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Description of key information

TBPA: 28 D rabbit dermal; 21 D rat inhalation
TCPA (tetrachlorophthalic anhydride): 13 Wk rat gavage, 13 WK mouse gavage

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was performed by the US National Toxicology Program on the related substance tetrachlorophthalic anhydride.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Once daily, 5 days/wk, for 13 weeks.
Remarks:
Doses / Concentrations:
0, 94, 187, 375, 750, 1500 mg/kg bw
Basis:
other: gavage dose
No. of animals per sex per dose:
10M/10F
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
See rat study
Sacrifice and pathology:
See rat study
Other examinations:
See rat study
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
No effects on sperm morphology and vaginal cytology.
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See results section.
Critical effects observed:
not specified
Conclusions:
Unlike rats, no adverse effects were seen in mice administered tetrachlorophthalic anhydride at doses as high as 1500 mg/kg bw per day, 5 d/wk, for 13 weeks.
Executive summary:

Unlike rats, no adverse effects were seen in mice administered tetrachlorophthalic anhydride at doses as high as 1500 mg/kg bw per day, 5 d/wk, for 13 weeks.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was performed by the US National Toxicology Program on the related substance tetrachlorophthalic anhydride.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Obtained from Simonsen Laboratories, Gilroy, CA.
Acclimated ~14 prior to start of study.
Age at study inititation: Rats (6 wks), Mice (5 wks)
Assigned to groups randomlly.
Fed NIH-07 Open Formula Mash ad libitum
Rats house 5/cage; Mice individually
Temperature 67-77 degrees F
30-70% relative humidity
Minimum of 10 air changes/hr.
Lighting 12 hr/d.

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Once daily, 5 d/wk, for 13 weeks.
Remarks:
Doses / Concentrations:
0, 94, 187, 375, 750, 1500 mg/kg bw
Basis:
other:
No. of animals per sex per dose:
10M/10F/dose
Control animals:
yes, concurrent vehicle
Details on study design:
wieghed weekly. necropsies on all animals. Measured weight of brain, heart, right kidney, liver, lung, spleen, right testis, and thymus. Complete histopathology on controls, all animals in the highest dose group with at least 60% survival, and on all animals including those that dies or were killed moribund before the end of the studies in the higher dose groups. Target tissues ID'd, and examined in all animals from the lower dose groups until a no effect level was determined. all gross lesions also examined histologically. In rats, the target organ was the kidney and was evaluated in all males and females in all dose groups. No target organs were ID'd in mice.

Clinical pathology performed in rats i nteh 0, 94, 375 and 1500 mg/kg groups on days 6, 20, and at the end of the study. Hematology performed in all animals at end of study. blood collected via retroorbital sinus after CO2 anesthesia.

Sperm morphology in male rats from the 0, 94, 375 and 750 mg/kg groups. Vaginal cytology performed on female rats from the 0, 94, 375 and 1500 mg/kg groups. Similar exams on mice in hte 0, 94, 375 and 1500 mg/kgg. Methods were those of Morrissey et al. 1988.




Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
5 M rats, 1500 mg/kg, died during wks 5-8 due to toxicity. 2 F rats, 1 each @ 750 and 1500 mg/kg died during wks 6 - 10 due to xicity.
Mortality:
mortality observed, treatment-related
Description (incidence):
5 M rats, 1500 mg/kg, died during wks 5-8 due to toxicity. 2 F rats, 1 each @ 750 and 1500 mg/kg died during wks 6 - 10 due to xicity.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean final body weights and weight gains of male rats in the 375, 750 and 1500 mg/kg groups and F rats in all dose groups were less than those of controls
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreased in rats of all groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative kidney weights increased in dose-dependednt manner in female rats. In males increased relative kidney weights from 187 mg/kg and above.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In male rats, renal tubule degnerative changes characterized by tubule epitheial necrosis at the higher dose levels and tubule dilation at lower dose levels. Necrosis of the tubule epithelium was seen in the nmajority ofmale and female rats in the 1500 m
Details on results:
Sperm morphology and vaginal cytology evaluations in rats revealed no changes between control and treated animals.
Dose descriptor:
LOAEL
Effect level:
94 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Clear evidence of renal toxicity.
Critical effects observed:
not specified
Conclusions:
Clear evidence of renal toxicity in rats was observed following administration of tetrachlorophthalic anhydride in corn oil by gavage for 13 weeks. The no-observed-adverse-effect level for histopathological lesions in this tissue was not achieved with doses as low as 94 mg/kg/d.
Executive summary:

Clear evidence of renal toxicity in rats was observed following administration of tetrachlorophthalic anhydride in corn oil by gavage for 13 weeks. The no-observed-adverse-effect level for histopathological lesions in this tissue was not achieved with doses as low as 94 mg/kg/d.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
94 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
K2
System:
urinary
Organ:
kidney

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is old, but well reported and included the majority of endpoints typical of a guideline study.
Qualifier:
no guideline available
Principles of method if other than guideline:
Whole body inhalation exposures for 5d/wk for 3 weeks.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Spartan
Sex:
male/female
Details on test animals or test system and environmental conditions:
housed individually in temperature and humidity controlled room. Purina Rat Chow and water available ad libitum.
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Each group placed in sealed 59.1 L gass chambers and exposed to a dynamic atmosphere containing the test article or air only. To prevent piling up during the exposure, rats were separated by sex into 4 units of 2 or 3 rats each. Addition of the test material was controlled by a Wright Dust Feeder. Dired and filtered air was passed through the mechanism and directly into the exposure chamber. Air flow was regulated by a flowmeter.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 hours, 5 days weekly for 3 weeks.
Frequency of treatment:
5 days weekly for 3 weeks.
Remarks:
Doses / Concentrations:
0, 2, 8 mg/L
Basis:
nominal conc.
No. of animals per sex per dose:
5M/5F
Dose descriptor:
NOAEC
Effect level:
2 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: lack of systemic toxicity
Critical effects observed:
not specified

Statistical analysis not performed.

Mean Male Body Weights (g). SD not available.

Group

Day of Test

0

7

14

21

Control

248.4

280.6

308.6

326.0

2 mg/L

247.4

261.0

275.6

307.8

8 mg/L

248.0

274.4

292.8

305.6

Mean Female Body Weights (g). SD not available.

Group

Day of Test

0

7

14

21

Control

226.0

236.2

250.8

259.2

2 mg/L

223.8

220.4

225.0

235.4

8 mg/L

220.8

222.8

232.8

229.0

Mean Weekly Food Consumption by Male Rats (g). SD not available.

Group

Week of Test

0

1

2

3

Control

164.4

186.4

197.2

171.6

2 mg/L

164.4

159.4

173.2

167.6

8 mg/L

163.8

161.8

166.2

154.2

Mean Weekly Food Consumption by Female Rats (g). SD not available.

Group

Week of Test

0

1

2

3

Control

138.6

135.0

148.4

141.0

2 mg/L

141.4

123.8

122.6

119.2

8 mg/L

142.8

120.6

130.6

114.6

Mean Bromine Content (ppm) of Selected Tissues After 21 Exposures, Male and Female Rats Combined. SD not available.

Group

Bromine Content (ppm)

Fat

Liver

Lung

Kidney

Blood

Control

1.50

3.14

11.64

8.23

7.83

8 mg/L

13.54

9.91

38.88

24.79

23.50
Conclusions:
NOAEC for systemic toxicity was 2 mg/L in this 3 wk inhalation study in rats.
Executive summary:

In a 21 d inhalation study, albino rats were exposed to a micronized form of the test article to atmospheric concentrations of 2 and 8 mg/L. Rats were expsosed for 4 h/d, 5 d/wk for 3 wk. A control group was exposed only to air in the test chambers. Observations were made daily and body weights and food consumption measured weekly. Hemtological, biochemical adn urinalysis studies were conducted at 20 d. Bromine analysis by neutron activation of liver, fat, kidney, lung and blood samples were conducted on samples collected at terminal necropsy.

Clinical observations in the treated groups included salivation, lacrimation, nasal discharge, and nasal porphyrin discharge, Respiratory congestion was observed in one animal at the 8 mg/L dose. No deaths occrred in either the control or treated groups. Slightly lower body weights were observed in treated animals than in the controls (statistical analysis was not performed). Food consumption was similar in control and treated animals. No compound-related hematological, biochemical or urinalysis changes were observed. Bromine analysis of selected tissues and blood by neutron activation indicated increased bromine values in the tissues and blood of animals in the 8 mg/L group over that from the control goup. No compound-related gross lesions were observed. A compound-related decrease in liver weight, and increase in lung weight was observed in both exposure levels. An increase in relative adrenal and thyroid weight in females at 8 mg/L may have been compound-related. Microscopically, an increase in inflamatory lung lesions in both experimental groups may have been compound related. No other lesions related to compound administration were seen in other tissues examined from the 8 mg/L group.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2 000 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is old, but well reported and included the majority of endpoints typical of a guideline study.
Qualifier:
no guideline available
Principles of method if other than guideline:
Repeated doses of test article applied to skin of rabbits for 28 days. Various parameters were monitored/measured throughout the study. Gross necropsy and histopathology performed at scheduled sacrifice. No guideline was available at the time of the study's conduct.
GLP compliance:
no
Remarks:
performed prior to GLPs
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
12/12 M/F rabbits were used on the study. The rabbits were housed individually in metal metabolism cages and maintained in a temperature and humidity controlled room. Purina Rabbit Chow and water were available ad libitum.
Type of coverage:
open
Vehicle:
other: saline
Details on exposure:
The test article was applied dermally at 0, 50, 500 or 5000 mg/kg/d, 5 days/week for 4 weeks. Three male and three female rabbits were used at each dose level. The control rabbits were treated with saline only at a volume of 12 ml on the same regimen as treated animals.

The dorsal skin of each rabbit was shaved with electric clippers as necessary during the study. The shin of one-half of the rabbits was abraded twice a week. The compound was mixed with a small amount (maximum of 12 ml) of saline to form a paste. The was spread over the skin with a glass rod. The rabbits were held in wooden stocks during the 6 hour test article administration period after which the backs were washed with tepid tap water and the rabbits were returned to their individual cages. Individual daily doses were based upont the body weights obtained weekly.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hrs/day
Frequency of treatment:
5 days/week for 4 weeks
Remarks:
Doses / Concentrations:
0, 50, 500, 5000 mg/kg/d
Basis:
nominal per unit body weight
No. of animals per sex per dose:
3M/3F per dose.
Control animals:
yes, concurrent vehicle
Positive control:
no
Observations and examinations performed and frequency:
The rabbits were observed daily for changes in general behavior and apppearance. Observations for dermal irritation were done prior to and following the 6 hr test article administration period. Individual body weights were recorded weekly. Once in the control group and on study day 14 and 26, blood and urine samples were collected from all rabbits.
Sacrifice and pathology:
All rabbits were sacrificed following 28 d of treatment. Selected tissues (approximately 28) in the control and 500 mg/kg/d groups were examined by histopathology (paraffin embeddded, sectioned, stained with hematoxylin and eosin). Skin, liver, kidney and bone marrow from the 50 mg/kg/d group were also examined histologically.
Other examinations:
Hematology: hemoglobin, hematorcrit, total RBC, total and differential WBC. Serum chemistries: glucose, BUN, SGOT, SGPT, SAP. Urinalysis: volume, pH, specific gravity, color and appearance, qualatative tests for albumin, glucose, bilirubin and occult blood. Bromine analysis: in the 50 and 500 mg/kg/d groups liver, fat, kidney, skin and blood were analyzed by neutron activation analysis.
Statistics:
Statistics were run on bromide levels: one way ANOVA with Dunnet's post test.
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
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, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Very slight to slight and occasionally moderate erythema was noted in control rabbits and in rabbits at the 50 mg/kg/d dose. Very slight to moderate erythema was noted for rabbits at the 500 and 5000 mg/kg/d doses. Moderate desquamation was noted for 3 of the rabbits at the 5000 mg/kg/d dose. One rabbit at the 5000 mg/kg/d dose showed marked ataxia, unable to lift head or right itself and dyspnea and was sacrificed in extremis. All of the rabbits at the 5000 mg/kg/d dose died or were sacrificed in extremis between days 10 and 26 of the study.

Body weights were similar in control, 50 and 500 mg/kg/d groups. Rabbits at the 5000 mg/kg/d dose lost weight prior to death. Organ weights among groups appeared comparable.

At day 14, 1 rabbit in the high dose group had a moderate increase in BUN. At day 26, the hematology, serum chemistry and urinalysis results in the one surviving rabbit at the high dose were: neutrophilia with lymphopenia, nucleated erythrocytes, marked increase in glucose and BUN, and albumiand glucose in the urine.

Deaths or declining condition necessitating early sacrifice of all rabbits at the high dose were considered compound-related. At necropsy, several rabbits in the high dose group had pale livers, accentuated liver lobulation and gastric irritation. These effects observed at necropsy may have been compound-related. No gross lesions were observed in the low and mid-dose groups. Microscopically, the only lesion seen in animals in the low and mid-dose groups considered compound related was a very slight hyperkeratosis of the application site in one rabbit in the mid-dose group.

Dose descriptor:
NOEL
Remarks:
mortality
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Mortality in the 5000 mg/kg/d group.
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Lack of effect on body weights, organ weights, hematology, urinalysis, serum chemistries. Slight effects on skin at site of application of test article.
Critical effects observed:
not specified

After treatment for 28 days, bromine levels measured in skin (50, 500 mg/kg/d) and blood (500 mg/kg/d) were statististically significantly higher when compared to the control group. In skin, mean measured bromine levels in the control, 50 and 500 mg/kg/d groups were 39.6, 712.0 and 726.5 ppm, respectively. Similarly, mean measured bromine levels in blood were 8.7, 10.0 and 13.3 ppm. No statistical differences were observed between the control and 50 or 500 mg/kg/d groups in bromine levels measured in the liver, fat or kidney. For the purposes of statistical comparison, meausrements from male and female rabbits in each dose group were combined (n=6/group).

Conclusions:
The NOEL for mortality was 500 mg/kg/d. The NOAEL for systemic toxicity was 500 mg/kg/d.
Executive summary:

The test article was applied dermally at 0, 50, 500 or 5000 mg/kg/d, 5 days/week for 4 weeks. Three male and three female rabbits were used at each dose level. The control rabbits were treated with saline only at a volume of 12 ml on the same regimen as treated animals. The rabbits were observed daily for changes in general behavior and apppearance. Observations for dermal irritation were done prior to and following the 6 hr test article administration period. Individual body weights were recorded weekly. Once in the control group and on study day 14 and 26, blood and urine samples were collected from all rabbits. All rabbits were sacrificed following 28 d of treatment. Selected tissues (approximately 28) in the control and 500 mg/kg/d groups were examined by histopathology (paraffin embeddded, sectioned, stained with hematoxylin and eosin). Skin, liver, kidney and bone marrow from the 50 mg/kg/d group were also examined histologically. All rabbits were sacrificed following 28 d of treatment. Selected tissues (approximately 28) in the control and 500 mg/kg/d groups were examined by histopathology (paraffin embeddded, sectioned, stained with hematoxylin and eosin). Skin, liver, kidney and bone marrow from the 50 mg/kg/d group were also examined histologically.

Very slight to slight and occasionally moderate erythema was noted in control rabbits and in rabbits at the 50 mg/kg/d dose. Very slight to moderate erythema was noted for rabbits at the 500 and 5000 mg/kg/d doses. Moderate desquamation was noted for 3 of the rabbits at the 5000 mg/kg/d dose.

One rabbit at the 5000 mg/kg/d dose showed marked ataxia, unable to lift head or right itself and dyspnea and was sacrificed in extremis. All of the rabbits at the 5000 mg/kg/d dose died or were sacrificed in extremis between days 10 and 26 of the study. Body weights were similar in control, 50 and 500 mg/kg/d groups. Rabbits at the 5000 mg/kg/d dose lost weight prior to death. Organ weights among groups appeared comparable. At day 14, 1 rabbit in the high dose group had a moderate increase in BUN. At day 26, the hematology, serum chemistry and urinalysis results in the one surviving rabbit at the high dose were: neutrophilia with lymphopenia, nucleated erythrocytes, marked increase in glucose and BUN, and albumin in the urine.

Deaths or declining condition necessitating early sacrifice of all rabbits at the high dose were considered compound-related. At necropsy, several rabbits in the high dose group had pale livers, accentuated liver lobulation and gastric irritation. These effects observed at necropsy may have been compound-related. No gross lesions were observed in the low and mid-dose groups. Microscopically, the only lesion seen in animals in the low and mid-dose groups considered compound related was a very slight hyperkeratosis of the application site in one rabbit in the mid-dose group.

The NOEL for mortality was 500 mg/kg/d. The NOAEL for systemic toxicity was 500 mg/kg/d.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit

Additional information

TBPA has been tested in a 28 day rabbit dermal and 21 day rat inhalation studies. In the inhalation study, no adverse effects were noted at 2 mg/L. In the dermal study, all rabbits at the top dose of 5000 mg/kg died or were sacrificed prior to the study's end. The NOAEL for systemic toxicity in that study was the next highest dose, 500 mg/kg. Hisptopathlogy was not performed at the 5000 mg/kg dose, and limited clinical pathology indicated an increase in BUN, and albumin and glucose in the urine. These changes are indicative of an effect on the kidney. TBPA's structural analog, tetrachlorophthalic anhydride or TCPA, has been tested in the rat and mouse in 13 week studies with administration via gavage. Mice were not affected by doses up to 1500 mg/kg. Rats, however, were affected and the LOAEL was 94 mg/kg. Although no clinical pathology changes clearly associated with treatment were observed, rats exhibitied dose-dependent increases in kidney weights and in the incidence and severity of renal tuble necrosis and/or dilation. Thus, TCPA and TBPA appear to be renal toxicants in the rat and rabbit, respectively. Mice, however, appear resistent.


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: dermal - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification