Tris(2-ethylhexyl) phosphate

Carcinogenicity

Description of key information

Conclusion: A carcinogenic effect of tris(2-ethylhexyl)phosphate in humans is unlikely.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD study or GLP defined.

Principles of method if other than guideline:

other: Two-Year oral gavage study in rats

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

2 years

Frequency of treatment:

5 d/w

Post exposure period:

no data

Remarks:

Doses / Concentrations:
male 2000 or 4000 mg/kg bw/d, female 1000 or 2000 mg/kg bw/d
Basis:

No. of animals per sex per dose:

50

Control animals:

other: corn oil

Details on study design:

Post-exposure period: no

Basis for effect level:

other: no relevant carcinogenic effect

Survival of Rats in the Two-Year gavage Studies

	Vehicle Control	2000 mg/kg	4000 mg/kg
Male (a)	50	50	50
Animals Initially in Study	8	9	7
Nonaccidental Deaths before Termination (b)	2	3	4
Accidentially Killed	40	37	39
Died During Termination Period	0	1	0
Survival P Values (c)	0.883	0.815	0.989
	Vehicle Control	1000 mg/kg	2000 mg/kg
Female (a)
Animals Initially in Study	50	50	50
Nonaccidental Deaths before Termination (b)	12	14	18
Accidentially Killed12	36	2	2
Died During Termination Period	2	34	30
Survival P Values (c)	36	0.662	0.194

(a) Terminal kill period: weeks 104 -105

(b) Includes moribund animals that were killed

(c) Results of live table trend test are inthe vehicle control column; those of the live table pairwise comparisons with the vehicle controls are in the dosed columns

Executive summary:

In a Two-Year study in male and female rats the animals were treated orally by gavage 5 days per week for 103 weeks. The doses of test substance administered were 1000 or 2000 mg/kg in female rats and 2000 or 4000 mg/kg in male rats respectively. The body weight gain in male rats in the 2000 and 4000 mg/kg dose group was significantly diminuated in comparison to the control group. Male rats showed a slightly higher incidence of follicular adenomas, cystadenomas and carcinomas of the thyroid in the highest dose group, but not statistically significant higher than the control group [2/49 (4%) in the 2000mg/kg group; 6/49 (12%) in the 4000 mg/kg group and 1/46 (2%) in the vehicle control group]. Also in male rats the number of pheochromocytoma in the adrenal gland was significantly heightened [9/50 (18%) in the 2000 mg/kg group; 12/50 (24%) in the 4000 mg/kg group and 2/50 (4%) in the vehicle control group) and additionally in the highest dose group 2 malign pheochromocytomas were observed. In female rats the incidence of pheochromocytomas was in the range of the control group. In the lowest dose group the incidences of fibroadenomas in the mammary gland was diminuated in female rats. The incidence of pheochromocytomas in the control group with 4% (2/50) was unusually low in comparison to the other long term tests of the same laboratory. Due to the heightened incidence of pheochromocytomas in male F344/N-rats the test substance was found to have an equivocal evidence for carcinogenicity. In female rats no evidences were found.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

A single key study with a reliability rating of 2, which is acceptable for the purpose of hazard assessment.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

Not applicable

Justification for classification or non-classification

The study does not meet the criteria for classification in accordance with Regulation (EC) No 1272/2008 (CLP).

Additional information

No human data is available.

In a Two-Year study in male and female rats the animals were treated orally by gavage 5 days per week for 103 weeks. The doses of test substance administered were 1000 or 2000 mg/kg in female rats and 2000 or 4000 mg/kg in male rats respectively. The body weight gain in male rats in the 2000 and 4000 mg/kg dose group was significantly diminuated in comparison to the control group. Male rats showed a slightly higher incidence of follicular adenomas, cystadenomas and carcinomas of the thyroid in the highest dose group, but not statistically significant higher than the control group [2/49 (4%) in the 2000mg/kg group; 6/49 (12%) in the 4000 mg/kg group and 1/46 (2%) in the vehicle control group]. Also in male rats the number of pheochromocytoma in the adrenal gland was significantly heightened [9/50 (18%) in the 2000mg/kg group; 12/50 (24%) in the 4000 mg/kg group and 2/50 (4%) in the vehicle control group] and additionally in the highest dose group 2 malign pheochromocytomas were observed. In female rats the incidence of pheochromocytomas was in the range of the control group. In the lowest dose group the incidences of fibroadenomas in the mammary gland was diminuated in female rats.

The incidence of pheochromocytomas in the control group with 4% (2/50) was unusually low in comparison to the other long term tests of the same laboratory (historical incidence in males 31.9% (425/1334); range 14-63%). Due to the heightened incidence of pheochromocytomas in male F344/N-rats the test substance was found to have an equivocal evidence for carcinogenicity. In female rats no evidences were found (NTP, 1984).

Manipulations which are necessary for the test of a substance cause a more or less intense stress in testing animals. This is expressed, among other things, by an enlargement of the adrenal gland or the depletion of the lymphatic tissue at lymphocytes. It is likely that stress can lead to neoplasms of the endocrine system (MAK, 47, 2009). Therefore the increased incidence of pheochromocytomas is not considered to be a compound-related effect.

In a Two-Year study in male and female B6C3F1 mice the animals were treated orally by gavage 5 days per week for 103 weeks. The doses of test substance administered were 500 or 1000 mg/kg. In male mice the survival was diminuated only in the lower dose group (500 mg/kg). In female mice, the incidence of hepatocellular carcinoma in the high dose animals was significantly increased relative to the concurrent control [control: 0/48 (0%); 500 mg/kg/day: 4/50 (8%) and 1000 mg/kg/day: 7/50 (14%)]. The statistical significance of this moderate increase hepatocellular carcinoma might be due to the low incidence of hepatocellular carcinoma in the concurrent control group. Haseman et al. (1998) reported historical control data on tumor incidences for B6C3F1 mice (and F344 rats) used in the NTP program. The most frequently occurring neoplasm in untreated females was liver adenoma/carcinoma (20.5%). This incidence is significantly higher than the reported incidences in the concurrent control group in this study (4% adenomas and 0% carcinomas). In addition, the incidence of hepatocellular carcinoma reported in the historical control data in females ranged from 0-20% (mean value 8.4; 113/1350 female mice). The reported incidence of hepatocellular carcinoma in the high and low tris(2-ethylhexyl)phosphate dose group (14 and 8%, respectively) is covered by the historical control values. In addition it is known that mice, in particular the B6C3F1 strain, are very sensitive for liver tumors (Maronpot R.R., 1987).

Since no indications of a mutagenic or chromosome-damaging effect were observed in comprehensive genotoxicity studies with tris(2-ethylhexyl)phosphate and a moderate increase in the incidence of hepatocellular carcinoma was observed only in female mice (not in male mice and not in rats), a carcinogenic effect in humans is unlikely at doses without systemic effects. This interpretation was shared by BUA (BUA 172, 1996) and EPA (FR 72).