Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea

Endpoint summary

Description of key information

- Repeated dose toxicity, oral: NOAEL/rat (Males): 6.54 mg/kg bw/day AI , NOAEL/rat (Females): 13.1 mg/kg bw/day AI, LOAEL/rat (Males) = 13.1 mg AI /kg bw/day AI, LOAEL/rat (Females): 39.2 mg/kg bw/day AI were established based on blood chemical changes and liver effects (OECD 408, GLP, Kr: 1).

- Repated dose toxicity, inhalation: No data available

- repeated dose toxicity dermal: No data available. However, the waiving is justified considering animal welfare since THPC urea is considered as corrosive.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

6.54 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The studies are GLP compliant with a high quality (Klimisch score = 1).

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

1- Repeated dose toxicity: Oral route

Two studies were available with reliability 1 according to Klimisch rating (Kr).

- A study report (Harlan, 2013) has been chosen as key study for this endpoint. This study was conducted according to OECD guideline 408 and in compliance with GLP. In this study, Tetrakis (hydroxymethyl) phosphonium chloride, oligomeric reaction products with urea (THPC-urea) was administered continuously by gavage to three groups, each of ten male and ten female Wistar rats, for 90 consecutive days, at dose levels of 6.54, 13.1 and 39.2 mg/kg bw/day (incorporating a correction factor for 65.4% purity). A control group of ten males and ten females was dosed with vehicle alone (Distilled water). Two recovery groups, each of ten males and ten females, were treated with the high dose (39.2 mg/kg bw/day AI) or the vehicle alone for 90 consecutive days and then maintained without treatment for a further twenty-eight days.

No treatment-related effects were detectedon Behavioural Assessment, Functional Performance Tests, Sensory Reactivity Assessments, Body Weight, Food Consumption, Oestrous Cycle Assessments, Ophthalmoscopy, Haematology, Urinalysis, Organ Weights and sperm analysis. However, the males treated with 39.2 mg/kg bw/day AI showed increases in alanine aminotransferase and aspartate aminotransferase levels compared to controls.Females treated with 39.2 mg/kg bw/day AI showed a reduction in total protein, albumin and calcium levels, with the reductions in albumin and calcium extending into the 13.1 mg/kg bw/day AI dose group. Calcium values were also lower at the lowest treatment level. Males treated at all dose levels also showed a reduction in total protein and calcium levels.

At necropsy,mottled appearance and pallor of the liver was recorded for three males treated at 39.2 mg/kg bw/day AI. One female treated with 39.2 mg/kg bw/day AI also showed a mottled appearance of the liver. No further treatment-related macroscopic abnormalities were detected.

Histopathological findings show treatment-related changes in the liver.Hepatocellular eosinophilic cytoplasmic vacuoles were observed in animals of either sex treated with 13.1 and 39.2 mg/kg bw/day AI, and males treated with 6.54 mg/kg bw/day AI. Among these animals, hepatocellular single cell necrosis andmicrovesicular hepatocellular degeneration were observed in males treated with 13.1 mg/kg bw/day AI and animals of either sex treated with 39.2 mg/kg bw/day AI. In the recovery animals, hepatocellular eosinophilic cytoplasmic vacuoles were still present for animals of either sex treated with 39.2 mg/kg bw/day AI. Increased incidence and/or severity of inflammatory cell foci were recorded in animals of either sex treated with 39.2 mg/kg bw/day AI. This was not evident in the recovery high dose animals.One male and three females treated with the high dose level showed minimal periportal hypertrophy observed in hepatocytes not containing eosinophilic vacuole, and minimal bile duct proliferation was recorded in three males and two females treatedwith 39.2 mg/kg bw/day AI. This was not evident in the recovery high dose animals.

Based on the results of this study, a ‘No Observed Adverse Effect Level’ (NOAEL) was established at 6.54 mg/kg bw/day active ingredient for males and 13.1 mg/kg bw/day active ingredient for females (liver effects).

- A study report (Harlan, 2010) has been chosen as supporting study. This study was conducted accoding to OECD 407 and in compliance with GLP. In this study, Tetrakis (hydroxymethyl) phosphonium chloride, oligomeric reaction products with urea (THPC-urea) was administered in rat for a period of up to twenty-eight days by gavage administration at dose levels of 0, 52, 104 and 162.5 mg Active Ingredient (AI)/kg bw/day, respectively. Due to excessive toxicity, the high dose was reduced to 130 mg AI/kg bw/day (Harlan, 2010). This key study was performed according to the OECD test guideline No. 407 and in compliance with GLP (Kr: 1).

The high dose animals showed significant clinical signs as episodes of hunched posture; ataxia, pilo-erection, increased salivation and emaciation , splayed gait, tiptoe gait, ptosis, lethargy, noisy and decreased respiration, sneezing, dehydration, hypothermia and stained snout, resulting in a rapid deterioration in physical health and the subsequent death of all the males and two females. The 104 mg AI/kg bw/day animals showed incidences of increased salivation, laboured and decreased respiration, pilo-erection, hunched posture and staining around the eyes and mouth. No clinical signs were observed in animals treated with 52 mg AI/kg bw/day. Reductions in bodyweight gain, dietary intake and food efficiency were seen in the high dose and 104 mg AI/kg bw/day males. Furthermore, an increase in water intake was observed in the high dose and 104 mg AI/kg bw/day animals of either sex. This is considered to be a result of the physiological response to the irritant test material. There were no treatment-related changes in behavioral and in sensory reactivity. No treatment-related changes were noted for haematology. A reduction in plasma chloride, calcium and cholesterol levels with an increase in inorganic phosphorus levels was detected in the 104 and 52 mg AI/kg bw/day males. In addition, a reduction in bilirubin levels was also seen in the 104 mg AI/kg bw/day for males. A reduction in plasma calcium, cholesterol, cholesterol and alkaline phosphatase levels was noted in all the female dose groups. Furthermore, an increase in alanine aminotransferase levels was seen in the high dose and 104 mg AI/kg bw/day females with an increase in aspartate aminotransferase observed in the high dose females. Macroscopic examination of the tissues showed episodes of mottled liver and stomach changes identified as raised limiting ridge at all dose tested. Stomach changes suggest a direct irritant effect of the test material on the forestomach and gastric mucosa. Histopathological examination of the liver revealed hydropic degeneration of periportal hepatocytes in animals of either sex at all treatment levels. Organ weight data supported this finding with increased liver weights in the high dose females and 104 mg AI/kg bw/day females. Therefore, the liver is considered to be a target organ. Liver toxicity was observed at all tested doses and only liver effects, or hepatotoxicity related effects, were detected at the lowest tested dose (52 mg AI/kg bw/day). The treatment-related effects, including deaths identified, were considered to be adverse. Thus, a NOAEL/NOEL could not be established, a LOAEL can be derived: 52 mg AI/kg bw/day based on liver effects.

 

2- Repeated dose toxicity: Dermal route

No repeated toxicity study conducted by dermal route was available. However, the waiving is justified considering animal welfare since THPC-urea is classified in category 1C, H314 (causes severe skin burns and eye damage) according to the CLP regulation (1272/2008) and as corrosive (C, R34) according to the Directive 67/548/EEC.

3- Repeated dose toxicity: Inhalation route

No data was available.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The key study was performed according to OECD 408 and in compliance with GLP (reliability: 1). The supporting study is an OECD 407, No NOAEL/NOEL was established in this study.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

1- Repeated dose toxicity: Oral route

Tetrakis (hydroxymethyl) phosphonium chloride, oligomeric reaction products with urea (THPC-urea) is classified for repeated dose toxicity as STOT RE 2 (H373) according to the criteria of the Regulation (EC) N° 1272/2008 and as Xn, R48/22 according to the criteria of the Directive 67/548/EEC based on:

- The LOAEL/rat (Males) - 90 days: 13.1 mg /kg bw/day AI determined in the key study (Liver effects) - The LOAEL/rat (Females) - 90 days: 39.2 mg/kg bw/day AI determined in the key study (Liver effects)

2- Repeated dose toxicity: Dermal route

No classification is possible due to lack of data

 

3- Repeated dose toxicity: Inhalation route

No classification is possible due to lack of data.