O,O'-dioctadecylpentaerythritol bis(phosphite)

Endpoint summary

Description of key information

Oral; NOEC > 3000 ppm; 90 days rat male/female; equivalent to OECD 408; Reyna (1972)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A non-GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

no

Principles of method if other than guideline:

Male and female Charles River albino rats (15 per sex per treatment group) were dosed with the test material in feed for 90 days at concentrations of 0 (control), 300, 1000 and 3000 ppm. Haematology, clinical chemistry and urinalysis were performed on the control and the high dose group on days 45 and 84. Animals were observed for signs of toxicity daily, and bodyweights were measured weekly. At the end of the 90 day period, all animals were necropsied and assessed for signs of systemic toxicity.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Charles River

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., North Wilmington, Mass., USA
- Weight at study initiation: 98-99 g males; 115 g females
- Housing: individually
- Diet: standard rat ration (ad libitum)

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): diet was prepared by blending the appropriate amount of test material with standard rat ration in a Hobart Mixer

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 300, 1000, 3000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

15 males and 15 females per dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: abnormal reactions and deaths

BODY WEIGHT: Yes
- Time schedule for examinations: study day 1 and weekly thereafter

FOOD CONSUMPTION: Yes
- Food consumption data were collected for five rats of each sex in every group weekly during the study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on study days 45 and 84
- Animals fasted: Yes
- How many animals: 10 animals per sex from the control and high dose group
- Parameters examined included: haematocrit value, erythrocyte count, haemoglobin concentration, total leukocyte count and differential leukocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on study days 45 and 84
- Animals fasted: Yes
- How many animals: 10 animals per sex from the control and high dose group
- Parameters examined included: blood urea nitrogen concentration, serum alkaline phosphatase activity, serum glutamic-pyruvic transaminase activity and fasted blood glucose concentration

URINALYSIS: Yes
- Time schedule for collection of urine: on study days 45 and 84
- Metabolism cages used for collection of urine: No data
- How many animals: 10 animals per sex from the control and high dose group
- Parameters examined included: glucose concentration, albumin concentration, microscopic elements examination, pH and specific gravity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Weights of the liver, kidneys, spleen, heart and brain of each rat were determined and recorded

HISTOPATHOLOGY: Yes
- The following tissues were stained with Haematoxylin-Eosin and subjected to microscopic examination: oesophagus, stomach (cardia, fundus, pylorus), small intestine (duodenum, jejunum, ileum), cecum, colon, liver, kidneys, spleen, pancreas, urinary bladder, pituitary gland, adrenal gland, testes, seminal vesicle, ovary, bone marrow, thyroid gland, parathyroid gland, salivary gland, prostate gland, heart, aorta, lung, lymph node (cervical, mesenteric), skeletal muscle, peripheral nerve, bone (femur), spinal cord, uterus, trachea, eye, optic nerve and brain (cerebrum, cerebellum and pons).

Statistics:

Statistical analyses were conducted upon the absolute organ weights and their corresponding ratios to the weight of the body and brain. An Analysis of Variance was conducted first and any significant effects disclosed by that treatment were further studied by t-tests.

Clinical signs:

no effects observed

Description (incidence and severity):

six deaths occurred resulting from trauma incurred during blood collection; they were not considered to be treatment-related.

Mortality:

no mortality observed

Description (incidence):

six deaths occurred resulting from trauma incurred during blood collection; they were not considered to be treatment-related.

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:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A single statistically significant difference in liver to bodyweight ratio was noted although it was not considered to be related to treatment with the test material

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: Six deaths occurred during the study. All of these deaths resulted from trauma incurred during the collection of blood samples. These deaths occurred in the control as well as the test groups and were not attributed to the ingestion of the test material. There were no untoward behavioural reactions among any of the animals during the study

BODY WEIGHT AND WEIGHT GAIN: No significant differences were noted, in body weights and total weight gains, between test and control rats

FOOD CONSUMPTION: Food consumption was comparable between control and treatment rats

HAEMATOLOGY: No remarkable differences were observed between control and treatment rats

CLINICAL CHEMISTRY: No remarkable differences were observed between control and treatment rats

URINALYSIS: No remarkable differences were observed between control and treatment rats

ORGAN WEIGHTS: A significant difference in liver to bodyweight ratio was observed in rats treated at 3000 ppm, however, the difference was considered to be normal for a random population of albino rats. the lack of any consistent dietary or sex related response indicates that none of the intergroup differences were related to the ingestion of the test material

GROSS PATHOLOGY: No outstanding differences were noted between test and control rats upon gross pathological examination

HISTOPATHOLOGY: Lesions were observed in some animals, most frequently in the trachea and lungs, indicating chronic murine pneumonia. These findings were noted in control as well as treated animals and were therefore considered not to be related to treatment with the test material

Dose descriptor:

NOEL

Effect level:

> 3 000 ppm

Based on:

test mat.

Remarks:

in diet

Sex:

male/female

Basis for effect level:

other: No abnormalities observed in any of the parameters tested.

Critical effects observed:

not specified

Table 1: Bodyweight

Dietary level (ppm)	Sex	Bodyweight (g) Week:														Total Average Weight Gain (g/rats)
		0	1	2	3	4	5	6	7	8	9	10	11	12	13
Control	M	99	153	200	233	299	342	378	399	430	469	491	501	501	520	421
	F	115	151	176	179	215	228	235	252	261	275	263	286	286	295	180
300	M	98	149	201	242	301	339	410	428	450	473	497	519	519	531	433
	F	115	146	173	177	207	222	250	257	264	276	279	288	288	296	181
1000	M	98	140	194	225	289	321	386	414	439	466	483	504	504	523	425
	F	115	147	175	179	218	223	252	264	276	289	292	303	303	305	190
3000	M	99	145	201	236	305	347	373	407	432	469	484	509	509	531	432
	F	115	146	175	177	215	227	245	256	268	283	292	295	295	313	198

 

Table 2: Food consumption

Dietary level (ppm)	Sex	Food Consumption (g/rat/seven days) Week:														Total Food Consumption (g/rat)
		0	1	2	3	4	5	6	7	8	9	10	11	12	13
Control	M	163	78	159	171	208	216	234	216	216	229	167	192	189	187	2409
	F	107	83	137	137	150	157	156	136	136	146	171	132	128	161	1801
300	M	158	96	143	164	191	194	209	184	184	225	151	198	175	212	2306
	F	114	71	127	126	131	139	128	124	124	140	99	162	113	138	1612
1000	M	136	105	168	186	198	205	194	204	204	226	163	205	200	240	2430
	F	106	87	132	141	150	143	148	145	145	148	117	130	133	147	1727
3000	M	193	105	175	190	211	206	191	195	195	229	194	200	195	222	2506
	F	117	88	133	138	142	137	154	122	122	151	105	133	127	145	1692

 

Table 3: Liver organ weight and ratio data (summary of mean values)

Dietary level (ppm)	Organ Weight (g)		Organ/bodyweight ratio (g/100 g)		Organ/brain weight ratio (g/g)
	Male	Female	Male	Female	Male	Female
Control	17.847	9.722	3.4286	3.2918	8.8455	5.2663
300	17.975	10.121	3.3770	3.4170	9.4797	5.6009
1000	17.392	9.829	3.3231	3.2415	9.3762	5.5207
3000	15.769	10.006	3.0970*	3.2714	8.1530	5.6215
* Statistically significant at the 95 % Confident level

Conclusions:

Following continued treatment with test material in the diet for a period of 90 days, no abnormalities were observed in any of the parameters tested. Under the conditions of the test, the no observed effect concentration for albino (Charles River) rats can therefore be concluded to be in excess of 3000 ppm when dosed in the diet.

Executive summary:

The toxicity of the test material following repeated exposure, over a 90 day period, to rats was investigated following a procedure similar to that outlined in standard guideline OECD 408. During the study, groups of 15 male and 15 female rats were exposed to test material at dietary levels of 300, 1000 and 3000 ppm. Under the conditions of the study, no abnormalities were revealed in bodyweight gain, food consumption, survival or in the hematology, clinical chemistry, urinanalysis and pathology parameters investigated. The no observed effect concentration can therefore be concluded to be in excess of 3000 ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The two available studies pre-date GLP. All followed a methodology equivalent to that outlined in the standardised guideline OECD 408. Since all studies were not conducted to GLP but were performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data, all were assigned a reliability score of 2 according to the criteria outlined by Klimisch (1977). The overall quality of the dataset is therefore good.

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

Oral

In the key study, the toxicity of the test material following repeated exposure, over a 90 day period, to rats was investigated following a procedure similar to that outlined in standard guideline OECD 408. During the study, groups of 15 male and 15 female rats were exposed to test material at dietary levels of 300, 1000 and 3000 ppm. Under the conditions of the study, no abnormalities were revealed in bodyweight gain, food consumption, survival or in the hematology, clinical chemistry, urinanalysis and pathology parameters investigated. The no observed effect concentration was therefore concluded to be in excess of 3000 ppm.

 

A supporting study is available in the form of a 90 day repeated dose toxicity study in dogs during which groups of 4 male and 4 female dogs were exposed to test material at dietary levels of 0, 300, 1000 and 3000 ppm. Under the conditions of the study, no abnormalities were revealed in bodyweight gain, food consumption, survival or in the hematology, clinical chemistry, urinanalysis and pathology parameters investigated. The no observed effect concentration can therefore be concluded to be in excess of 3000 ppm.

Inhalation

In accordance with Column 1 of Annex VIII of Regulation (EC) 1907/2006, the short-term repeated dose toxicity study (28 days) required under information point 8.6.1 should be conducted using the most appropriate route of administration. Inhalation exposure of the substance is considered to be minimal during manufacture and use. Furthermore, the repeated-dose toxicity has already been adequately addressed via the oral route.

Dermal

In accordance with Column 1 of Annex VIII of Regulation (EC) 1907/2006, the short-term repeated dose toxicity study (28 days) required under information point 8.6.1 should be conducted using the most appropriate route of administration. Since skin contact during production/use is unlikely and there is little likelihood of absorption through the skin, the dermal route should not be considered the most appropriate route. Furthermore, the repeated-dose toxicity has already been adequately addressed via the oral route.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Reyna was selected as the key study since the test material investigated is relevant to the substance under evaluation in the dossier and the study was conducted in an appropriate rodent species. As the more suitable model, the current study was selected as the key study.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for specific organ toxicity, repeated dose. The effects observed in the main study are not considered to be toxicologically significant and do not indicate any signs of organ dysfunction.