Benzonitrile

Endpoint summary

Description of key information

Several sub-acute and sub-chronic studies (up to 90 days) are available for the oral and inhalation route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Dose / conc.:

40 mg/kg bw/day (nominal)

Remarks:

Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes

Key result

Dose descriptor:

NOAEL

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: mortality; body weight; gross pathology; behavior

Critical effects observed:

not specified

Conclusions:

Application or 40 mg benzonitrile/kg/d for 28 days did not cause any adverse effect in Wistar rats.

Executive summary:

Application or 40 mg benzonitrile/kg/d for 28 days did not cause any adverse effect in Wistar rats.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1994

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

22 mg/kg bw/day (nominal)

Dose / conc.:

66 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

Dose / conc.:

600 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5

Control animals:

yes

Dose descriptor:

dose level: LD100

Effect level:

2 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: animals died within 2 days

Dose descriptor:

LOAEL

Effect level:

600 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No mortality; ataxia, hypoactivity; histopathology: karyomegaly and necrosis in hepatocytes

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

2000 mg/kg: All animals died within 2 days

600 mg/kg:

- No mortality

- Ataxia, hypoactivity

- histopathology: karyomegaly and necrosis in hepatocytes

200 mg/kg: No effects

Conclusions:

Application of 2000 mg benzonitrile/kg/day in mouse leads to symptoms of poisoning. All animals died within 2 days. At 600 mg/kg/d no mortality was reported but ataxia and hypoactivity was reported. Histopathology revealed karyomegaly and necrosis in hepatocytes. The NOAEL was 200 mg/kg.

Executive summary:

Application of 2000 mg benzonitrile/kg/day in mouse leads to symptoms of poisoning. All animals died within 2 days. At 600 mg/kg/d no mortality was reported but ataxia and hypoactivity was reported. Histopathology revealed karyomegaly and necrosis in hepatocytes. The NOAEL was 200 mg/kg.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1994

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 days

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

11 mg/kg bw/day (nominal)

Dose / conc.:

33 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5

Control animals:

yes

Dose descriptor:

dose level: LD100

Effect level:

1 000 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: Application of 1000 mg/kg/day in rat leads to symptoms of poisoning (ataxia, loss of motor functions, salivation). All animals died within 5 days. Pathological examination revealed tubular vacuolar degeneration in 9/10 animals.

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no kidney damage was reported.

Critical effects observed:

not specified

1000 mg/kg/day:

- Symptoms of poisoning: ataxia, loss of motor functions, salivation

- All animals died within 5 days;

- Pathology: tubular vacuolar degeneration in 9/10 animals

300 mg/kg/d:

- No mortality; no kidney damage

Conclusions:

Application of 1000 mg/kg/day in rat leads to symptoms of poisoning (ataxia, loss of motor functions, salivation). All animals died within 5 days. Pathological examination revealed tubular vacuolar degeneration in 9/10 animals. At 300 mg/kg/d no mortality and no kidney damage was reported.

Executive summary:

Application of 1000 mg/kg/day in rat leads to symptoms of poisoning (ataxia, loss of motor functions, salivation). All animals died within 5 days. Pathological examination revealed tubular vacuolar degeneration in 9/10 animals. At 300 mg/kg/d no mortality and no kidney damage was reported.

Reference 4

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

37.5 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

75 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

150 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

600 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

No. of animals per sex per dose:

10

Control animals:

yes

Key result

Dose descriptor:

NOAEL

Effect level:

37.5 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no data

Critical effects observed:

not specified

No substance related deaths occurred in both male and female mice. Both sexes in the 300 and 600 mg/kg bw dose group showed hyperactivity and ataxia. Female mice of the 600 mg/kg bw dose group displayed delayed startle responses to acoustic signals. Body weight gain of the male and female mice of the 600 mg/kg bw dose group was reduced by 21.5 % and 14.6 %, respectively, compared to the control. At the end of the experiment male and female mice in the 75 mg/kg bw dose groups and higher dose groups had significantly increased relative and absolute liver weights. In female mice of the 37.5 mg/kg bw dose group only the absolute liver weight was increased. Histopathological examinations of male mice of the 300 and 600 mg/kg bw dose groups as well as of female mice of the 600 mg/kg bw dose group revealed centrilobular hypertrophy of liver cells, increase of Kupffer cells, mineralization and cell necrosis. Kidneys of male and female mice of the three and two highest dose groups, respectively, displayed dose-related dilations of the tubuli of the inner cortex. The maximum tolerated dose for male and female mice was reported to be 37.5 mg/kg bw (no further details reported; NTP, 1994). 

Conclusions:

The NOAEL in a 90 day oral gavage study was reported to be 37.5 in female and male mice.

Executive summary:

The NOAEL in a 90 day oral gavage study was reported to be 37.5 in female and male mice.

Reference 5

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

19 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

37.5 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

75 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

150 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Basis: actual ingested

No. of animals per sex per dose:

10

Control animals:

yes

Key result

Dose descriptor:

NOAEL

Effect level:

37.5 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: nephropathy

Dose descriptor:

NOAEL

Effect level:

75 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: Nephropathy

Critical effects observed:

not specified

Over a total observation period of 13 weeks no deaths occurred. Hyperactivity and aggressiveness could be observed in rats dosed at 150 and 300 mg/kg bw. Female rats of the 300 mg/kg dose group showed a reduced strength in the hind legs and delayed response to thermic stimuli. Body weight gain of the male and female rats of this dose group was reduced by 10.6 % and 6.7 %, respectively, compared to the control. At the end of the experiment male rats in the 75 mg/kg bw dose groups and higher dose groups had significantly increased relative and absolute kidney weights. Histopathology showed a dose-dependent degeneration and enlargement of the tubuli in males of the 75 mg/kg bw dose group and higher. According to the authors these alterations are similar to the “hydrocarbon-nephropathy”. In female rats of the two highest dose groups kidney alterations are characterized by vacuolar degeneration of the cortex tubuli. The no effect level for nephropathy for male and female rats was 37, 5 mg/kg bw and 75 mg/kg bw, respectively (no further details reported; NTP, 1994). A possible α-2u-globulin nephropathy was not discussed.

Conclusions:

The NOAEL in a 90 day oral gavage study was reported to be 37.5 and 75 mg/kg/day in female and male rats, respectively.

Executive summary:

The NOAEL in a 90 day oral gavage study was reported to be 37.5 and 75 mg/kg/day in female and male rats, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

37.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Remarks:

Original reference in foreign language (Russian)

Qualifier:

no guideline followed

Principles of method if other than guideline:

exposure to 0.07 (+/- 0.01) mg/l air for 4 h/d (5 d/week; 4.5 month) in a 750 l chamber; dynamic method.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 hours/day

Frequency of treatment:

5 days/week; 4.5 month

Dose / conc.:

70 mg/m³ air (nominal)

Remarks:

Basis: nominal conc.

No. of animals per sex per dose:

10 per age (young/adult/old)

Control animals:

yes

Dose descriptor:

conc. level: 70 mg/m³

Effect level:

70 mg/m³ air (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: decrease of haemoglobin

Critical effects observed:

not specified

First transient effects in adult rats occur after 5 days, normalizing until the end of the first month (except some CNS effects). After 90 days there was a significant decrease in the number of red blood cells in adults, together with an decrease in haemoglobin and increase in the number of leucocytes.

Conclusions:

Subchronic exposure to Benzonitrile causes effects like a significant decrease in the number of red blood cells, decrease in haemoglobin and increase in the number of leucocytes. In contrast to acute exposure no age-dependency was found at a concentration of 0.07 mg/l in this study.

Executive summary:

In an inhalation toxicity study groups of 10 male albino rats of different ages (young, adult and old: body weight ranging from 60 to 370 g) were exposed to benzonitrile for 4 h in a 750 l chamber 5 days/week for 4.5 months at a concentrations of 0.07 mg/l air.

A significant decrease in the number of red blood cells, a decrease in haemoglobin and an increase in the number of leucocytes were observed. In contrast to acute exposure no age-dependency was found in this study.

Due to the poor documentation it is not possible to assess the relevance and reliability of this study.

Reference 2

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1961

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Qualifier:

no guideline available

Principles of method if other than guideline:

inhalation of 460 ppm benzonitrile for 3 consecutive days (6 h/d). Observation period 14-21 days

GLP compliance:

no

Limit test:

no

Species:

other: cats, rabbits, guinea pigs, rats, mice

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 h /d

Frequency of treatment:

3 consecutive days

Dose / conc.:

1 937 mg/m³ air (nominal)

Remarks:

Doses / Concentrations: 460 ppm
Basis: nominal conc.

No. of animals per sex per dose:

total of 2 cats, 2 rabbits, 2 guinea pigs, 4 rat (2/sex), 10 mice (5/sex)

Control animals:

not specified

Dose descriptor:

conc. level: 1937 mg/m³

Effect level:

1 937 mg/L air (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

Critical effects observed:

not specified

The cats showed no symptoms during and after the first inhalation exposure but developed imbalance and jumpiness in the course of the following exposure. Moreover, mydriasis, inappetence and a reduction in body weightcould be observed. One cat died 7 days after exposure (pyic pleuropneumonia, Perikarditis fibrinosa). The surviving cat was free of symptoms after 5 days. Rabbits and guinea pigs did not display any symptoms. One of 4 rats died after the third exposure (abscess of the throat). The other rats remained free of symptoms. Mice showed temporary apathy, imbalance, lateral position (one animal) and narcosis. 6 and 2 mice died after the second and third exposure, respectively. Autopsy of these animals revealed atelectasis of the lungs in five cases and pronounced lobular pattern of the liver. In two further animals a significant increase in fat deposits in liver was detected.

Conclusions:

Exposure of cats, rabbits, guinea pigs, rats and mice to 460 ppm benzonitril (1.9 mg/l) for 3 days (6h/d) results in species specific adverse effects. One of 2 cats died after 7 days. Rabbits and guinea pigs were did not show any symtomes. One of 3 rats died after the third exposure days. 8/10 mice died during the exposure period.

Executive summary:

Exposure of cats, rabbits, guinea pigs, rats and mice to 460 ppm benzonitril (1.9 mg/l) for 3 days (6h/d) results in species specific adverse effects. One of 2 cats died after 7 days. Rabbits and guinea pigs were did not show any symtomes. One of 3 rats died after the third exposure days. 8/10 mice died during the exposure period.

Reference 3

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1961

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Qualifier:

no guideline available

Principles of method if other than guideline:

Inhalation of 97 ppm benzonitrile for 2 weeks (5 d/w, 6 h/d) . Observation period 14-21 days

GLP compliance:

no

Limit test:

no

Species:

other: cats, rabbits, guinea pigs, rats, mice

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 h /d

Frequency of treatment:

2 weeks, 5 d/w

Dose / conc.:

408 mg/m³ air (nominal)

Remarks:

Doses / Concentrations: 97 ppm
Basis: nominal conc.

No. of animals per sex per dose:

total of 2 cats, 2 rabbits, 2 guinea pigs, 4 rat (2/sex), 10 mice (5/sex)

Control animals:

not specified

Dose descriptor:

conc. level: 408 mg/m³

Effect level:

408 mg/L air (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

mortality

Critical effects observed:

not specified

Two out of 10 mice died after day 2 and 9 of exposure. All other animals survived. No abnormal findings were reported.

Conclusions:

Inhalation of 97 ppm benzonitrile for 6 h/d caused mortality in 2/10 mice after day 2 and 9 of exposure. In cats, rabbits, guinea pigs and rats 97 ppm did not cause mortality or any gross abnormalities during a 2 week exposure .

Executive summary:

Inhalation of 97 ppm benzonitrile for 6 h/d caused mortality in 2/10 mice after day 2 and 9 of exposure. In cats, rabbits, guinea pigs and rats 97 ppm did not cause mortality or any gross abnormalities during a 2 week exposure .

Reference 4

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline available

Principles of method if other than guideline:

exposure of rats of different ages to 0.07 mg/l air for 4 h/d (5 d/week; 4.5 month); assessment of morphological changes in internal organ

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

not specified

Remarks on MMAD:

MMAD / GSD: no details reported

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 h/day

Frequency of treatment:

5 days/week for 4.5 months

Dose / conc.:

70 mg/m³ air (nominal)

No. of animals per sex per dose:

5

Control animals:

not specified

Dose descriptor:

dose level: 70 mg/m³

Effect level:

70 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: some age-dependent changes in lungs, liver, adrenal gland and spleen were reported

Critical effects observed:

not specified

Changes in the inner organs are found to be age-depending in rats when exposed to 0.07 mg benzonitrile/l air, 4 h/day, 5 days/week for 4.5 months. There were no macroscopic changes in any age group and no significant histopahological changes in young rats. In adult and old rats changes in lungs, liver, adrenal gland and spleen were observed at different levels, including pericholangitis with granular epithelial dystrophy and accumulation of erythrocytes in the capillaries of the bile duct, necrosis of liver cells, hyperplasia of spleen follicles, and inflammation of the adrenal cortex.

Conclusions:

Reputed dose exposure to Benzonitrile by inhalation caused histopathological changes of the inner organs. The degree of the changes varied distinctly between young, adult and aged rats.

Executive summary:

In a subchronic repeated dose inhalation toxicity study groups of 5 male albino rats of different age (young, adult and old: body weight ranging from 60 to 370 g) were exposed to benzonitrile for 4 h, 5 days/week for 4.5 months at a concentrations of 0.07 mg/l air.

Benzonitrile caused significant histopathological changes in visceral organs of adult but not in young rats. 

Due to the poor documentation it is not possible to assess the relevance and reliability of this study.

Reference 5

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Qualifier:

equivalent or similar to guideline

Guideline:

other: Russian guideline

Principles of method if other than guideline:

Russian methods and guidelines

GLP compliance:

no

Limit test:

no

Species:

other: rabbits and rats

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 h/day

Frequency of treatment:

5 days/week for 4.5 months

Dose / conc.:

10 mg/m³ air (nominal)

Remarks:

Basis: nominal conc.

Dose / conc.:

70 mg/m³ air (nominal)

Remarks:

Basis: nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes

Dose descriptor:

conc. level: 70 mg/m³

Effect level:

70 mg/m³ air (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: Reduced body weight, reduced activity of Cholinesterase activity; decrease of blood protein concentration; disturbance of detoxification in rat liver; increased urine production; anaemia; dystrophic and inflammatory changes in rat liver and lungs

Dose descriptor:

conc. level: 10 mg/m³

Effect level:

10 mg/m³ air (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: decrease in body weight; increase in Cholinesterase and Cytochrom oxidase activity; all physiological effects were transient; no morphological changes in visceral organs;

Critical effects observed:

not specified

Conclusions:

Subchronic repeated exposure to 70 mg/m³ Benzonitril by inhalation for 4 h/day caused severe health effects in rats and rabbits. Effects at 10 mg/m³ were considered transient. Due to the poor documentation it is not possible to assess the reliability of this study.

Executive summary:

20 rabbits and 20 rats were exposed to Benzonitrile at concentratons of 70 and 10 mg/m³ for 4 h/day, 5 days/week, 4.5 months. The clinical symptoms resemble those of Benzol intoxication. Effects at 10 mg/m³ were considered transient. The author concluded a threshold value of 10 mg/m³ and a maximum permissible concentration in the air of working areas of 1 mg/m³.

 

Due to the poor documentation it is not possible to assess the reliability of this study.

Reference 6

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Qualifier:

equivalent or similar to guideline

Guideline:

other: Russian guidelines

Principles of method if other than guideline:

Russian guidelines

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 h

Frequency of treatment:

5 days/week for 4 weeks

Dose / conc.:

70 mg/m³ air (nominal)

Remarks:

Doses / Concentrations: 0.07 +/- 0.01 mg/l

No. of animals per sex per dose:

no details reported

Dose descriptor:

conc. level: 70 mg/m³

Effect level:

70 mg/m³ air (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: lower red cell blood count, as well as erythrocytes and leukocytes in the peripheral blood, shift of the albumin-globulin ratio through increase of the α-1, α-2 and β-globulin in the blood serum

Critical effects observed:

not specified

Subchronic inhalation test using benzonitril on adult rats

 

Index	5-days			10-days			30-days
	control	test	P	control	test	P	control	test	P
Erythrocytes (in Mio.)	8.5 ± 0.1	7.2 ± 0.4	< 0.05	8.0 ± 0.3	7.9 ± 0.3		8.0 ± 0.3	8.8 ± 0.3
Leukocytes (in thousands)	10.9 ± 0.9	8.0 ± 0.7	< 0.05	11.0 ± 0.8	9.4 ± 0.8		10.5 ± 0.8	13.3 ± 1	< 0.05

 

The primary reaction of rat organs upon exposure to low level concentrations of benzonitrile occurs at an earlier stage in adult rats than in juvenile or older rats. The reaction is also earlier compensated.

The primary reaction shows in lower red cell blood count, as well as erythrocytes and leukocytes in the peripheral blood, the sum of the impacts, shift of the albumin-globulin ratio through increase of the α-1, α-2 and β-globulin in the blood serum. The character of the reaction does not change with the age of the animals.

 

Conclusions:

Exposure of rats to 70 mg benzonitrile/m³ for 4 weeks (5 d/w) results in a lower red cell blood count, lower amount of erythrocytes and leukocytes in the peripheral blood and a shift of the albumin-globulin ratio through increase of the α-1, α-2 and β-globulin in the blood serum.

Executive summary:

Exposure of rats to 70 mg benzonitrile/m³ for 4 weeks (5 d/w) results in a lower red cell blood count, lower amount of erythrocytes and leukocytes in the peripheral blood and a shift of the albumin-globulin ratio through increase of the α-1, α-2 and β-globulin in the blood serum.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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

Oral:

Subacute (14 days) studies are available in rat and mouse (NTP, 1994). Application of 1000 mg/kg/day in rat led to symptoms of poisoning (ataxia, loss of motor functions, salivation). All animals died within 5 days. Pathological examination revealed tubular vacuolar degeneration in 9/10 animals. At 300 mg/kg/d no mortality and no kidney damage was reported. Application of 2000 mg benzonitrile/kg/day in mouse led to symptoms of poisoning. All animals died within 2 days. At 600 mg/kg/d no mortality was reported but ataxia and hypoactivity was reported. Histopathology revealed karyomegaly and necrosis in hepatocytes. The NOAEL was 200 mg/kg.

According to Chaev and Foussard-Blanpin (1990) the application or 40 mg benzonitrile/kg/d for 28 days did not cause any adverse effect in Wistar rats.

Sub-chronic studies are available in rat and mouse (NTP, 1994). The NOAEL in a 90 day oral gavage study in rats was reported to be 37.5 and 75 mg/kg/day in females and males, respectively. The NOAEL in a 90 day oral gavage study in mice was reported to be 37.5 in both sexes.

Inhalation:

Results of long-term inhalation studies are available from Agaev (1975, 1977) and BASF (1961).

20 rabbits and 20 rats were exposed to benzonitrile at concentrations of 70 and 10 mg/m³ for 4.5 months (4 h/day, 5 days/week). The clinical symptoms resemble those of benzol intoxication. Effects at 10 mg/m³ were considered transient. The author concluded a threshold value of 10 mg/m³ and a maximum permissible concentration in the air of working areas of 1 mg/m³. In an inhalation toxicity study groups of 10 male albino rats of different ages (young, adult and old: body weight ranging from 60 to 370 g) were exposed to benzonitrile for 4 h in a 750 l chamber 5 days/week for 4.5 months at a concentrations of 0.07 mg/l air. A significant decrease in the number of red blood cells, a decrease in haemoglobin and an increase in the number of leucocytes were observed. In contrast to acute exposure no age-dependency was found in this study. Due to the poor documentation it is not possible to assess the relevance and reliability of these studies (Agaev, 1977). Exposure of rats to 70 mg benzonitrile/m³ for 4 weeks (5 d/w) results in a lower red cell blood count, lower amount of erythrocytes and leukocytes in the peripheral blood and a shift of the albumin-globulin ratio through increase of the α-1, α-2 and β-globulin in the blood serum (Agaev, 1975)

Exposure of cats, rabbits, guinea pigs, rats and mice to 460 ppm benzonitril (1.9 mg/l) for 3 days (6 h/d) results in species specific adverse effects (BASF, 1961). One of 2 cats died after 7 days. Rabbits and guinea pigs did not show any symptoms. One out of 3 rats died after the third exposure days. 8/10 mice died during the exposure period. Inhalation of 97 ppm benzonitrile for 6 h/d caused mortality in 2/10 mice after day 2 and 9 of exposure. In cats, rabbits, guinea pigs and rats 97 ppm did not cause mortality or any gross abnormalities during a 2 week exposure (BASF, 1961 (2)).

Justification for classification or non-classification

Based on the available data a classification for specific target organ toxicity is not warranted.