Registration Dossier

Administrative data

Description of key information

1) An Oral Reproduction/Developmental Toxicity Screening Study in Rats, NOAEL: 150 mg/kg bw/day;
2) Repeated dose toxicity, oral, 28-day, rats, NOAEL 1000 mg/kg bw/day;
3) Repeated dose toxicity, oral, 14-day, rats NOAEL 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The key study is GLP compliant and of 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

An Oral Reproduction/Developmental Toxicity Screening Study in Rats

This study was conducted to generate information concerning the effects of the test item (reaction product of amines, C12-14,-tert-alkyl, alcohol, C14-18, C18 unsat, and phosphorus pentoxide) after repeated exposures on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of the conceptus, and parturition (Thorsrud, 2013, Report No. 1928 -005). According to OECD Guideline 421, three treatment groups of twelve CD [Crl:CD(SD)] rats/sex/group were administered the test article at dose levels of 150, 500, or 1000 mg/kg/day. One additional group of twelve animals/sex served as the control and received the vehicle, peanut oil (arachis oil NF). The vehicle or test article was administered to all groups daily via oral gavage at a dose volume of 2 mL/kg/dose. Dosing began 14 days prior to pairing and continued to euthanasia (43 days total) for the parental (P) males. Observations of the P animals included clinical signs, body weights and body weight change, and food consumption during the premating/mating, gestation, and lactation periods, and parturition and litter data. At study termination, necropsy examinations were performed on all surviving P animals, and organs and tissues were collected, weighed, and examined for select groups. Dams losing their entire litter were subjected to a necropsy.

Once daily administration of "reaction product of amines, C12-14,-tert-alkyl, alcohol, C14-18, C18 unsat, and phosphorus pentoxide" by oral gavage to male rats for 7 weeks and female rats for two weeks prior to mating, through gestation and lactation at dose levels of 150, 500, and mg/kg/day produced clinical findings consisting of postdose salivation and yellow discoloured hair in both male and female animals predominantly at 500 and 1000 mg/kg/day. Additional clinical findings were noted in the females predominantly at 500 and 1000 mg/kg/day that included increased activity, few/absent faeces, and vulvar discharge. Two females at 1000 mg/kg/day had to be euthanized moribund close to the time of parturition. Test article-related changes in body weight and food consumption were limited to females at 500 and 1000 mg/kg/day. 

Test article-related macroscopic findings were present in the adrenal gland, thymus, and stomach of females at 1000 mg/kg/day. Test article-related organ weight changes were present in the ovaries, liver, kidneys, adrenal glands, and thymus at 500 and 1000 mg/kg/day. Test article-related microscopic findings were present in the ovaries, liver, kidneys, adrenal glands, stomach, and duodenum. Most findings were predominantly observed at 1000 mg/kg/day, but were also noted to some extent in animals at 500 mg/kg/day.

Based on the results obtained from this study, the No-Observed-Adverse-Effect-Level (NOAEL) for general toxicity in parental male and female animals was considered to be 150 mg/kg/day, which was generally based on, but not limited to, significant clinical findings, decreases in body weight and food consumption (primarily females), as well are organ weight changes and microscopic findings at 500 and 1000 mg/kg/day. However, mating, fertility, and fecundity indices were unaffected by treatment with the test item at dose levels up to 1000 mg/kg/day, the highest dose level tested.

Oral 28 -day study in rats

An oral 28 -day study was undertaken to investigate the systemic oral toxicity of the test item in rats (Dunster and Watson, 2012, according to OECD 407). The test item was administered by gavage to three groups, each of five male and five female Wistar rats, for twenty-eight consecutive days, at the dose levels of 30, 300 and 1000 mg/kg bw/day. A control group of five males and five females was dosed with vehicle alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated with the high dose (1000 mg/kg bw/day) or the vehicle alone for twenty-eight consecutive days and then maintained without treatment for a further fourteen days. Clinical signs, body weight change, food and water consumption were monitored during the study. Haematology, blood chemistry and urinalysis were evaluated for all non-recovery group animals at the end of the treatment period and for all recovery group animals at the end of the treatment-free period. There were no unscheduled deaths during the study and no toxicologically significant effects were detected. Moreover, there were no treatment related changes in the behavioural parameters measured and no toxicologically significant changes were detected in the functional performance parameters measured. In addition, there were no treatment related changes in sensory reactivity scores for treated animals when compared to controls.

The body weight was statistically significant reduced in the non-recovery males treated with 1000 mg/kg bw/day (p<0.05) during Weeks 1 and 3 of the study resulting in a slightly lower mean overall body weight gain when compared to control animals. Recovery was evident following fourteen days without treatment. No toxicologically significant effects were detected in non-recovery females treated with 1000 mg/kg bw/day or in animals of either sex treated with 300 or 30 mg/kg bw/day. However, no adverse effects on food intake or food efficiency were detected, but water consumption was increased in non-recovery animals of either sex treated with 1000 mg/kg bw/day during the treatment period and slightly increased during the recovery phase of the study. No toxicologically significant findings were detected in the haematological parameters measured. Non-recovery males treated with 1000 mg/kg bw/day showed an increase in alanine aminotransferase whilst females from this treatment group showed an increase in phosphorus concentration and a reduction in albumin when compared to controls. No such effects were detected in animals of either sex treated with 300 or 30 mg/kg bw/day. No toxicologically significant effects were detected in the analytical parameters examined in the urine and no toxicologically significant macroscopic abnormalities were detected in necropsy.

Gross pathology revealed that the organ weight in the non-recovery animals of either sex treated with 1000 mg/kg bw/day showed a statistically significant increase in liver weight, both absolute and relative to terminal body weight. The effect on liver weight also extended to 300 mg/kg bw/day males. No such effects were detected in females treated with 300 mg/kg bw/day or animlas of either sex treated with 30 mg/kg bw/day. In histopathological examinations, the following treatment related findings were recorded:

Liver: Centrilobular hepatocellular hypertrophy was recorded in non-recovery animals of either sex treated with 1000 mg/kg bw/day and in males treated with 300 mg/kg bw/day.

Thyroid: Increased incidence and severity of follicular thyroid hypertrophy was recorded in non-recovery animals of either sex treated with 1000 mg/kg bw/day.

Kidney: Hyaline droplets nephropathy was recorded in non-recovery males treated with 1000 or 300 mg/kg bw/day.

In conclusion resulted the administration of "reaction product of amines, C12-14,-tert-alkyl, alcohol, C14-18, C18 unsat, and phosphorus pentoxide" to rats for a period of twenty-eight consecutive days at dose levels of up to 1000 mg/kg bw/day in treatment related effects in animals of either sex treated with 1000 mg/kg bw/day and in males treated with 300 mg/kg bw/day. The effects detected in 1000 mg/kg bw/day animals and 300 mg/kg bw/day males were confined to body weight reductions (1000 mg/kg bw/day males only), blood chemical changes (1000 mg/kg bw/day animals only), organ weight changes, microscopic liver and thyroid changes (1000 mg/kg bw/day animals only) and microscopic kidney changes (males only). The microscopic changes are considered to be adaptive in nature or species specific and do not represent “serious damage” to health. The body weight and blood chemical changes are considered to be a consequence of the adaptive microscopic liver changes and also do not represent “serious damage” to health. Therefore the “No Observed Adverse Effect Level” (NOAEL) is considered to be 1000 mg/kg bw/day.

Range-finding 14 -day study in rats

A test was undertaken prior to the 28 -day repeated dose toxicity study as a range-finding test to investigate the systemic oral toxicity of the test item in rats (Liwska, 2012). The test item was administered by gavage to three groups, each of three male and three female Wistar Han™:RccHan™:WIST strain rats, for fourteen consecutive days, at dose levels of 250, 500 and 1000 mg/kg bw/day. A control group of three males and three females was dosed with vehicle alone (Arachis oil BP). Clinical signs, body weight change, dietary intake and water consumption were monitored during the study. All animals were subjected to gross necropsy examination.There were no unscheduled deaths during the study. Incidents of increased salivation were evident in animals of either sex treated with 1000 mg/kg bw/day on Day 4 and between Days 8 to 9 and in animals of either sex treated with 500 or 250 mg/kg bw/day on Day 9 only. These findings are often observed following unpalatable and/or slightly irritant test item formulations and can be considered of no toxicological importance.

There were no adverse effects on body weight development evident in all treated animals throughout the study period. There were no adverse effects detected on food consumption in treated animals when compared to controls throughout the treatment period. Daily measurements of water consumption revealed increased water intake in animals of either sex treated with 1000 mg/kg bw/day throughout the treatment period. This finding can be associated with slightly irritant nature of the test item, and as such is considered of no toxicological importance. No such effects were evident in animals of either sex treated with 500 or 250 mg/kg bw/day. No macroscopically observable abnormalities were detected during necropsy.

In conclusion, the oral administration of "reaction product of amines, C12-14,-tert-alkyl, alcohol, C14-18, C18 unsat, and phosphorus pentoxide" to rats for a period of fourteen consecutive days at dose levels of 250, 500 and 1000 mg/kg bw/day produced no toxicologically significant effects in the parameters measured. The “No Observed Adverse Effect Level” (NOAEL) and a suitable high dose level for use on future toxicity studies was, therefore, considered to be 1000 mg/kg bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
GLP-Guideline study with the longest duration.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No relevant route of exposure.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
No relevant route of exposure. Local effects are sufficiently covered by systemic effects.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The substance is neither a skin irritant nor a skin sensitiser. Thus, the evaluation of this endpoint is not justified. One oral study for DNEL extrapolation is available.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The substance is neither a skin irritant nor a skin sensitiser. Thus, the evaluation of this endpoint is not justified. One oral study for DNEL extrapolation is available.

Justification for classification or non-classification

The substance "reaction product of amines, C12-14,-tert-alkyl, alcohol, C14-18, C18 unsat, and phosphorus pentoxide" did not cause relevant

significant toxicological effects after repeated oral exposure. Therefore, the registered substance does not meet the criteria for classification and will not require labelling, according to the European regulation (EC) No. 1272/2008.