Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

OECD 407 (Leser, Bayer AG, 1991): 28d NOAEL = 100 mg/kg bw/day
OECD 408 (equiv.) (Stauffer Chemical Co., 1981): 90d NOAEL = 52 mg/kg bw/day

Hazards identified by EU Risk Assessment in May 2008:
- A 13 week feeding study in rats indicated liver and thyroid as the main target organs affected by TCPP. A LOAEL of 52 mg/kg/day is derived for this study.
- In a 2-generation reproductive toxicity study in which rats were fed TCPP in the diet over two successive generations, the low-dose of 99 mg/kg for females is considered to be the LOAEL for parental toxicity.
No data are available on inhalation and dermal repeated dose toxicity.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well reported study, non-guideline, non-GLP. Endpoint study record transfered from Draft EU Risk Assessment, 2008
Qualifier:
no guideline available
Principles of method if other than guideline:
To determine the toxic effects of the test substance in rats when administered in the diet for three months. Four dose levels were used. Clinical signs were observed twice daily and food consumption and body weight were determined weekly. Clinical chemistry and haematology were determined at initiation, mid-study and termination; urinanalysis was conducted midstudy and at termination. Gross pathology and histopathology were also perfomed. In addition, a measure of brain cholinesterase was performed at the end of the study.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
Fyrol PCF
lot no ERC-4800-3-10
tris(2-chloroisopropyl)phosphate 70%, 2-chloropropanol phosphate 23%
Stored at ambient temperature
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River LAbs, Wilmington Mass
- Age at study initiation: 6 weeks
- Weight at study initiation: males 186-243g; females 121-160
- Fasting period before study: no
- Housing: individually housed
- Diet (e.g. ad libitum): Purina certified rodent chow blended with 1% Mazola corn oil , ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: two weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not given
- Humidity (%): not given
- Air changes (per hr): not given
- Photoperiod (hrs dark / hrs light): not given


IN-LIFE DATES: From:11 Dec 1979 To: 14 Mar 1980
Route of administration:
oral: feed
Vehicle:
other: rat feed
Details on oral exposure:
rats were fed diets containing 0, 800, 2500, 7500 and 20000 ppm of TCPP for a period of thirteen weeks. This 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
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Samples of the blended diet were analysed for homogeneity and concentration of the test substance. The results were:

low dose: 6 Dec 1979; 5 samples; 910 +- 53 ppm; 9 Jan 1980; 10 samples; 710+-40 ppm
low intermediate dose: 6 Dec 1979; 5 samples; 2500+-310ppm; 9 Jan 1980; 10 samples 2100+-47ppm
high intermediate dose: 6 Dec 1979; 5 samples; 7700+-160ppm; 9 Jan 1980; 10 samples; 7500+-190ppm
high dose: 6 Dec 1979; 5 samples; 21000+-550; 9 Jan 1980; 10 samples; 2000 +-1300ppm
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
800 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2500 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
7500 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
20000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
Animals were observed for clinical signs twice daily and food consumption and weight gain was measured weekly. 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. Urine samples were taken for urinalysis at six weeks and at termination.
The following parameters were determined:
Haematology: packed cell volume; haemoglobin concentration; total erythrocyte, leukocyte and platelet counts; mean corpuscular volume; mean corpuscular haemoglobin; mean corpuscular haemoglobin concentration; blood smears for differential leukocyte counts.

Clinical Chemistry: BUN; LDH; ALT; AST; inorganic phosphate; Alkaline phosphatase; creatinine; direct and total bilirubin; cholesterol; glucose; albumin ; total protein; Na, K, Cl, Ca.

Urinanalysis:colour; turbidity; specific gravity; pH; protien; glucose; ketones; bilirubin; urobilogen. Sediment was examined microscopically.
Sacrifice and pathology:
Complete necropsy was carried out after terminal sacrifice.
The brain, adrenals, heart, liver, kidneys, gonads and thymus were weighed at study termination. Additional tissues and all significant gross lesions were collected as specified in the protocol. All tissue samples were routinely processed, sectioned at 5µm and stained with hematoxylin and eosin. Samples of all tissues from high dose and control animals were examined microscopically. Liver, kidney, heart, thyroid and all significant gross lesions from low and mid-dose animals were examined microscopically.
Other examinations:
Brain cholinesterase activity was measured at termination.
Statistics:
Body and organ weights , food consumption and clinical pathology determinants are reported individually and summarised as the group mean( +- standard deviation) according to treatment and sex. Quantal data, such as clinical observations, gross pathology observations and histopathology findings are reported individually and summarized in incidence tables.
Data summarised as means were analysed statisticallyusing one-way analysis of variance. When significant effects were indicated by the analysis of variance, Dunnett's method for multiple comparisons with control was applied. Differences were considered significant when p< 0.05
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 examined
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
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:
no effects observed
Dose descriptor:
NOAEL
Effect level:
ca. 2 500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: 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.
Dose descriptor:
LOAEL
Effect level:
ca. 800 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: see remarks on result
Remarks on result:
other:
Remarks:
Based on the increase in absolute and relative liver weights (16% on the low dose males compared to controls), accompanied by mild thyroid follicular cell hyperplasia, observed in males of all dose groups a LOAEL of 800 ppm (equivalent to 52 mg/kg/day) was established, but a clear dose response was only observed in the two highest dose groups.
Critical effects observed:
yes
Lowest effective dose / conc.:
52 mg/kg bw/day (actual dose received)
System:
other: liver and thyroid
Organ:
other: increased liver weight in all dosed males, periportal hepatocyte swelling in the high dose group and mild thyroid follicular cell hyperplasia in males at all doses and females at the highest dose
Treatment related:
yes

There were no treatment-related mortalities. No clinical observations were considered to be related to treatment. 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). 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. The only histopathological finding related to this was periportal hepatocyte swelling (hypertrophy) in the high dose groups (9/20 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, respectively). 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. There were no significant alterations in clinical chemistry, haematology or urinalysis parameters and no treatment-related changes in plasma, erythrocyte or brain cholinesterase activity. A slightly excessive fatty infiltration indicative of mild bone marrow hypoplasia was seen in three high dose females.

Executive summary:

In an oral repeated dose toxicity study the test substance was axdministered to rats (20/sex/group) at dietary concentrations of 0, 800, 2500, 7500 or 20000 ppm for three months. Rats given 20000 ppm showed significantly (p<0.05) reduced body weight at most weekly intervals from weeks 4 through 12 in the males and weeks 6 through 12 in the females. No other treatment related clinical signs were noted. Significantly (p<0.0.5) higher absolute and relative liver weights were found in male rats of all groups fed the test substance and female groups given 7500 and 20000 ppm. In this study, the toxicologic significance of this observation cannot be ascertained. mean relative kidney weights of male groups given 2500, 7500 and 20000 ppm were significantly (p<0.05) greater than that of controls. hepatic morphologic change considered related to treatment was found only in rats given 20000 ppm, and was characterized by very mild swelling of cells located in the peroportal region of the hepatic lobule. Very mild cortical tubular degenerative changes were found in kidneys of male rats given 7500 ppm and in both sexes given 20000 ppm. Sternal bone marrow of three female rats given 20000 ppm was very mildly hypoplastic. Very mild thyroid follicular hyperplasia was found in male rats in all groups given the test substance and in females given 20000 ppm. Evaluation of hematological and clinical chemistry data, as well as cholinesterase activity in the brain, plasma and erythrocytes showed no change related to treatment. There were no deaths attributed to treatment with the test substance.

Based on the increase in absolute and relative liver weights, accompanied by mild thyroid follicular cell hyperplasia, observed in males of all dose groups a LOAEL of 800 ppm (equivalent to 52 mg/kg/day) 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 absolute and relative liver weights observed in females dosed at 7500 ppm and above.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No OECD Guideline defined.
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Cited as Directive 84/449/EEC, B.7
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
IUCLID4 Test substance: other TS

TS-Freetext:
Tris chloroisopropyl phosphate.
Purity: 97.85% including all isomers as per 1.1 - 1.4.

- Name of test material (as cited in study report): Tris-chloroisopropylphosphate
- Molecular formula (if other than submission substance): C9H18Cl3O4P
- Molecular weight (if other than submission substance): 327.6
- Physical state: clear colourless liquid
- Analytical purity: 97.85%
- Lot/batch No.: 002871
- Expiration date of the lot/batch: 13 Dec 1991
- Storage: Ambient temperature
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann , Borchen, DE
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males 198-223g; females 133-147g
- Fasting period before study: no
- Housing:individually in Type II MAkrolon cages
- Diet (e.g. ad libitum): Altromin 1324 pellets ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-2C
- Humidity (%): 55%
- Air changes (per hr): approx 10
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle


IN-LIFE DATES: From: 03 Sept 1990 To: 01 Oct 1990
Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
groups of 6 male and 6 female Wistar rats were dosed daily by gavage with 0, 10, 100 or 1000 mg/kg body weight TCPP formulated in DAB 9 peanut oil. A constant dosing volume of 2ml/kg was used throughout the study. The doses were selected based on a preliminary 7-day study in which male Wistar rats were dosed with 0, 10, 100 or 1000 mg/kg body weight. In that preliminary study, the test animals exhibited no reaction to the treatment at any of the doses.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The homogeneity and stabiltiy of the test substance in the treatment medium over a period of fours hours and over the five-day period of use were analytically verified prior to study initiation. In this procedure, 0.5 mg and 1000mg samples of tris-chloroisopropylphosphate were eighed out and blended with 1 ml of DAB9 peanut oil, the formulations were held at ambient temperature and analysed at the beginning and end of a four hour and five day holding time.
The content of test substance in the treatment formulations was checked once during the study period. In this procedure, samples of the treatment formulations being used were analysed.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily, gavage
Remarks:
Doses / Concentrations:
10, 100 or 1000 mg/kg
Basis:

No. of animals per sex per dose:
6/dose/sex
Control animals:
yes
Details on study design:
Post-exposure period: No

- Dose selection rationale: based upon a seven day rangefinding study
- Rationale for animal assignment (if not random):
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):
Observations and examinations performed and frequency:
In the 28-day study, animals were checked twice daily for morbidity, mortality and general clinical signs. A detailed individual animal clinical examination was made weekly. Ophthalmic examinations of all animals in the control and highest-dose groups were performed three days before the first treatment and in the fourth week of treatment. Body weights were recorded prior to the first treatment and at weekly intervals thereafter. Laboratory tests of blood and urine from all animals of every group were carried out at study termination.
Weekly food and water intakes were determined on an individual animal basis.
The following clinical pathology parameters were determined:
Haematology: differential blood count; erythrocyte morphology; erythrocyte count; haemoglobin concentration; haemocrit; hepato-quick; leukocyte count; mean corpuscular haemoglobin; mean corpuscular haemoglobin concentration; mean corpuscular cell volume; thrombocyte count.

Clinical chemistry: alkaline phosphatase; AST; ALT; albumin; bilirubin; cholesterol; total protein; BUN; creatinine; inorganic phosphate; Cl; Ca; Na, K; glucose.

Urinanalysis: blood; bilirubin; protein; ketone bodies; pH; urobilinogen; sediment; creatinine; osmolality; volume
Sacrifice and pathology:
The organs and tissues of necropsied animals at the end of the study were subjected to detailed gross pathological inspection. The following organs were weighed prior to fixation: brain, testes (pair), liver, lungs, spleen, Kidneys(pair) and adrenals (pair).
Other examinations:
Histopathology was examined in the brain, heart, spleen, epididymides, adrenals, kidneys, ovaries, prostate, seminal vesicles and uterus from all control and highest dose group animals, as well as all altered organs and tissues from all groups. The livers of all animals from all groups were examined.
Statistics:
The following data were presented as arithmetic means and standard deviations calculated fro individual animal data: body weight, food intake and water intake determinations, clinical laboratory tests and organ weights.
The cohort results were subjected to a two-tailed comparison with those of the control cohort using the Mann-Whitney U-test aqt significance levels of Alpha=5% and Alpha =1%.
Statistically significant deviations are initially only considered evidence for anomalies, whereas the biological and toxicological significance are primarly taken into consideration in the assessment.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
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:
no effects observed
Details on results:
One male and two females in the 1000 mg/kg treatment group died, the male at the end of the first week of treatment and the two females at the beginning of the second week. The male was in poor general condition, was emaciated and exhibited a bloody muzzle. The authors of the study report have indicated that the presumed cause of death was treatment error. Since no male died in the preliminary study at levels up to and including 1000 mg/kg, the mortality of the male animal is not considered to be test substance related. The two females exhibited no clinical signs prior to or on the day they died. These two mortalities could be treatment related.
Regarding clinical signs during the study, all females in the 1000 mg/kg group exhibited a squatting position at 10 mins after dosing for the first 3 days of dosing. This persisted for about three to five hours on the first two days and for approximately one hour on the third day. No further clinical signs were observed. The ophthalmic examinations of the control and highest-dose group animals prior to study initiation and in the fourth week of the study indicated no unusual findings.
The body weight determinations of TCPP-treated males and females indicated slightly higher results than those of control animals, but the differences were minor and did not reach statistical significance. There was no dose-response effect and so the effect is not considered treatment-related. The mean daily food intakes in all groups were comparable to that of controls.
There were no changes in white and red blood cell populations in any treatment group when compared to controls, with the exception of the lower monocyte count observed in the mid and high dose males. In male rats in the two highest treatment groups, the monocyte count was statistically significantly (p<0.05) lower when compared to the control group (1.7% for the 100 mg/kg treatment group and 1.6% for the 1000 mg/kg group, compared to a control value of 4.1%). The count was also reduced in the 10 mg/kg treatment group (2.3%), but this did not reach statistical significance. There were no changes in alkaline phosphatase or aspartate aminotransferase enzyme activities in any of the treated animals. A statistically significant (p<0.01) depression of alanine aminotransferase activity was seen in high-dose male (by 46%) and female (by 34%) animals. The low dose female group saw a statistically significant (p<0.01) increase in this enzyme¿s activity (increased by 28%). There was also an increase in glucose observed in the treated male animals. This reached statistical significance (p<0.05) in the low (4 mmol/L) and high dose (p<0.01) (4.05 mmol/L) groups when compared to a control value of 3.57 mmol/L. There were some changes observed in the clinical chemistry investigations, but these appeared to be isolated deviations from the controls and were relatively minor and not dose-dependent. For these reasons, they are not considered to be of toxicological significance. Potassium was statistically significantly (p<0.05) increased in the low dose male animals (5.5 mmol/L) and inorganic phosphorous was statistically significantly (p<0.05) decreased in the mid-dose females. The semi-quantitative determinations of the pH, bilirubin, glucose, urobilinogen and ketonic bodies levels indicated no changes among any treatment group when compared to levels in control animals. Quantitative determination of creatinine levels indicated a statistical significant (p<0.05) increase in creatinine in the high-dose males when compared to controls (78 mcmol compared to 63 mcmol). Protein was also statistically significantly (p<0.01) increased in this treatment group (12.3 mg compared to 9.2 mg).
No macroscopic findings attributable to the test substance were reported at scheduled necropsy. The animals that died during the study exhibited dark red dis-colourations in the lungs. The absolute liver weights were statistically significantly (p<0.01) increased by 30% and 42% in male and female high dose animals respectively, when compared to controls. The relative liver weights were statistically significantly (p<0.01) increased by 27% and 34% in high dose males and females respectively, when compared to controls. In addition, relative liver weights were statistically significantly (p<0.05) increased in the low-dose male animals (increased by 6%) and in the mid-dose female animals (increased by 7%). The increase in liver weights was accompanied by slight hypertrophy of the periacinary hepatocytes in one of the mid-dose males (remainder of mid dose males exhibited minimal periacinary hepatocyte hypertrophy) and in all of the high-dose males. No hepatic alterations were noted in treated females.
Dose descriptor:
NOAEL
Effect level:
100 other: mg/kg
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

RM-Freetext:
Results:  Increased mortality in the females of the high
dose group.  No effect on body weight gain.  No effects on
food consumption.  In the high dose group there was an
increase in water intake.  No effect on haematological
parameters or clinical chemistry or urinary parameters.  No
effects seen at autopsy.  Histological examination revealed
adaptive effects in the liver of high dosed animals only.

Executive summary:

In an oral repeated dose toxicity study male and female Wistar rats received a daily oral dose of TCPP given by gavage for 28 days.

Doses tested were : 0; 10; 100; 1000 mg/kg bw.

Increased mortality in the females of the high dose group could be observed (2/6animals).

No effect on body weight gain and food consumption was detected.

In the high dose group there was an increase in water intake. No effects were observed on haematological parameters or clinical chemistry or urinary parameters and at autopsy.

Histological examination revealed adaptive effects in the liver of high dosed animals only.

The NOAEL in female and male Wistar rats was 100 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
52 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Key studies are submitted for sub-acute and sub-chronic toxicity, in accordance with Annexes VIII and IX of REACH. They are also supported by observations from a 2-generation reproductive toxicity study.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

Hazards identified by EU Risk Assessment in May 2008:

"A study is available in which male and female rats were fed diets containing TCPP for 13 weeks at concentrations corresponding to mean substance intake values of up to 1349 mg/kg/day and 1745 mg/kg/day for males and females respectively. This study indicated the liver and thyroid to be the main target organs affected by TCPP. Effects observed included statistically significant increases in absolute and relative liver weights in males at all doses and females at the two highest doses, periportal hepatocyte swelling in high dose groups and mild thyroid follicular cell hyperplasia in males at all doses and females at the highest dose. Based on the increase in both absolute and relative liver weights, accompanied by mild thyroid follicular cell hyperplasia observed in males of all dose groups, a LOAEL of 52 mg/kg/day is derived. This LOAEL is taken in preference to the NOAEL which was identified in a 4-week study in which rats were dosed with TCPP at concentrations of 0, 10, 100 and 1000 mg/kg/day, as it was derived from a study of longer duration. The 4-week study also showed the liver as the target organ, with increased liver weight changes observed in the high dose groups, accompanied by hepatocyte hypertrophy in all high–dose males and one mid-dose male and changes in ALAT activity in high-dose animals. A two-week study in which rats were fed diets of TCPP at concentrations corresponding to mean substance intake values of up to 1636 mg/kg/day for males and 1517 mg/kg/day for females showed no major clinical signs of toxicity. There was a significant reduction in weight gain and food consumption in high dose males during week 2, but there were no other significant findings. In a 2-generation reproductive toxicity study in which rats were fed TCPP in the diet over two successive generations, the low-dose of 99 mg/kg for females is considered to be the LOAEL for parental toxicity. This is based on decreased body weight and food consumption seen in mid and high dose parental animals and the effects on uterus weight seen in all dosed animals. For males, a NOAEL of approximately 85 mg/kg is derived for parental toxicity, based on decreased body weights, food consumption and organ weight changes observed at mid and high dose groups. No data are available on inhalation and dermal repeated dose toxicity."

 

Updated relevant information (March 2018):

Tris(chloropropyl)phosphate (M20263) [= TCPP] is currently within the testing procedure of the National Toxicology Program (NTP) with the following repeated dose toxicity tests:

- 13 week repeated dose toxicity study in rats (status: completed; but results not available yet)

- 13 week repeated dose toxicity study in mice (status: completed; limited information on results available, see description below)

- 2 year carcinogenicity studies on rats (status: histopathology in progress; results not available yet)

- 2 year carcinogenicity studies on mice (status: histopathology in progress; results not available yet)

http://ntp.niehs.nih.gov/testing/status/agents/ts-m20263.html

As soon as the entire new information is publically available it should be integrated in the data base for TCPP and the toxicolgical assessment should be updated.

A 13 week feeding study was performed by NTP with male and female B6C3F1 mice. Only limited data on study results are available up to now on the NTP webpage. No assessment report is available and the results have to be estimated by tables and figures. No information is given on organ weights, hematology and clinical chemistry. Doses of 1250 up to 20000 ppm, according to actual ingested doses of about 220, 500, 1000, 2400, and 4500 mg/kg bw/day for males and 200, 450, 900, 1800, and 3500 mg/kg bw/day for females can be roughly calculated from the tables. No mortality was observed.

In male mice the body weight at termination decreased dose dependently by about 4, 11, 16, 21, and 25% compared to control, although food consumption increased by about 4, 7, 14, and 31%, and 10%. No information is available yet on organ weights, hematology, clinical chemistry, and sperm morphology. In the liver of males hepatocyte hypertrophy occurred starting at a dose of about 500 mg/kg bw/day. In the kidney renal tubule cytoplasmic alterations were seen also starting at a dose of about 500 mg/kg bw/day. From the available data the dose of about 220 mg/kg bw/day in males showed no relevant adverse effects on body weight and organ integrity.

In female mice the body weight at termination decreased slightly at doses of 900 mg/kg bw/day and higher by about 5, 10, and 19% compared to control. Food consumption increased slightly to 115% at 900 mg/kg bw/day and again decreased at higher doses to about 104% at the highest dose level. No information is available yet on organ weights, hematology, clinical chemistry, and vaginal cytology evaluations.In the liver of females hepatocyte hypertrophy occurred starting at a dose of about 900 mg/kg bw/day.From the available data the dose of about 450 mg/kg bw/day in females showed no relevant adverse effects on body weight and organ integrity.

 

In conclusion:

As discussed in the EU Risk Assessment in May 2008 the results of a 13 week feeding study in rats indicate the liver and thyroid to be the main target organs affected by TCPP in rats. A LOAEL of 52 mg/kg bw/day was derived in this study. In a 2-generation reproductive toxicity feeding study a LOAEL of 99 mg/kg bw/day was considered for maternal toxicity. This was based on decreased body weight and food consumption seen in mid and high dose parental animals and effects on uterus weight seen in dosed females without histopathological correlate. For males, a NOAEL of approximately 85 mg/kg bw/day was derived.

Preliminary results obtained from the NTP webpage for a 13 week feeding study on male mice indicate a dose-dependently reduced body weight at termination and that liver and kidney are the main target organs affected by TCPP. Female mice seem to be less susceptible than male mice with a reduction in body weight and adverse liver effects at higher doses. On the basis of the available results a dose of 220 mg/kg bw/day for male mice and 450 mg/kg bw/day for female mice showed no relevant adverse effects on body weight and organ integrity.

The LOAEL of 52 mg/kg bw/day taken from the rat 13-week study is thus taken forward for DNEL derivation.

As soon as the full testing results are publically available for the newly performed NTP studies the assessment of repeated dose toxicity for TCPP has to be amended and revised.

Justification for classification or non-classification

EU Risk Assessment in May 2008: Based on the available studies, TCPP needs no classification for repeated dose toxicity according to EU guidelines.

Update March 2018: The conclusion of non-classification for repeated dose toxicity is confirmed and compliant with EU Regulation 1272/2008.