Registration Dossier

Acute oral toxicity: LD50 > 10000 mg/kg bw, rat, similar to OECD Guideline 401, study performed before implementation of GLP

Acute dermal toxicity: LD50 > 2800 mg/kg bw, rat/rabbit, similar to OECD Guideline 402, study performed before implementation of GLP

Acute inhalation toxicity: not neccessary du to low acute systemic toxicity

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no information available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

initial weight variation in male animals exceeded 20% of the mean weight

GLP compliance:

no

Remarks:

study performed before implementation of GLP

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: young adults
- Weight at study initiation: males 169-286 g and females 163-194 g
- Fasting period before study: overnight
- Housing: in groups of five in screenbottomed stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25°C

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50% w/v
- Amount of vehicle (if gavage): 8 mL/kg bw
- Justification for choice of vehicle: preliminary observations

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

Doses:

10 g/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: several times within first 24 hours, after that daily; no body weight recording
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other:

Remarks:

1/5 males and 1/5 females died

Mortality:

One male and one female died on the second and third day after test substance treatment, respectively

Clinical signs:

other: Within a few hours after treatment the rats showed sluggishness and several rats lost consciousness for a few hours. One male and one female which died later showed encrustrations round eyes and nostrils. The survivors recovered within 24 hours and look

Gross pathology:

No abnormalities were observed at necropsy.

None of the rats treated with DMSO showed reaction upon treatment.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 of Caprinoguanamine in rats was > 10000 mg/kg bw.

Executive summary:

In an acute oral toxicity study similar to OECD guideline 401, 5 male and 5 female, fasted, young Wistar strain rats were given a single oral dose of Caprinoguanamine in DMSO at a limit dose of 10000 mg/kg bw and observed for 14 days. 5 male and 5 female rats were treated with an equal amount of DMSO (8 mL/kg bw).

Within a few hours after treatment the rats showed sluggishness and several rats lost consciousness for a few hours. One male and one female showed encrustations round eyes and nostrils. They died on the second and third day after test substance treatment, respectively. The survivors recovered within 24 hours and looked quite healthy at the end of the observation period. None of the rats treated with DMSO showed any reaction upon treatment. No abnormalities were observed at necropsy.

Oral LD50 (rat, females/males) > 10000 mg/kg bw

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

10 000 mg/kg bw

Quality of whole database:

Study similar to OECD 401 Guideline, study performed before implementation of GLP

Endpoint conclusion:

no study available

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no information available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

similar to version of May 1982.

Deviations:

yes

Remarks:

Only two animals per sex per dose level and half of the animals received the material on abraded skin.

GLP compliance:

no

Remarks:

study performed before implementation of GLP

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 2.43 to 2.95 kg
- Fasting before dosing: no
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°C

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

TEST SITE
- Area of exposure: trunk
- % coverage: 10%
- Type of wrap if used: the treated area was covered with a thin layer of cellulose sheet and wrapped in polyethylene foil.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.0, 0.7, 1.4, 2.8 g/kg bw
- Constant volume used: yes
- For solids, paste formed: partly solution, partly suspension

VEHICLE
- Amount(s) applied (volume or weight with unit): 9 mL/kg bw
Half the number of animals received the material on the intact skin, the other half on the abraded skin.

Duration of exposure:

24 hours

Doses:

0.0, 0.7, 1.4, 2.8 g/kg bw

No. of animals per sex per dose:

2

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weekly
- Necropsy of survivors performed: yes
- Other examinations performed: food consumption, water intake, haematology, histopathology (heart, liver, kidney, spleen, treated and untreated skin)

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 800 mg/kg bw

Based on:

act. ingr.

Mortality:

One rabbit treated with 1.4 g/kg bw and one treated with 2.8 g/kg bw died during the observation period. Both deaths were not regarded as treatment related.

Clinical signs:

other: During or at the end of the 24-hour exposure period the skin of the rabbits of the hightest dose group showed slight to moderate erythema. In the course of the subsequent observation period, the rabbits of the hightest dose group showed slight to moderate

Gross pathology:

At necropsy pathological changes related to treatment were observed only in the skin of the rabbits of the high dose group. They consisted of slight to moderate scaliness.

Other findings:

Food and water intake and haematological data of the rabbits of the test group were comparable with those of controls.
At microscopic examination, dose-related histopathological changes were found only in skin. They were characterised by acanthosis, hyperkeratosis and signs of inflammation in the dermis. The severity of the skin lesions was of a mild degree in animals of the hightest dose group.
Microscopic examination of the liver, kidneys, heart and spleen did not reveal abnormalities that could be related to treatment.

The animal of the hightes dose group that died during the observation period showed smal haemorrhagic erosions in the stomach and marked lobular bronchopneumonia.

Examination of the animal of the intermediate dose group that died during the observation period did not provide any information to establish the cause of death.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 of Caprinoguanamine in rabbits was > 2800 mg/kg bw.

Executive summary:

In an acute dermal toxicity study similar to OECD guideline 402, 8 male and 8 female adult New Zealand White albino rabbits were divided into four dose groups and received doses of 0.0, 0.7, 1.4, 2.8 g/kg bw Caprinoguanamine in propylene glycol half of the animals on intact skin and half on the animals on abraded skin. After treatment the animals were observed for two weeks with regard to general appearance and behaviour, mortality, local skin reactions, growth, and food and water intake. At the end of the experimental period examinations were carried out for possible haematological changes and histopathological changes.

During or at the end of the 24-hour exposure period the skin of the rabbits of the highest dose group showed slight to moderate erythema. In the course of the subsequent observation period, the rabbits of the highest dose group showed slight to moderate scaliness of the treated skin. One rabbit treated with 1.4 g/kg bw and one treated with 2.8 g/kg bw died during the observation period. Both deaths were not regarded as treatment related.

Body weight gain, food and water intake and haematological data of the rabbits of the test group were comparable with those of controls. At microscopic examination, dose-related histopathological changes were found only in skin. They were characterised by acanthosis, hyperkeratosis and signs of inflammation in the dermis. The severity of the skin lesions was of a mild degree in animals of the highest dose group.

Microscopic examination of the liver, kidneys, heart and spleen did not reveal abnormalities that could be related to treatment.

Dermal LD50 (rabbit, females/males) > 2800 mg/kg bw

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 800 mg/kg bw

Quality of whole database:

Study similar to OECD 402 Guideline (May 1987), study performed before implementation of GLP

Acute oral toxicity

In an acute oral toxicity study similar to OECD guideline 401, 5 male and 5 female, fasted, young Wistar strain rats were given a single oral dose of Caprinoguanamine in DMSO at a limit dose of 10000 mg/kg bw and observed for 14 days. 5 male and 5 female rats were treated with an equal amount of DMSO (8 mL/kg bw).

Within a few hours after treatment the rats showed sluggishness and several rats lost consciousness for a few hours. One male and one female showed encrustations round eyes and nostrils. They died on the second and third day after test substance treatment, respectively. The survivors recovered within 24 hours and looked quite healthy at the end of the observation period. None of the rats treated with DMSO showed any reaction upon treatment. No abnormalities were observed at necropsy.

Oral LD50 (rat, females/males) > 10000 mg/kg bw

Similar results were obtained with the structurally similar read-across substances Acetoguanamine and Melamine:

An acute oral toxicity study with Acetoguanamine groups of five male and five female rats were given a single dose of 2.0, 2.2, 2.4, 2.6, 2.8, 3.0 g test substance / kg bw. and observed for a 14 -day period.

Then the survivors were killed and examined grossly.

The LD50 for Acetoguanamine was calculated to be 2.74 g/kg body weight.

In an acute oral toxicity study according to NTP standards, groups of five male and five female F344/N rats were administered single doses of melamine (2150 to 10000 mg/kg body weight) in corn oil by gavage. Animals were observed for 2 weeks.

2/5 males and 0/5 females died at 2150 mg/kg bw; 1/5 males and 2/5 females died at 3160 mg/kg bw; 4/5 males and 3/5 females died at 4640 mg/kg bw; all animals that received 6810 or 10000 mg/kg bw died.

Oral LD50 Males = 3161 mg/kg bw (95% C.I. 1344 - 4722)

Females = 3828 mg/kg bw (95% C.I. 2787 - 5255)

A slightly higher acute oral toxicity was observed after exposure to the structurally similar source substance Benzoguanamine:

In an acute oral toxicity study 5 male and 5 female, fasted, young Wistar strain rats per dose were given 1200, 1400, 1600, and 1800 mg/kg bw of Benzoguanamine as 20% suspension in water and were observed for 14 days.

The mortality was 20% at 1200 mg/kg bw, 60% at 1400 mg/kg bw, 40% at 1600 mg/kg bw and 90% at 1800 mg/kg bw.

In all dose groups, a few hours after the treatment the affected animals became sluggish and gradually lost consciousness. Some animals showed these symptoms for three days. Deaths occured only during the first three days. After that period, all surviving animals recovered rather quickly and at the end of the 14-day period, they looked quite healthy. No abnormalities were seen in the in survivors at necropsy.

Oral LD50 (rat, females/males) = 1470 mg/kg bw

Acute inhalation toxicity

The acute systemic toxicity of Caprinoguanamine is very low. The LD50 was shown to be > 10000 mg/kg bw via the oral route in rat and > 2800 mg/kg bw for the dermal route in rabbit determined in relevant and reliable studies. Based on toxicokinetic assessment absorption via inhalation is expected to occur. As a worst case assumption a maximum two times higher than the oral absorption rate is taken over from the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8. Based on the oral-to-inhalation extrapolation, no acute systemic toxicity via inhalation is expected. The test substance is not classified dangerous for eye and skin irritation/corrosion and sensitisation, thus there is no indication to expect severe local irritation after inhalation exposure. Further Caprinoguanamine has a low vapour pressure (1.62 10-4 Pa), excluding inhalation exposure by vapours. The inhalation of dusts and aerosols is prevented by appropriate RMMs. Thus, there is no concern with respect to respiratory irritation. Given that acute systemic toxicity is unlikely to occur and there is no concern with respect to respiratory irritation, testing by the inhalation route is scientifically not necessary according to REACH Regulation Annex XI 1 and 3. In addition adequate risk management measures are applied to ensure that the manufacture and use of the test substance do not result in an exposure via inhalation.

Acute dermal toxicity

In an acute dermal toxicity study similar to OECD guideline 402, 8 male and 8 female adult New Zealand White albino rabbits were divided into four dose groups and received doses of 0.0, 0.7, 1.4, 2.8 g/kg bw Caprinoguanamine in propylene glycol half of the animals on intact skin and half on the animals on abraded skin. After treatment the animals were observed for two weeks with regard to general appearance and behaviour, mortality, local skin reactions, growth, and food and water intake. At the end of the experimental period examinations were carried out for possible haematological changes and histopathological changes.

During or at the end of the 24-hour exposure period the skin of the rabbits of the highest dose group showed slight to moderate erythema. In the course of the subsequent observation period, the rabbits of the highest dose group showed slight to moderate scaliness of the treated skin. One rabbit treated with 1.4 g/kg bw and one treated with 2.8 g/kg bw died during the observation period. Both deaths were not regarded as treatment related.

Body weight gain, food and water intake and haematological data of the rabbits of the test group were comparable with those of controls. At microscopic examination, dose-related histopathological changes were found only in skin. They were characterised by acanthosis, hyperkeratosis and signs of inflammation in the dermis. The severity of the skin lesions was of a mild degree in animals of the highest dose group.

Microscopic examination of the liver, kidneys, heart and spleen did not reveal abnormalities that could be related to treatment.

Dermal LD50 (rabbit, females/males) > 2800 mg/kg bw

Based on relevant, reliable and adequate data, Caprinoguanamine does not have to be classified and labelled according to the CLP Regulation (EC) No 1272/2008 with respect to acute toxicity.