastro-intestinal observations (e.g., reddened, black or mucous contents, black material adhered to the mucosa). No gross changes related to the test substance were observed in survivors at necropsy (Tables 3A and 3B). Necropsy of one surviving female in the 2000 mg/kg group revealed an enlarged kidney, however, this effect was judged incidental.

Any other information on results incl. tables

Table 1A Mortality and Clinical Signs in Males

Dose (mg/kg)	Observation	Tim of Observation
		Hours				Days
		1	2	4	5	1	2	3	4	5	6	7	8	9	10	11	12	13	14
500	No. Alive No. Dead Normal   Salivation	6 0 4   2	6 0 5   1	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0	6 0 6   0
2000	No. Alive No. Dead Normal   Salivation Diarrhoea Analgenital area*	6 0 5   1 0 0	6 0 4   0 1 2	6 0 4   0 0 2	6 0 4   0 0 2	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0
5000	No. Alive No. Dead Normal   Tremors Ataxic Passive Analgenital area* Faeces: scant Faeces: none Eyes† Muzzle†	6 0 6   0 0 0 0 0 0 0 0	6 0 6   0 0 0 0 0 0 0 0	6 0 5   0 0 0 1 0 0 0 0	6 0 1   1 0 5 1 0 0 0 0	6 0 2   0 1 1 2 0 2 1 2	5 1 3   0 0 0 0 1 0 1 0	5 1 4   0 0 0 0 0 0 1 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0	5 1 5   0 0 0 0 0 0 0 0

*brown-stained

†fur surrounding is red stained

 

Table 1B Mortality and Clinical Signs in Females

Dose (mg/kg)	Observation	Tim of Observation
		Hours				Days
		1	2	4	5	1	2	3	4	5	6	7	8	9	10	11	12	13	14
500	No. Alive No. Dead Normal   Salivation Diarrhoea	6 0 5   1 0	6 0 3   0 3	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0	6 0 6   0 0
2000	No. Alive No. Dead Normal   Diarrhoea Faeces: scant Analgenital area‡	6 0 6   0 0 0	6 0 5   1 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 0   0 6 2	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0	6 0 6   0 0 0
5000	No. Alive No. Dead Normal   Convulsions Tremors Twitching Hyperreflexive Passive Prostrate Salivation Diarrhoea Analgenital area* Faeces: none Drop sheet† Muzzle† Tail-tip missing	6 0 4   0 0 0 0 0 0 1 1 0 0 0 0 0	6 0 3   0 2 0 0 0 0 1 0 0 0 0 0 0	5 1 0   1 1 3 1 2 3 0 0 1 0 0 0 0	3 3 1   0 0 0 0 2 0 0 0 0 0 0 0 0	1 5 0   0 0 0 0 0 0 0 0 0 1 0 1 0	1 5 0   0 0 0 0 1 0 0 0 1 1 1 1 0	1 5 0   0 0 0 0 0 0 0 0 1 1 1 1 1	0 6 0   0 0 0 0 0 0 0 0 0 0 0 0 0	All animals died within 4 days of dosing

‡yellow-stained

*brown-stained

†fur surrounding is red stained

 

Table 2 Individual Bodyweights (g) - Males

500 mg/kg	Day Number*				Bodyweight Change‡
Animal No.	0**	7	14	F.D.†
92-01889 92-01884 92-01908 92-01886 92-01887 92-01895	203 199 201 200 206 217	292 288 286 273 271 309	342 327 353 323 336 364	- - - - - -	139 128 152 123 130 147
Mean SD N	204 7 6	287 14 6	341 16 6	- - -	137 11 6
2000 mg/kg
92-01833 92-01899 92-01888 92-01902 92-01896 92-01903	210 223 197 210 204 218	294 328 281 304 296 313	366 395 340 362 363 379	- - - - - -	156 172 143 152 159 161
Mean SD N	210 9 6	303 16 6	368 18 6	- - -	157 10 6
5000 mg/kg
92-01904 92-01905 92-01907 92-01893 92-01891 92-01885	197 209 212 204 214 222	264 257 289 238 - 275	312 319 349 285 - 345	- - - - 184 -	115 110 137 81 - 123
Mean SD N	210 9 6	265 19 5	322 26 5	- - -	113 21 5

*If a weight is not shown, then the animal died before indicated day.

**Fasted body weights on the day of dosing.

†Found-dead body weights for animals that survived beyond the day of treatment.

‡Body-weight change is the difference between the Day 14 and Day 0 body weights.

  

Table 3A Necropsy Observations in Males

Dose (mg/kg)	500	2000	5000
	S	S	S	D
Number of Animals	6	6	5	1
No Gross Changes	6	6	5	0
Observations Intestines: reddened mucous filled Stomach: black material adhered to mucosal surface filled with black material	0 0   0   0	0 0   0   0	0 0   0   0	1 1   1   1

(S) Survivors

(D) Decendents

 

Table 3B Necropsy Observations in Females

Dose (mg/kg)	500	2000	5000
	S	S	D
Number of Animals	6	6	6
No Gross Changes	6	5	0
Observations Stomach: contains black material black material adhered to mucosal surface reddened contains solid white material Intestines: contains white mucous pale Kidney: enlarged	0 0   0 0   0 0   0	0 0   0 0   0 0   1	1 3   3 1   1 1   0

(S) Survivors

(D) Decendents 

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral LD50 for males was greater than 5000 mg/kg. The acute oral LD50 for females was 3162 mg/kg, with 95% confidence limits of 2000 and 5000 mg/kg.

Executive summary:

The acute oral toxicity of DMBC was assessed in rats, in accordance with OECD Guideline 401, US EPA 40 CFR Part 158; Guideline 81-1, US EPA 40 CFR Section 798.1175 and Japan 59 NohSan Notification No. 4200.

 

Male and female rats (6 rats/sex/dose) were gavaged with corn oil dispersions of the test substance at 500, 2000, or 5000 mg/kg body weight (10 mL/kg). In the 5000 mg/kg group, all female rats died within 4 days and one out of six male rats died within 2 days of dose administration. Clinical signs indicative of neurotoxicity (e.g., passive, ataxia, tremors, hyperreflexia, opisthotonos and twitching of the extremities) were observed in males and females in the 5000 mg/kg group. No deaths or signs of neurotoxicity were observed in males or females in the 500 and 2000 mg/kg dose groups.

 

Since there was a statistically significant sex-related difference in mortality, the LD50 was calculated separately for males and females. The acute oral LD50 for males was >5000 mg/kg. The acute oral LD50 for females was 3162 mg/kg (95% confidence limits of 2000 and 5000 mg/kg).