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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given: comparable to guidelines.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
review article or handbook
Title:
European Union Risk Assessment Report TRIS(2-CHLORO-1-METHYLETHYL) PHOSPHATE (TCPP)
Author:
European Commission Joint Research Centre
Year:
2008
Bibliographic source:
In: RISK ASSESSMENT of May 2008

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
-Analytical purity: 70%
-Impurities: 22% 2-chloropropanol phosphate
-Lot No.: 4800-3-10

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
no data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The diet dose corresponds to mean substance intake values of 0, 52, 160, 481, and 1349 mg/kg/day for males and 0, 62, 171, 570, and 1745 mg/kg/day for females.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 800, 2500, 7500, 20000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
20 f and 20 m in each group
Control animals:
yes, concurrent no treatment
Details on study design:
no data
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

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

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were taken for clinical chemistry (including plasma and erythrocyte acetylcholinesterase concentration) and haematological measurements at initiation of the study, at the midpoint and at termination.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: - Time schedule: Blood samples were taken for clinical chemistry (including plasma and erythrocyte acetylcholinesterase concentration) and haematological measurements at initiation of the study, at the midpoint and at termination.

URINALYSIS: Yes
- Time schedule for collection of urine: Urine samples were taken for urinalysis at six weeks and at termination.

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Complete necropsy was carried out after terminal sacrifice. Liver, kidney, heart, thyroid and all significant gross lesions from low and mid-dose animals were examined microscopically.
Other examinations:
no data
Statistics:
no data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
-There were no treatment-related mortalities.
-No clinical observations were considered to be related to treatment.

BODY WEIGHT AND WEIGHT GAIN
-A slight, but statistically significant (p<0.05) reduction in mean body weight was apparent from day 22 of the study until termination in the high dose males (7.75% less than controls at day 80) and from day 35 in high dose females (11.8% less than controls on day 80).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
-No effects.

FOOD EFFICIENCY
-No data.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
-No data.

OPHTHALMOSCOPIC EXAMINATION
-No data.

HAEMATOLOGY
-No effects.

CLINICAL CHEMISTRY
-No effects.

URINALYSIS
-No effects.

NEUROBEHAVIOUR
-No data.

ORGAN WEIGHTS
-The mean absolute and relative liver weights were statistically significantly (p<0.05) increased in all male groups given TCPP and in females given 7,500 ppm and 20,000 ppm. In males given 800 ppm the group mean relative hepatic weight exceeded the control group mean by 16%. The absolute liver weight in this low dose group was also 16% greater than control. Relative liver weight of males given 20,000 ppm exceeded the control mean by 41% (absolute liver weight was 31% greater than controls for this group). In females given 7500 and 20,000 ppm, the mean relative liver weight exceeded that of controls by 20% and 30% respectively.

GROSS PATHOLOGY
-No effects.

HISTOPATHOLOGY: NON-NEOPLASTIC
-The only histopathological finding related to this was periportal hepatocyte swelling (hypertrophy) in the high dose groups (7/20 males and 8/20 females). 0/20 male and 5/20 female control animals showed liver periportal swelling. Relative kidney weights were statistically significantly (p<0.05) increased in males at the two highest doses (13% and 16% greater than control). There was some evidence of histopathological change in the renal cortical tubule with the finding of mild degenerative change (hyaline droplet formation) in the two highest dose groups in males (12 animals and 7 animals, respectively) and vacuolation in females dosed with the highest dose (4 animals, compared to 1 control animal). The hyaline droplet formation is a male rat specific nephropathy and is not relevant for humans. Mild thyroid follicular cell hyperplasia was recorded in males at all doses (0/20, 2/20, 2/20, 5/20, and 8/20 at 0, 800, 2,500, 7,500 or 20,000 ppm respectively). This was seen in 5/20 females of the 20,000 ppm group, compared to 0/20 in the control group.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-No data.

HISTORICAL CONTROL DATA (if applicable)
-No data.

OTHER FINDINGS
-A slightly excessive fatty infiltration indicative of mild bone marrow hypoplasia was seen in three high dose females.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
ca. 800 ppm
Sex:
male
Basis for effect level:
other: the increase in absolute and relative liver weights, accompanied by mild thyroid follicular cell hyperplasia
Dose descriptor:
NOAEL
Effect level:
ca. 2 500 ppm
Sex:
female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No death or clinical signs of toxicity were noted except for reduced body weight gain in both sexes at the highest dose. Significant increases in absolute and relative liver weights were observed in all treated male groups and in females at >=7500 ppm. Mean kidney weights were significantly increased in males at >=7500 ppm, but not in females. Histopathological lesions were observed in the liver (periportal swelling) of high-dose males only, in the kidney (mild cortical tubular degeneration) of males at >=7500 ppm, and females at 20000 ppm, and in the thyroid (very mild follicular hyperplasia) in all treated males and in high-dose females. Sternal bone marrow of three high-dose rats (sex not specified) was mildly hypoplastic. There were no treatment-related effects on hematology, clinical chemistry, or cholinesterase activity of brain, plasma, or erythrocytes.

All histopathologic changes were considered reversible.

Applicant's summary and conclusion

Conclusions:
-A LOAEL of 800 ppm (equivalent to 52 mg/kg/day) based on the increase in absolute and relative liver weights, accompanied by mild thyroid follicular cell hyperplasia, observed in males of all dose groups is derived from this study for males.
-A NOAEL of 2500 ppm (equivalent to 171 mg/kg/day) is derived for females, based on increased liver weights observed in females dosed at 7500 ppm and above.
-The effects on the thyroid in the male animals at all doses and the females at the highest dose could be secondary to altered liver metabolic activity.
Executive summary:

In the 90 -day feeding study, groups of CD rats were administered Fyrol PCF (70% tris(2-chloroisopropyl) phosphate and 22% 2-chloropropanol phosphate) in the diet at concentrations of 0, 800, 2500, 7500, or 20000 ppm for 13 weeks. The lowest exposure level, 800 ppm in diet (equivalent to 52 mg/kg/day), was a LOAEL for males, based on increased liver weight and thyroid histopathology. In females, the NOAEL was 2500 ppm in diet (equivalent to 171 mg/kg/day) based on increased liver weights observed in females dosed at 7500 ppm and above.