Potassium hexadecyl hydrogen phosphate

Endpoint summary

Description of key information

The substance was orally administered by means of a feed admix to Fü SPF albino rats of both sexes at daily dose levels of 50, 200, and 800 mg per kg bw for a period of 13 consecutive weeks. Animals of a control group received the normal rat maintenance diet without test article. All test groups comprised 10 males and 10 females. Mortality, clinical signs, body weights, feed intake, and water consumption were recorded. The NOAEL was 800 mg/kg bw/day, the highest dose tested.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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:

1998-05-17 until 1998-08-18

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Ibm: RORO (SPF), also known as SPF Fü albino rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute of Biological and Medical Research, Füllinsdorf, Switzerland
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: female 151.0-172.0 g; male 155.3-161.0 g
- Housing: 2 animals per cage, conventional air-conditioned room
- Diet: ad libitum, NAFAG standard rat maintenance diet, No. 850 (pulverized)
- Water : tap water, ad libitum
- Acclimatisation period: 9 days (males), 10 days (females)

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2C°
- Humidity: 55 ± 10 %
- Photoperiod: artificial light for 12 hours and darkness for 12 hours per day

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Route of administartion and frequency: orally, as feed admix. 7 days per week for a period of 92 days

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

92 days

Frequency of treatment:

7 days per week

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

Dose / conc.:

800 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10 animals per sex per group

Control animals:

yes, plain diet

Details on study design:

- Rationale for animal assignment: as in the guideline. The rat is a readily available rodent species acceptable to regulatory authorities, with documented susceptibility to a wide range of toxic substances. Furthermore, data were available from studies conducted in the performing laboratory on haematology, clinical chemistry, metabolism and background pathology in untreated rats of this strain, in addition, there were adequate references in the scientific literature to assist in the assessment of any changes observed in treated animals. All rats were randomly allocated to the test groups.

Positive control:

None

Observations and examinations performed and frequency:

The 1st treatment day is defined as day 0, week 0. The 2nd treatment day is defined as day 1, week 1. The 1st treatment week started on day 1 and terminated on day 7.

CAGE SIDE OBSERVATIONS: yes
- Time schedule: once weekly

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: mortality and general state of health were daily controlled

BODY WEIGHT: yes
- Time schedule for examinations: recorded on days 0 (immediately prior to treatment), 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, and 91.

FOOD CONSUMPTION: yes
- The amount of feed consumed by the rats of each cage was measured at weekly intervals.

WATER CONSUMPTION AND COMPOUND INTAKE: yes (only by the control group and the 800 mg/kg bw/day dose group)
- Time schedule for examinations: The weight of water consumed by the rats of each cage was measured from day 16 (M - 02/06/1988; F - 03/06/1988) to day 55 (M - 11/07/1988; F - 12/07/1988).

OPHTHALMOSCOPIC EXAMINATION: yes
- Time schedule for examinations: prior to treatment and at the termination of the study
- Dose groups that were examined: the control group and the 800 mg/kg bw/day dose group

HAEMATOLOGY AND CLINICAL CHEMISTRY : yes (blood was collected from the retroorbital vein plexus)
- Time schedule for collection of blood: prior to treatment and at week 13 (males 2 days before study termination and females 1 day before study termination)
- Anaesthetic used for blood collection: yes (superficial ether anaesthesia)
- Animals fasted: yes (over night)
- How many animals: all study animals
- Parameters examined (hematology): Haemoglobin (HB), Erythrocyte count (RBC), packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), thrombocytes (PTL), white blood cells (WBC), reticulocytes (RETI)
- Parameters examined (clinical chemistry): total bilirubin (P-TOBIL), urea (P-UREA), alanine aminotranferase (P-ALT), alkaline phosphatase (P-ALP), creatinine (P-CREAT), cholesterols (P-TOCHO), hydroxybutyrate dehydrogenase (P-HBD)

URINALYSIS: Yes
- Time schedule for collection of urine: week 2 and week 12
- Metabolism cages used for collection of urine: yes
- Animals fasted: yes (rat feed and water were withheld during the collection period)
- Parameters examined: colour, volume, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, urinary sediment

NEUROBEHAVIOURAL EXAMINATION: no data

Sacrifice and pathology:

GROSS PATHOLOGY: yes. All rats, which were subjected to full necropsy and macroscopic post mortem examination, had an overnight fasting and were deeply narcotized with carbon dioxide and exsanguinated by incision of the neck. The following organs dissected free from fat and other contiguous tissue were weighed from all sacrificed animals (wet weight; paired organs = weight of both organs together): brain, liver, kidneys, testes, ovaries, heart (without auricles), adrenals. The relative organ weights were calculated on the basis of the body weights of day 91.

HISTOPATHOLOGY: yes. The following organs and tissues were taken from all animals:
pituitary gland, adrenal glands, aorta, sciatic nerve, thyroid gland, parathyroid glands, trachea, esophagus, heart, lungs, liver, salivary glands, spleen, pancreas, thymus, lymph nodes, kidneys, urinary bladder, stomach duodenum, jejunum, ileum, cecum, colon, rectum, skin, skeletal muscle, cerebrum, cerebellum, uterus, ovaries, eyes, bone, bone marrow, prostate, seminal vesicles, testes, and epididymides.
Histopathological evaluation was done for the control and high dose group.

Statistics:

Data were processed to give group mean values (X) and standard deviations (SD), where applicable. Appropriate statistical analyses were used to assess the significance of the results: Jonckheere-Test and the U-Test.

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 specified

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

The slightly increase water consumtion was not regarded as adverse effect.

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

No toxicological relevant effects were observed in any of the dosed animals in any of the parameters examined.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No toxicological relevant effects were observed in any of the dosed animals

Key result

Critical effects observed:

no

- The test substance is a potassium salt and caused a slightly increased water consumption (compared were amimals of the control group with those of group the 800 mg/kg bw/day dose group only). PCV (packed cell volume) and RBC (red bllod cell count) values were slightly decreased in all male dose groups as well as in the female high dose group as a result of the increased water intake. These hamatologic changes were not considered to be of toxicological importance.

Conclusions:

NOAEL = 800 mg/kg bw/day

Executive summary:

The test article was orally administered by means of a feed admix to Fü SPF albino rats of both sexes at daily dose levels of 50, 200, and 800 mg per kg bw for a period of 13 consecutive weeks. Animals of a control group received the normal rat maintenance diet without test article. All test groups comprised 10 males and 10 females. Mortality, clinical signs, body weights, feed intake, and water consumption were recorded. Eyes were examined. Haematology and biochemistry determinations were performed. All rats were autopsied and organs were weighed. Organs and tissues of the control and the high dosed rats were histopathologically examined.

No deaths related to treatment occured throughout the test period. The treatment with the test substance up to 800 mg/kg bw/day was well and asymptomatically tolerated. There were no adverse effects on body weight development and feed consumption. Slightly decreased PCV (packed cell volume) and RBC (erythrocyte count) values were considered to be a result of an increasing thirst effect of the test substance. Ophthalmoscopy, biochemistry, organ weighing, macroscopic and microscopic examination did not reveal undesired/ toxicological related effects. Thus, a NOAEL value of 800 mg/kg bw/day was concluded.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

800 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Comparable to OECD guideline 408.

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

Repeated dose toxicity: oral

The test article was orally administered by means of a feed admix to Fü SPF albino rats of both sexes at daily dose levels of 50, 200, and 800 mg per kg bw for a period of 13 consecutive weeks. Animals of a control group received the normal rat maintenance diet without test article. All test groups comprised 10 males and 10 females. Mortality, clinical signs, body weights, feed intake, and water consumption were recorded. Eyes were examined. Haematology and biochemistry determinations were performed. All rats were autopsied and organs were weighed. Organs and tissues of the control and the high dosed rats were histopathologically examined.

No deaths related to treatment occured throughout the test period. The treatment with the test substance up to 800 mg/kg bw/day was well and asymptomatically tolerated. There were no adverse effects on body weight development and feed consumption. Slightly decreased PCV (packed cell volume) and RBC (erythrocyte count) values were considered to be a result of an increasing thirst effect of the test substance. Ophthalmoscopy, biochemistry, organ weighing, macroscopic and microscopic examination did not reveal undesired/ toxicological related effects. Thus, a NOAEL value of 800 mg/kg bw/day was concluded.

Repeated dose toxicity: dermal

In accordance with REACH Annex IX, column 2, a subchronic dermal repeated dose toxicity study (section 8.6.2) is not required as a repeated dose oral study is available. Available information on acute toxicity (dermal), as well as oral repeated dose toxicity together with toxicokinetic/ absorption findings indicate a lower dermal absorption (10 % ) compared to oral absorption (50 % in the GIT) (see section 7.1). Consequently, the repeated dose toxicity was adequately adressed by the oral route (see section 7.5.1), allowing evaluation of systemic toxic effects after dermal exposure.

Repeated dose toxicity: inhalation

In accordance with REACH Annex IX, column 2, a subchronic inhalation repeated dose toxicity study (section 8.6.2) is not required, as information on subchronic oral toxicity is available and performed by the exposure route which is considered as most appropriate route of exposure. Exposure to humans through the inhalation route is not likely, taking in account the nature of the substance. The vapour pressure of potassium hexadecyl hydrogen phosphate is very low (2.89 E-3 Pa at 25°C) based on a vapour pressure study (see section 4.6 ). Further, exposure to potassium hexadecyl hydrogen phosphate via inhalation is not likely as particles are not inhalable (L50 = 213 µm) based on the results of a granulometry study (see section 4.5). Thus, further testing is not required.

Justification for classification or non-classification

Based on the results and considerations detailed above, the substance is not subjected to classification and labelling for repeated dose toxicity according to Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.