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REACH

Propylenediamine

EC number: 201-155-9 | CAS number: 78-90-0

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

INHALATION:

(OECD TG 412, GLP): NOAEC (vapour, rat) = 100 mg/m³ for systemic toxicity (highest tested dose), 5 mg/m³ for local effects in nasal cavity

Due to corrosive properties and flammability, 1,2 PDA is handled under closed conditions with no or low exposure of workers. Additionally, a weight of evidence approach shows that aside from corrosion as the leading health effect only limited systemic toxicity occurs at high doses.

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:

weight of evidence

Study period:

12 August 2015 - 28 January 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: on the first day of treatment, the animals were 9 weeks old.
- Weight at study initiation: the males had a mean body weight of 425 g (range: 383 g to 479 g) and the females had a mean body weight of 265 g (range: 234 g to 300 g)
- Fasting period before study: no
- Housing: the animals were housed in twos or threes of the same sex and in the same group, in polycarbonate cages with stainless steel lids
- Diet (e.g. ad libitum): SSNIFF R/M-H pelleted maintenance diet
- Water (e.g. ad libitum): tap water (filtered with a 0.22 µm filter)
- Acclimation period: 35 days before the beginning of the treatment period.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%,
- Air changes (per hr): approximately 8 to 15 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

IN-LIFE DATES: From: 17 September 2015 To: 28 January 2016

Route of administration:

oral: gavage

Vehicle:

other:

Remarks:

Drinking water treated by reverse osmosis

Details on oral exposure:

TYPE OF FORMULATION:
solution in the vehicle.

PREPARATION OF DOSING SOLUTIONS:
- Preparation procedure:
The test item was weighed and mixed with the required quantity of vehicle. The pH of the dose formulation was adjusted to 8.0 (± 0.5) with a solution of hydrochloric acid (HCl 5N, VWR Prolabo®); the volume of HCl added was recorded for each concentration. The final pH was checked and recorded by using a pH-meter.
- Frequency of preparation and storage conditions:
Fresh dose formulations were prepared on the day of administration and kept at room temperature prior to administration.

VEHICLE
- Concentration in vehicle: 10, 50 and 150 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg/day.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas Chromatography with FID detection (GC-FID).

Duration of treatment / exposure:

13 weeks.

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Dose / conc.:

750 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Groups 1 and 4: 15 males and 15 females
Groups 2 and 3: 10 males and 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
The dose-levels were selected based on the results of a previous toxicology study performed in the same species. Male and female Sprague-Dawley rats received Diethylaminopropylamine (as pH-neutralized dose formulations) daily, by gavage, at dose-levels of 100, 300 or 1000 mg/kg/day for 2 weeks. At 1000 mg/kg/day, in-life observations were limited to ptyalism in both sexes, and lower body weight gain at treatment initiation resulted in a lower final body weight in males. Histopathology findings consisted of minimal to slight hyperplasia of squamous cells, associated with minimal to slight hyperkeratosis within the forestomach in all males and females given 1000 mg/kg/day.Thus, based on these available data, the following dose-levels were selected for the present study: 50, 250 and 750 mg/kg/day.

- Post-exposure recovery period in satellite groups: 6 weeks

Observations and examinations performed and frequency:

MORBIDITY AND MORTALITY: Yes
- Time schedule: each animal was checked for mortality and morbidity once a day during the acclimation period and at least twice a day during the treatment and treatment-free periods, including weekends and public holidays.

CLINICAL OBSERVATIONS: Yes
- Time schedule: each animal was observed once a day, at approximately the same time, for the recording of clinical signs.

DETAILED CLINICAL EXAMINATION: Yes
- Detailed clinical examinations were performed on all animals once before the beginning of the treatment period and then at least once a week until the end of the study.

FUNCTIONAL OBSERVATION BATTERY: Yes
- Time schedule: all main animals were evaluated once in Week 13 (before the daily treatment). As no relevant changes were observed at the end of the treatment period, FOB examinations were not carried out at the end of the treatment-free period.

MOTOR ACTIVITY: Yes
- For each animal, motor activity was measured by automated infra-red sensor equipment over a 60 minute period.

BODY WEIGHT: Yes
- Time schedule for examinations: the body weight of each animal was recorded once before the beginning of the treatment period, on the first day of treatment and at least once a week until the end of the study.

FOOD CONSUMPTION: Yes
- Time schedule: The quantity of food consumed by the animals in each cage was recorded at least once a week, over a 6 or 7-day period, during the study.Food consumption was calculated per animal and per day.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmological examinations were performed on all animals, before the beginning of the treatment period, on all main animals on one occasion at the end of the treatment period.As no relevant changes were detected in the treated animals at the end of the treatment period, the recovery animals were not examined at the end of the treatment-free period.

MONITORING OF ESTROUS CYCLE: Yes
The estrous cycle stage was determined for each female sacrificed at the end of the treatment period, from a fresh daily vaginal lavage (stained with methylene blue) for 21 consecutive days before the end of the treatment period.In view of the findings observed at the end of the treatment period, these examinations were carried out daily for 5 consecutive days before the end of the treatment-free period.

HAEMATOLOGY: Yes
- Time schedule for peripheral blood: the parameters were determined for all surviving animals sacrificed at the end of the treatment period.
- Time schedule for bone marrow: two bone marrow smears were prepared from the femoral bone (at necropsy) of all animals sacrificed on completion of the treatment or treatment-free period.In view of the findings observed at the end of the treatment period, these examinations were also carried out at the end of the treatment-free period.

CLINICAL CHEMISTRY: Yes
- Time schedule: the parameters were determined for all surviving animals sacrificed at the end of the treatment period. In view of the findings observed at the end of the treatment period, these examinations were also carried out at the end of the treatment-free period.

URINALYSIS: Yes
- Time schedule: the parameters were determined for all surviving animals sacrificed at the end of the treatment period.In view of the findings observed at the end of the treatment period, these examinations were also carried out at the end of the treatment-free period.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: all main animals were evaluated once in Week 13 (before the daily treatment).
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity.

SEMINOLOGY: Yes
- Time schedule: before sacrifice at the end of the treatment period, each male was anesthetized by an intraperitoneal injection of sodium pentobarbital.As no relevant treatment-related changes were observed at the end of the treatment period, these examinations were not carried out at the end of the treatment-free period.
- Epididymal sperm
Sperm from the cauda epididymis was sampled for motility and morphology investigations.
The cauda of the left epididymis was separated from the corpus using a scalpel and subsequently kept at 20°C pending further investigation.
- Epididymal sperm motility
The sperm was evaluated on a slide, after appropriate dilution. The number of motile and immotile spermatozoa from a sample of 200 spermatozoa was evaluated under a microscope using a 40-fold magnification. Results were expressed as the proportion of motile and non-motile spermatozoa.
- Epididymal sperm morphology
The morphology was determined from a sperm smear, after eosin staining and counting of 100 spermatozoa per slide. Results were expressed as the proportion of spermatozoa in each of the following categories:
. normal,
. normally shaped head separated from flagellum,
. abnormal head separated from flagellum,
. abnormal head with normal flagellum,
. abnormal head with abnormal flagellum,
. normally shaped head with abnormal flagellum.
. Epididymal sperm count
After thawing, the left cauda epididymis was weighed, minced and homogenized in a saline-triton solution using a Polytron.
An aliquot of the suspension was sampled and the number of spermatozoa was counted in a microscope slide counting chamber.
Results were expressed as the number of spermatozoa per cauda and per gram of cauda.
- Testicular sperm
At necropsy, the left testis was sampled and frozen at -20°C for further sperm count investigation. After thawing, the left testis was weighed (without the albuginea) and ground. The resulting preparation was diluted and sperm heads resistant to homogeneization (i.e. elongated spermatids and mature
spermatozoa) were counted in a microscope slide counting chamber. Results were expressed as a number of sperm heads per gram of testis and the daily sperm production rate was calculated (a time divisor of 6.10 which represents the duration of spermatogenic cycle of homogenization-resistant testicular spermatids).

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
A complete macroscopic post-mortem examination was performed on all animals. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.

ORGAN WEIGHTS: Yes
The body weight of each animal was recorded before sacrifice. The organs specified in the Tissue Procedure Table were weighed wet as soon as possible after dissection. The ratio of organ weight to body weight (recorded immediately before sacrifice) was calculated.

HISTOPATHOLOGY: Yes
A microscopic examination was performed on:
- control and high-dose animals (groups 1 and 4) sacrificed at the end of the treatment period and one prematurely sacrificed female (group 4),
- all macroscopic lesions from all low- and intermediate-dose animals (groups 2 and 3) sacrificed on completion of the treatment period. According to microscopic findings observed in the control and high-dose animals (groups 1 and 4), the following tissues from low- and intermediate-dose animals (groups 2 and 3) and from the recovery animals (groups 1 and 4) were examined: brain, forestomach, gut-associated lymphoid tissue, kidneys, mesenteric lymph nodes (males only), pituitary gland, spleen and thymus.

Statistics:

Citox software was used to perform the statistical analyses of body weight, food consumption, hematology, blood biochemistry and urinalysis data. PathData software was used to perform the statistical analysis of organ weight data (level of significance: 0.05 or 0.01).

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 750 mg/kg/day, signs of poor clinical condition (thin appearance, hunched posture, piloerection, bent head, loud and/or abdominal breathing, and/or dyspnea) were noted in 1/15 males for few days and 3/14 females from Week 11. Thin appearance, hunched posture, dyspnea, abdominal, loud breathing and/or bent head were considered to be adverse at this dose-level in 3/14 females (one out of three females also showing a large chronic hematoma in the cranium at microscopic examination) as these signs were not just transient in contrast to males. Red discoloration of urine or vagina was transiently noted in 1/15 males and 2/14 females together with soiled urogenital region in one female.At 250 mg/kg/day, loud breathing (in 2/10 males) and red discoloration of the vagina (in 1/10 females) were observed.At 50 mg/kg/day, hunched posture and piloerection were noted in 1/10 females for 2 days in Week 13.These signs were not dose-related. They were considered to be of minor toxicological significance as they were sporadically observed at these dose-levels.Ptyalism was transiently observed in 12/15 males and 14/14 females given 750 mg/kg/day (generally from Week 2 or 3) and in 1/15 males and 2/15 females given 250 mg/kg/day (between Weeks 11 and 13). Reflux at dosing noted in 2/15 males and 2/15 females on one occasion at the high dose-level was considered to be test item treatment-related.These signs, commonly observed when a test item is administered by gavage, were considered not to represent an adverse effect.The other clinical signs recorded during the study, i.e. alopecia, scabs, soiled nose and mouth, soiled head and neck, wound, thinning of hair, opacity of eyes, bent tail, nodosities, chromodacryorrhea and/or chromorhynorrhea were observed both in control and test item-treated animals with no dose-relationship. They were therefore considered to be unrelated to the test item treatment.Test item treatment-related clinical signs were no longer observed over the treatment-free period.In follow-up to a wound on the neck region of one group 2 male, an antiseptic solution (povidone iodine, Vetedine®), was applied once or twice a day for 12 days. See table 1.

Mortality:

mortality observed, treatment-related

Description (incidence):

One femake given 750 mg/kg/day was sacrificed for ethical reasons on Day 72 (Week 11). Prior to sacrifice, thin appearance, piloerection, hunched posture, ptyalism, loud breathing, hypoactivity and coldness to the touch were observed. A body weight loss (-53 g, i.e. -20% of its Day 1 body weight) was recorded between Days 1 and 71, along with a low mean food consumption in the cage (up to -28% when compared to controls).At necropsy, the spleen was enlarged, the stomach was distended with food and the stomach wall showed a red discoloration of approximately 0.2 cm in diameter. The thymus showed red discoloration of up to 0.5 cm in diameter. Test item-related microscopic vacuoles were observed in the white matter from the brain (hippocampus, cingulum, cerebral peduncle and cerebellum), in the pars nervosa of the pituitary gland, in the renal tubules, in the choroid plexus, in the spleen and in the GALT.These vacuoles in brain, kidneys and pars nervosa were considered to have probably contributed to the moribundity of this animal.In addition, the following lesions which may be related partly with stress were noted: atrophy of the ovaries, uterus and vagina, pancreas degranulation, increased adipose tissue in the bone marrow associated with decreased cellularity of the hematopoietic cells and thymus atrophy. This unscheduled death was considered to be probably test item treatment-related.No other unscheduled deaths were observed during the study period.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At 750 mg/kg/day in males, when compared with controls, lower mean body weight gain was recorded throughout the treatment period (-21% vs. controls). This was statistically significant during the first and the third months (p<0.01 and p<0.05, respectively), leading to a slightly, non-statistically significant, lower mean body weight on completion of the treatment period (-6% vs. controls). This effect was attributed to the test item treatment, but considered as non-adverse. During the recovery period, a higher mean body weight gain was observed in males previously treated with 750 mg/kg/day, leading to a terminal mean body weight similar to the control animals.At 50 and 250 mg/kg/day in males, no relevant effects were noted on body weight or body weight gain during the study period.At all dose-levels of the test item in females, some instances of lower mean body weight gain, statistically significant on few occasions, were reported compared with controls over the treatment or treatment-free period. As these differences were occasional, not dose-related and/or of minimal amplitude, and did not affect the mean body weight, they were considered to be of no toxicological importance. Slight mean body weight loss (-5 g vs. +3 g in controls) was also recorded in females previously given 750 mg/kg/day during the last 2 weeks of the treatment-free period. This was considered to be fortuitous. See table 2.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In females, transient statistically significant lower mean food consumption, when compared with controls, was noted in the fourth week of treatment at 250 mg/kg/day (-10%) and first week at 750 mg/kg/day (-15%). The opposite trend was noted in males given 750 mg/kg/day between weeks 6 and 8 (+8% to +9%; p<0.05). As these differences were of isolated occurrence, not dose-related and/or of opposite trends, they were considered to be of no toxicological importance.No relevant effects were observed on food consumption in the other test item-treated animals during the treatment period.Mean food consumption was slightly higher in previously test item-treated animals during the treatment-free period.See table 3.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No findings were observed at the end of the treatment period.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

At 750 mg/kg/day in males, lower red blood cell parameters (statistically significant for most of them), including mean red blood cell count, mean hemoglobin concentration and mean packed cell volume, were noted. Minimal increase in reticulocyte count was also noted and correlated to the slight decrease in red blood cell mass. However, these differences were mainly due to the contribution of one male (showing blood in urine and renal tubular vacuolation). These effects were considered to be test item treatment-related but of minor toxicological importance as values remained within or were close to the range of historical control values.At 750 mg/kg/day, lower mean eosinophil counts were observed in males and females, whereas higher neutrophil counts were recorded in some males and females suggesting a stress leukogram for 4/10 males and 2/9 females. Prolonged prothrombin time was recorded in males and to a lesser extent in females. In the absence of any other significant changes and since values remained within or were close to the range of historical control values, these differences were considered to be of minor toxicological importance.A decreasing tendency in hemoglobin concentration and packed cell volume was observed in males given 250 mg/kg/day.The other statistically significant differences between control and test item-treated animals, namely in monocyte counts (females given 50 mg/kg/day) were considered to be of no toxicological importance as they were of low magnitude and/or noted with no dose-relationship.No test item-related effects on the hematology parameters were observed at the end of the treatment-free period.See table 4.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

When compared with mean control values, statistically significant blood biochemistry changes were observed:- lower mean sodium levels (-1% in females at 250 mg/kg/day and in males and females at 750 mg/kg/day),- lower mean chloride level (-2% in males at 750 mg/kg/day), - higher mean inorganic phosphorus level (+8 and +15% at 250 mg/kg/day, and +15 and +12% at 750 mg/kg/day, in males and females, respectively),- lower mean protein and albumin levels (-5% in males at 750 mg/kg/day) along with lower mean creatinine level (-9% in males at 750 mg/kg/day),- higher triglyceride levels (+38 and +58% in females at 250 and 750 mg/kg/day, respectively),- higher aspartate aminotransferase activity in males at 750 mg/kg/day (+23%) and higher alanine aminotransferase activity in males and females at 750 mg/kg/day (+88 and +62%, respectively). Although changes in the markers and electrolytes of the renal function (Na+, Cl-, inorganic phosphorus, proteins and albumin) are not consistent with each other, a relationship to microscopic vaculoation of kidneys and/or to vasopressin vacuoles in the pituitary gland could not be excluded.At 750 mg/kg/day, high aspartate aminotransferase activity (> 100 U/L) in 4/10 males and 3/10 females was also associated with high alanine aminotransferase activity in males (> 75 U/L) and females (> 60 U/L) (as well as in 2/10 females at 50 mg/kg/day). These findings were not associated with histological changes in the liver.All the above described findings were considered to be of minor toxicological importance were of minimal magnitude.The other statistically significant differences observed between control and test item-treated animals, namely in the potassium and triglyceride levels (males at 50 mg/kg/day) and total bilirubin level (males at 250 mg/kg/day and males and females at 750 mg/kg/day with many values below the lower limit of quantification) were considered to be within the range of physiological values or incidental and not test item-related as they were of low magnitude, of opposite trend and/or noted with no dose-relationship. Test item-related effects on the blood biochemistry parameters were no longer observed at the end of the treatment-free period.See table 5.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

At 750 mg/kg/day, significant hematuria was noted in 2/10 males and 2/10 females at the end of the treatment period. In the absence of hyperglycemia, glucosuria observed in 3 males could be indicative of a tubular resorption problem. Moreover, in one male, the presence of proteins (= 3 g/L), bilirubin (high-level), nitrites, urobilinogen (= 66 µmol/L) and marked turbid appearance of urine were noted. Higher mean urine volume in males given 250 mg/kg/day, was considered to be incidental and not test item-related as it was of low magnitude and not dose-related.At the end of the treatment-free period, the lower mean urine volumes in males and females previously treated with the high dose level were not considered to be treatment-related as they were not observed at the end of the treatment period and were not associated with any other changes in the urine parameters.See table 6.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

At 750 mg/kg/day, higher, test item-related, mean number of horizontal movements and rearing was noted in males (+24% and +31% vs. controls, respectively) and females (+22% and +76% vs. controls, respectively). There were no correlating clinical signs during the study. This finding observed with a low incidence and mainly due to the contribution of one male and one female was therefore considered to be of minor toxicological importance.At 50 and 250 mg/kg/day, a higher mean number of rearing movements was noted in males and females (between +20 and +44% vs. controls). In view of the slight severity, and as there was no correlating higher mean number of horizontal movements, these findings, mainly due to the contribution of one male and one female at 50 mg/kg/day, were considered to be of no toxicological importance.Differences from controls in grooming and defecation were noted in isolated animals at all dose-levels. In view of the very slight severity and incidence, and in absence of correlating clinical signs during the study, these findings were considered to be unrelated to the test item treatment. Other changes, including alopecia, ptyalism and abdominal breathing, were observed in one or two animals given 50 or 750 mg/kg/day, correlating with clinical signs already observed. Lower mean landing foot splay values were noted in females given 750 mg/kg/day (85 mm vs. 105 mm in controls). These findings were considered to be incidental (alopecia) or were considered to be of minor toxicological importance as they were of isolated occurrence (ptyalism and abdominal breathing) or did not correlate with any other findings (landing foot splay).See table 7.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the end of the treatment periodThere were higher relative-to-body kidney weights in males and females treated at 750 mg/kg/day when compared with controls (+17%, p<0.01 and +14%, p < 0.05, respectively). These organ weight differences were partially related to a lower terminal body weights, with a statistically significant decrease in males. A relationship of these kidney weights changes to microscopic vacuolation of renal tubules could not be established.There were lower absolute and relative-to-body thymus weights in males and females treated at 750 mg/kg/day (up to -24%; statistical significance not reached). This organ weight difference was considered to be related to test item administration and/or stress and correlated with increased incidence and severity of microscopic lymphoid atrophy.All other weight differences were minimal, did not correlate with macroscopic or microscopic findings and were considered no to be test item treatment-related.At the end of the treatment-free periodThere were slightly higher absolute and/or relative-to-body kidney weights in males and females previously treated at 750 mg/kg/day (up to +14% in males; absolute weights; p<0.01). This organ weight difference was considered not to be related to previous test item administration in males in view of the low magnitude of these differences, of the absence of microscopic correlates and of the absence of kidney weight differences at the end of the treatment period. In females, the higher relative-to-body kidney weight difference was considered to be related with the lower terminal body weights There were lower absolute and relative-to-body thymus weights in females previously treated at 750 mg/kg/day (up to -56% in absolute weights; statistical significance not reached). This organ weight difference was considered to be related to test item administration and/or stress and correlated in part with the minimal increased severity of microscopic lymphoid atrophy in females previously treated at 750 mg/kg/day when compared with controls.Consequently, there was no reversibility of the difference in thymus weights in females. All other weight differences were minimal, did not correlate with macroscopic or microscopic findings and were considered no to be test item treatment-related. These included the higher uterus weights in females previously treated at 750 mg/kg/day probably related with the estrus cycle.See table 8.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Unscheduled death There were no test item-related gross findings in the prematurely sacrificed female.At the end of the treatment periodThere were no test item-related gross findings with the exception of the 1 cm in diameter tan discoloration of the right kidney from 1/10 males treated at 750 mg/kg/day which correlated with moderate renal tubular vacuolation, and the small thymus seen in 1/9 females treated at 750 mg/kg/day which correlated with marked lymphoid atrophy. This affected female had also a marked hematoma in the cranium (see microscopic section).The few other gross findings were considered to be unrelated to test item administration since they were seen also in control group, were not dose-related and/or were considered to be part of the normal background in the rats of these strain and age kept under laboratory condition. At the end of the treatment-free periodThere were no test item-related gross findings suggesting the reversibility or the previous gross findings.The few gross findings were considered to be unrelated to test item administration since they were seen also in control group and/or were considered to be part of the normal background in the rats of these strain and age kept under laboratory condition.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Unscheduled death One female treated at 750 mg/kg/day and sacrificed on Day 72 had several microscopic findings:- slight vacuolation of the white matter in the brain (hippocampus, cingulum, cerebral peduncle, cerebellum) and in the choroid plexus,- moderate vacuoles in the pars nervosa of the pituitary gland,- marked vacuoles in the renal tubules,- minimal vacuoles in the spleen and in the GALT.The vacuolation in the white matter from the brain was not seen in the test item-treated animals at the end of the treatment period. The vacuoles in the pituitary gland, kidneys, spleen and GALT were seen also in the test item-treated animals at the end of the treatment period at similar or lower severityThese findings were considered to be related with the test item administration and the vacuoles in the brain with extended distribution, kidneys and pars nervosa were considered to have contributed to the moribundity of this animal.In addition, the following lesions were noted:- slight to moderate atrophy of the ovaries, uterus and vagina,- minimal pancreas degranulation,- increased severity of the adipose tissue in the bone marrow associated with moderate decreased cellularity of the hematopoietic cells,- slight thymus atrophy.These findings may be related with the test item administration and/or stress. The moribundity of this female was considered to be probably related with the test item administration.At the end of the treatment periodVacuoles in several organsMinimal to marked vacuoles were seen in the kidneys (tubules and, to a lesser severity, glomeruli), brain (choroid plexus), pars nervosa (pituitary gland), spleen, mesenteric lymph node and GALT (Gut Associated Lymphoid Tissue) in males and females treated at 750 mg/kg/day and were related with the test item administration. It is noteworthy that these vacuoles were present in the choroid plexus from only 2/10 females treated at 250 mg/kg/day.These vacuoles were round, of moderate to large size (15-50 µm in diameter) and devoid of any staining except those recorded in the pituitary gland which were pale and eosinophilic. The empty vacuoles in brain, spleen, lymph node and GALT were scattered, multifocal while the vacuoles in the pars nervosa were diffuse. An immunohistochemistry staining of vasopressin was performed in the pituitary gland from one control male, two high-dose males and two high-dose females. In the control, there was a diffuse moderate staining of the pars nervosa (pituitary gland), with a more pronounced staining in the neuronal ends. This staining was seen with a higher severity (marked) in the test item treated males and females, with accentuated staining in the neuronal ends and vacuoles seen with hematoxylin/eosin. This suggested that the vacuoles contained vasopressin and may be consistent with enlarged neuronal ends containing increased amount of vasopressin.The pars nervosa from all animals was not present on the submitted slide. That is why the number of lesions out of the number of present pars nervosa was recorded in individual data.ForestomachDose-related, minimal to slight, focal or multifocal orthokeratotic hyperkeratosis was seen in males and females treated at 250 and 750 mg/kg/day and was related with the test item administration. ThymusIncidence of minimal lymphoid atrophy was seen in some males and females of all control and treated groups. A slight and a marked atrophy were observed in one male and one female treated at 750 mg/kg/day, respectively. This correlated with the lower weights of thymus of these two animals but was not associated with change in the white blood cells count and cellularity. The thymus effects were most probably related with stress.In addition, there was a minimal increased vacuolation in the cortex of the adrenal gland from one male treated at 750 mg/kg/day and in the liver (macrovacuoles; centrilobular location) from one female treated at 750 mg/kg/day. A relationship to test item administration could not be excluded. There were no test item-related findings in testes after a detailed examination of these organs.The few other microscopic findings were not considered to be associated with the test item administration because these findings were consistent with spontaneous and background findings described in the literature or their appearance was similar to changes found in controls.Specifically, in one male treated at 250 mg/kg/day, there was a fibrosarcoma in the skin which correlated with macroscopic 2 x 1.5 cm mass. This tumor is not rare in rats. Since it was seen in a single male from intermediate group, it was considered not to be related to the test item administration. One female treated at 750 mg/kg/day had a fibroadenoma in the mammary gland. This tumor is not rare in this strain and is known to occur in rats as young as 12-week old. This animal had also a decidual reaction (or deciduoma) associated with mucification of the vagina, blood and cell debris in the lumen from vagina and uterus. This condition is not rare in the female rats of these strain and age.A PAS staining of the uterus from this female confirm the diagnosis of decidual reaction in the uterus (PAS positivity for the granules in the large cells which suggested that they contain glycogen).One female treated at 750 mg/kg/day had a large chronic hematoma in the cranium (probably close to the nasal meatus) which correlated with white mass at gross examination. The cause of this hematoma was not clear. It was associated with moderate lymphoid atrophy in the spleen, in the mesenteric lymph node and with minimal to slight degranulation of the salivary gland and pancreas. These last findings were possibly related with stress subsequent to the hematoma in the skull.At the end of the treatment-free period- Vacuoles in several organsMinimal vacuoles were seen in the kidneys (tubules) of one female and in brain (choroid plexus) of two females previously treated at 750 mg/kg/day and was related with the test item administration. No vacuoles were seen in males.This suggested reversibility of these test item treatment-related findings.- ForestomachMinimal orthokeratotic hyperkeratosis was seen in 1/5 males and 1/5 females previously treated at 750 mg/kg/day but also in 1/5 control females. This suggested reversibility of these test item treatment-related finding.- ThymusMinimal or slight lymphoid atrophy was seen in males and females of the control and/or previously treated at 750 mg/kg/day. For one female treated at 750 mg/kg/day, the slight atrophy was associated with a low weight of thymus, but it was not the case for the other animals presenting a minimal or slight atrophy. These effects seem therefore of spontaneous occurrence.For all these organs, this suggested reversibility of these test item treatment-related finding.See tables 9 and 10.

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

- Estrous cycle (see table 11): There were no statistically significant test item-related effects on mean estrous cycle length or mean number of cycles. However a trend towards an increase in mean estrous cycle length was observed in females given 250 or 750 mg/kg/day at the end of the treatment period. This was considered to be of no toxicological significance in the absence of statistical significance and of differences in estrous cycles at microscopic examination of the genital tract. Differences from controls were no longer observed at the end of the treatment-free period.

- Seminology (no effects observed)
No test item-related effects were noted on the epididymal sperm motility or morphology.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

Key result

Critical effects observed:

Table 1: Clinical signs (surviving animals)

Sex	Male				Female
Dose-level (mg/kg/day)	0	50	250	750	0	50	250	750
Thin appearance	-	-	-	1	-	-	-	1
Hunched posture	-	-	-	-	-	1	-	2
Piloerection	-	-	-	-	-	1	-	1
Bent/tilted head	-	-	-	-	-	-	-	1
Abnormal reddish color . urine . vagina	-	-	-	1	- -	- -	- 1	1 1
Soiled urogenital region	-	-	-	-	-	-	-	1
Loud breathing	-	-	2	1	-	-	-	1
Abdominal breathing	-	-	-	-	-	-	-	1
Dyspnea	-	-	-	-	-	-	-	1
Total affected animals	0/15	0/10	2/10	2/15	0/15	1/10	1/10	5/14
Ptyalism	-	-	1	12	-	-	2	14
Reflux at dosing	-	-	-	2	-	-	-	2
Total affected animals	0/15	0/10	1/10	12/15	0/15	1/10	2/10	14/14

-: no clinical signs.

Table 2: Body weight

Sex	Male					Female
Dose-level (mg/kg/day)	0	50	250		750	0	50	250	750
Treatment period
Mean BW gain Days 1/29	+102	+110	+101	+72**		+42	+35	+30**	+32
Mean BW gain Days 29/57	+56	+62	+60	+62		+19	+20	+22	+22
Mean BW gain Days 57/92	+35	+31	+31	+20*		+15	+10	+11	+4
Mean BW gain Days 1/92	+194	+202	+191	+154**		+76	+66	+63	+65
% from controls	-	+4	-2	-21		-	-13	-17	-14
Mean body weight on Day 1	418	428	438*	421		264	264	265	267
Mean body weight on Day 92	612	631	629	575		341	330	328	332
% from controls	-	+3	+3	-6		-	-3	-4	-3
Treatment-free period
Mean BW gain Days 92/133	+33	-	-	+58**		+15	-	-	+6*
Mean BW on Day 133	622	-	-	628		366	-	-	348
% from controls	-	-	-	+1		-	-	-	-5

Statistically significant from controls: *: p<0.05, **: p<0.01, -: not applicable.

Table 3: Food consumption

Sex	Male				Female
Dose-level (mg/kg/day)	0	50	250	750	0	50	250	750
Treatment period
Days 1 to 29	32.1	33.4	33.9	32.2	22.7	21.4	21.4	21.3
Days 29 to 57	30.8	32.5	32.5	33.1	22.3	21.9	21.3	21.8
Days 57 to 92	30.4	31.5	31.1	31.0	21.4	21.1	20.2	20.5
Days 1 to 92	31.0	32.4	32.4	32.0	22.0	21.5	20.9	21.1
% from controls	-	+5	+5	+3	-	-2	-5	-5
Treatment-free period
Days 92 to 133	28.0	-	-	29.8	19.8	-	-	20.7
% from controls	-	-	-	+6	-	-	-	+5

No statistics.

-: not applicable.

Table 4: Hematology

Sex	Male
Dose-level (mg/kg/day)	0	50	250	750
End of treatment period
Red blood cell count (T/L)	9.57 (7.96-10.67)	9.28	9.18	8.40** (8.85)^a
Hemoglobin (g/dL)	16.1 (13.3-17.1)	15.5	15.4*	14.4** (15.1)^a
Packed cell volume (L/L)	0.50 (0.41-0.55)	0.48	0.47*	0.44** (0.45)^a
Reticulocytes (%)	2.45 (1.47-3.54)	2.83	2.95	5.37* (3.08)^a
Reticulocytes (T/L)	0.23	0.25	0.27	0.36 (0.27)^a
Neutrophils (G/L)	2.36 (0.80-5.80)	2.15	2.50	2.73 (2.87)^a
Eosinophils (G/L)	0.20 (0.04-0.36)	0.20	0.18	0.02** (0.02)^a
Prothrombin time (s)	22.0 (18.6-23.8)	22.3	22.6	24.4** (24.7)^a
End of treatment-free period
Red blood cell count (T/L)	9.84	/	/	9.71
Hemoglobin (g/dL)	16.0	/	/	16.2
Packed cell volume (L/L)	0.48	/	/	0.49
Reticulocytes (%)	2.09	/	/	2.17
Reticulocytes (T/L)	0.21	/	/	0.20
Neutrophils (G/L)	3.39	/	/	2.70
Eosinophils (G/L)	0.21	/	/	0.19
Prothrombin time (s)	21.2	/	/	19.8

/: not applicable; Statistically significantfrom controls: *: p<0.05 and**: p<0.01.

( ): minimum-maximum values from historical control data (HCD).

( )^a: excluding animal E25833 from the mean calculation. No statistics.

Sex	Female
Dose-level (mg/kg/day)	0	50	250	750
End of treatment period
Red blood cell count (T/L)	8.60 (7.16-9.51)	8.66	8.63	8.33
Hemoglobin (g/dL)	15.4 (13.2-17.0)	15.5	15.4	15.1
Packed cell volume (L/L)	0.46 (0.38-0.51)	0.46	0.46	0.44
Reticulocytes (%)	2.29 (1.15-2.84)	2.25	2.18	3.07
Reticulocytes (T/L)	0.20	0.20	0.19	0.25
Neutrophils (G/L)	1.54 (0.40-2.92)	1.36	1.67	2.28*
Eosinophils (G/L)	0.15 (0.06-0.25)	0.15	0.10	0.02**
Prothrombin time (s)	22.4 (16.5-23.9)	22.4	22.8	23.8
End of treatment-free period
Red blood cell count (T/L)	8.62	/	/	8.90
Hemoglobin (g/dL)	15.5	/	/	15.8
Packed cell volume (L/L)	0.45	/	/	0.46
Reticulocytes (%)	1.78	/	/	1.55
Reticulocytes (T/L)	0.16	/	/	0.14
Neutrophils (G/L)	1.47	/	/	0.94
Eosinophils (G/L)	0.13	/	/	0.11
Prothrombin time (s)	22.9	/	/	23.9

/: not applicable; Statistically significantfrom controls: *: p<0.05 and**: p<0.01.

( ): minimum-maximum values from historical control data (HCD).

Table 5: Blood biochemistry

Sex	Male
Dose-level (mg/kg/day)	0	50	250	750
End of treatment period
Sodium (mmol/L)	144.0	143.9	143.3	142.7**
Chloride (mmol/L)	105.4	105.4	104.4	103.5**
Inorganic phosphorus (mmol/L)	2.09	2.08	2.25*	2.40**
Creatinine (µmol/L)	38.22	36.59	36.14	34.70*
Proteins (g/L)	64.1	64.5	63.3	61.0*
Albumin (g/L)	37	37	36	35**
Triglyceride (mmol/L)	1.03	1.47*	0.89	1.12
Aspartate aminotransferase (U/L)	87	77	87	107*
Alanine aminotransferase (U/L)	40	36	42	75**
End of treatment-free period
Sodium (mmol/L)	143.7	/	/	143.1
Chloride (mmol/L)	105.7	/	/	105.3
Inorganic phosphorus (mmol/L)	2.02	/	/	2.07
Creatinine (µmol/L)	37.10	/	/	36.05
Proteins (g/L)	66.2	/	/	67.2
Albumin (g/L)	37	/	/	37
Aspartate aminotransferase (U/L)	94	/	/	87
Alanine aminotransferase (U/L)	43	/	/	39

/: not applicable;statistically significantfrom controls: *: p<0.05 and**: p<0.01.

Sex	Female
Dose-level (mg/kg/day)	0	50	250	750
End of treatment period
Sodium (mmol/L)	143.0	143.1	141.9*	141.2**
Chloride (mmol/L)	105.1	106.1	105.1	103.8
Inorganic phosphorus (mmol/L)	1.78	1.65	2.04**	2.00*
Creatinine (µmol/L)	36.13	38.42	36.21	36.28
Proteins (g/L)	66.4	66.5	64.8	64.1
Albumin (g/L)	38	39	38	38
Triglyceride (mmol/L)	0.48	0.48	0.66*	0.76**
Aspartate aminotransferase (U/L)	80	98	73	82
Alanine aminotransferase (U/L)	37	47	35	60*
End of treatment-free period
Sodium (mmol/L)	142.1	/	/	142.1
Chloride (mmol/L)	105.6	/	/	106.5
Inorganic phosphorus (mmol/L)	1.58	/	/	1.44
Creatinine (µmol/L)	41.65	/	/	38.64
Proteins (g/L)	69.9	/	/	68.5
Albumin (g/L)	41	/	/	41
Aspartate aminotransferase (U/L)	90	/	/	75
Alanine aminotransferase (U/L)	45	/	/	30

/: not applicable;statistically significantfrom controls: *: p<0.05 and**: p<0.01.

Table 6: Urinalysis

Sex	Male				Female
Dose-level (mg/kg/day)	0	50	250	750	0	50	250	750
End of treatment period
Presence of glucose (approx. 5.5 mmol/L)	0	0	0	3	0	0	0	0
Presence of blood
. low	2	1	0	0	0	0	0	1
. moderate	0	0	0	0	0	1	0	1
. high	0	0	0	2	0	0	0	2
Red blood cells	1	4	2	6	0	0	1	3
. 1 - few in some fields	1	4	2	4	0	0	1	1
. 2 - few in all fields	0	0	0	0	0	0	0	1
. 3 - several in all fields	0	0	0	1	0	0	0	1
. 4 - large number in all fields	0	0	0	1	0	0	0	0
End of treatment-free period
Presence of glucose (approx. 5.5 mmol/L)	0	na	na	0	0	na	na	0
Presence of blood	0	na	na	0	0	na	na	0
Red blood cells	0	na	na	0	0	na	na	0

na: not applicable.

Table 7: Motor activity

Sex	Male				Female
Dose-level (mg/kg/day)	0	50	250	750	0	50	250	750
Horizontal movements	373	400	371	461	522	590	548	635
% from controls	-	+7	-1	+24	-	+13	+5	+22
Rearing	108	137	130	142	144	207	206	254
% from controls	-	+27	+20	+31	-	+44	+43	+76

-: not applicable.

Table 8: Organ weights

Main organ weight differences in male groups (express in percentage, when compared to controls)

Sex	Male
Group	2	3	4
Dose-level (mg/kg/day)	50	250	750
Number of examined animals	10	10	10
Body weight at sacrifice	+1	0	-9*
- Kidneys
.absolute	+8	+6	+6
.relative-to-body	+6	+6	+17**
- Thymus
.absolute	+4	+7	-16
.relative-to-body	+2	+6	-7

Statistically significant from controls: *: p<0.05, **: p<0.01.

The significance concerned the organ weights values and not the percentages.

Main organ weight differences in female groups (express in percentage, when compared to controls)
at the end of the treatment period

Sex	Female
Group	2	3	4
Dose-level (mg/kg/day)	50	250	750
Number of examined animals	10	10	9
Body weight at sacrifice	-1	-2	-4
- Kidneys
.absolute	0	-1	+8
.relative-to-body	+1	+1	+14*
- Thymus
.absolute	+8	+5	-24
.relative-to-body	+9	+7	-24

Statistically significant from controls: *: p<0.05.

The significance concerned the organ weights values and not the percentages.

Table 9: Microscopic findings at tne end of the treatment period

	Males				Females
Group	1	2	3	4	1	2	3	4
Dose-level (mg/kg/day)	0	50	250	750	0	50	250	750
Number of examined individuals	10	10	10	10	10	10	10	9
Kidney; vacuoles; tubules
Grade 1	1	-	-	2	-	-	-	3
Grade 2	-	-	-	-	-	-	-	2
Grade 3	-	-	-	1	-	-	-	-
Grade 4	-	-	-	-	-	-	-	1
Kidney; vacuoles; glomerulus
Grade 1	-	-	-	4	-	-	-	-
Grade 2	-	-	-	-	-	-	-	1
Brain; vacuoles; choroid plexus
Grade 1	-	-	-	9	-	-	2	5
Grade 2	-	-	-	1	-	-	-	3
Pituitary gland*; vacuoles
Grade 1	0/8	1/7	0/6	6/9	0/10	0/9	0/7	3/6
Grade 2	0/8	0/7	0/6	1/9	0/10	0/9	0/7	1/6
Spleen; vacuoles
Grade 1	-	-	-	7	-	-	-	2
Mesenteric lymph node; vacuoles
Grade 1	-	-	-	3	-	na	na	-
GALT; vacuoles
Grade 1	-	-	-	3	-	-	-	2
Thymus; lymphoid atrophy
Grade 1	2	5	5	4	2	1	2	2
Grade 2	-	-	-	1	-	-	-	-
Grade 4	-	-	-	-	-	-	-	1
Forestomach; hyperkeratosis
Grade 1	-	-	1	5	-	-	3	6
Grade 2	-	-	-	-	-	-	-	1

-: not seen in this group.

na: not applicable.

*out of the number of present pars nervosa.

Table 10: Microscopic findings at the end of the treatment-free period

	Males		Females
Group	1	4	1	4
Dose-level (mg/kg/day)	0	750	0	750
Number of examined individuals	5	5	5	5
Kidney; vacuoles; tubules
Grade 1	-	-	-	1
Brain; vacuoles; choroid plexus
Grade 1	-	-	-	2
Thymus; lymphoid atrophy
Grade 1	-	2	3	2
Grade 2	1	-	-	1
Forestomach; hyperkeratosis
Grade 1	-	1	1	1

-: not seen in this group.

Table 11: Estrous cycle

Dose-level (mg/kg/day)	0	50	250	750
Treatment period
Number of cycles	4.2	3.9	3.8	3.2
Cycle length (days)	4.2	4.3	5.1	5.9
Number of females having a mean average cycle of 4-5 days	7	6	5	4
Treatment-free period
Number of cycles	1.0	na	na	1.0
Cycle length (days)	4.0	na	na	4.0
Number of females having a mean average cycle of 4-5 days	2	na	na	1

na: not applicable.

Conclusions:

The toxicity of the test item, Diethylaminopropylamine (as pH-neutralized dose formulations), was evaluated after daily oral administration (gavage) to Sprague-Dawley rats at dose-levels of 50, 250 or 750 mg/kg/day for 13 weeks followed by a 6-week treatment-free period. Under the experimental conditions of the study, clinical signs of poor condition were observed at the dose level of 750 mg/kg/day in four females, which induced the premature sacrifice of one of them more severely affected.No other adverse effects were observed in the study.Consequently, the NOAEL (No Observed Adverse Effect Level) was established at 750 mg/kg/day in males and 250 mg/kg/day in females.

Executive summary:

The potential toxicity of Diethylaminopropylamine (as pH-neutralized dose formulations) was evaluated following daily oral administration (gavage) to rats for 13 weeks. On completion of the treatment period, designated animals were held for a 6-week treatment-free period in order to evaluate the reversibility of any findings. This GLP study was carried out according to OECD test guideline No. 408 (21 September 1998). Sprague-Dawley rats were treated daily by the oral route (gavage) with the test item, Diethylaminopropylamine, for 13 weeks as follows: one group of 15 males and 15 females at the dose-level of 750 mg/kg/day (group 4) and two other groups of 10 males and 10 females at dose-levels of 50 (group 2) or 250 (group 3) mg/kg/day. One group of 15 males and 15 females received the vehicle only (drinking water treated by reverse osmosis) under the same experimental conditions, and acted as a control group (group 1). A constant dosage volume of 5 mL/kg/day was used. At the end of the treatment period, the animals were sacrificed, except for the first five group 1 and 4 animals per sex, which were kept for a 6-week treatment-free period. The actual test item concentrations in the dose formulations prepared for use in Weeks 1, 4, 8 and 13 were determined using agas chromatography with flame ionization detection analytical method. The animals were checked daily for mortality and clinical signs.Detailed clinical examinations were performed weekly and a Functional Observation Battery (FOB) was conducted in Week 13. Body weight was recorded pre-test, on the first day of treatment and then once a week. Food consumption was recorded weekly. Ophthalmological examinations were performed on all animals before the beginning of the study and on control and test item-treated animals at the end of the treatment period (Week 13). Hematology, blood biochemistry and urinary investigations were performed at the end of the treatment and treatment-free periods (Weeks 13 and 20). Additional blood samples were collected in Weeks 13 and 20 for possible analysis of thyroid hormones levels. The estrous cycle was determined for all females over 21 or 5 consecutive days at the end of the treatment or treatment-free period, respectively. Seminology investigations (count, motility and morphology) were performed on all males at sacrifice at the end of the treatment period. On completion of the treatment or treatment-free period, the animals were sacrificed and a full macroscopic post-mortem examination was performed. Designated organs were weighed and selected tissues were preserved. A microscopic examination (including testicular staging) was performed on designated tissues from control and high-dose animals sacrificed at the end of the treatment period and from animals that died prematurely and on all macroscopic lesions from all low- and intermediate-dose animals (groups 2 and 3) sacrificed on completion of the treatment period. PAS staining in the uterus in one high-dose female and immunohistochemistry for vasopressin in the pituitary gland on one control male and two high-dose males and females were examined. The brain, forestomach, gut-associated lymphoid tissue, kidneys, mesenteric lymph nodes (males only), pituitary gland, spleen and thymus of the low- and intermediate-dose animals (groups 2 and 3) sacrificed at the end of the treatment period and of the control and high-dose animals (groups 1 and 4) sacrificed at the end of the treatment-free period were also microscopically examined as changes were revealed in these organs at the end of the treatment period.

Actual concentrations of Diethylaminopropylamine in the dose formulations administered to the animals during the study remained within an acceptable range (-6.5% to +9.2%) compared to the nominal concentrations. During the treatment period, three females given 750 mg/kg/day showed clinical signs which were considered to be adverse (i.e.hunched posture, dyspnea, abdominal, loud breathing and/or bent head). Hunched posture and piloerection were transiently noted in one female given 50 mg/kg/day. Ptyalism was observed with a dose-related incidence at 250 and 750 mg/kg/day and reflux at dosing was noted in few males and females given 750 mg/kg/day on one occasion.These signscommonly observed when a test item is administered by gavage, were considered not to be an adverse effect. One female given 750 mg/kg/day more severely affected, showed signs of poor clinical condition and therefore was sacrificed in Week 11. Microscopic findings were noted (i.e. vacuoles in the pars nervosa of the pituitary gland, in the renal tubules, in the white matter from the brain, in the choroid plexus, in the spleen and in the GALT). At Functional Observation Battery examination, slightly higher incidences of horizontal movements and rearing were recorded in males and females given 750 mg/kg/day. Body weight gain was slightly lower in males given 750 mg/kg/day during the first and the third months of the treatment period, leading to a slightly lower body weight on completion of the treatment period (-6% vs. controls). Food consumption was not affected by the test item treatment. No ophthalmology findings were observedat the end of the treatment period. Estrous cycle was not altered by the test item treatment. The epididymal sperm motility and morphology and the spermatozoa count were unaffected by the test item treatment. At hematology investigations, minimally to slightly lower hemoglobin concentration and packed cell volume were noted in males from 250 mg/kg/day as well as lower red blood cell count in males given 750 mg/kg/day. This was accompanied with slight increase in reticulocyte count at 750 mg/kg/day. There were also non-adverse lower eosinophil count and prolonged prothrombin time in males and females treated at 750 mg/kg/day.These variations were considered to be of minor toxicological importance. At blood biochemistry investigations, changes in the markers of the renal function (lower sodium and chloride levels, higher inorganic phosphorus levels and lower protein and/or albumin levels) observed in males and/or females from 250 mg/kg/day could be secondary to the electrolytes imbalance induced by the intake of chloride ions used to neutralize the test item. A minimal increase of higher aspartate aminotransferase and alanine aminotransferase activity was observed in males and females given 750 mg/kg/day. All these changes were considered to be of minor importance. At urinary investigations, hematuria in males and females given 750 mg/kg/day along with glucosuria in males were suggestive of a tubular resorption problem. Reversibility of these laboratory findings was noted at the end of the treatment-free period. At the end of the treatment period, microscopic vacuoles were seen in the kidneys (correlated with tan discoloration), brain (in choroid plexus), pars nervosa (pituitary gland), spleen, mesenteric lymph node and/or GALT in males and females treated at 750 mg/kg/day and at a lesser extent, at 250 mg/kg/day in isolated females. There was also a non-adverse orthokeratotic hyperkeratosis in the forestomach from males and females treated at 750 mg/kg/day and increased severity and incidence of lymphoid atrophy in the thymus from males and surviving females treated at 750 mg/kg/day which correlated with small thymus and lower weights and may be related in part with stress.

Under the experimental conditions of the study, clinical signs of poor condition were observed at the dose-level of 750 mg/kg/day in four females, which induced the premature sacrifice of one of them more severely affected. No other adverse effects were observed in the study.

Consequently, the NOAEL (No Observed Adverse Effect Level) was established at 750 mg/kg/day in males and 250 mg/kg/day in females.

Endpoint conclusion

Species:: rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen all close all

Reference 1

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: about 8 weeks
- Weight at study initiation: mean body weight: 244 g (male), 167 g (female)
- Housing: 5 animals per cage in Polysoldon cages on Type Lignocel fibres (dustfree bedding) with wooden gnawing blocks
- Diet: mouse/rat laboratory diet “GLP”, 10 mm pellets (Provimi Kliba SA, Kaiseraugst, Basel Switzerland) ad libitum
- Water: tap water ad libitum
- Acclimation period: 9-10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aerodynamic exposure system (cylindrical inhalation chamber made of stainless steel sheeting and cone-shaped outlets and inlets
- Method of holding animals in test chamber: glass exposure tubes
- System of generating vapors: thermostated vaporizer with thermostat and continous infusion pumps
- Air flow rate: 1.5 m³/h

TEST ATMOSPHERE
- Brief description of analytical method used: HPLC
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 h per day

Frequency of treatment:

20 exposures (5 days per week for 4 weeks)

Dose / conc.:

5 mg/m³ air (analytical)

Dose / conc.:

18.5 mg/m³ air (analytical)

Dose / conc.:

100 mg/m³ air (analytical)

No. of animals per sex per dose:

Control animals:

yes

Observations and examinations performed and frequency:

Mortality, Clinical observations, Body weight data, Food consumption, Ophtalmology

Sacrifice and pathology:

Clinical pathology (hematology, clinical chemistry), Pathology (necropsy, organ weights, histology)

Statistics:

Dunnett´s test, Kruskal-Wallis test, Wilcoxon test

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The body weight change of the male and female animals of the low concentration (5 mg/m³) was significantly slightly increased on study days 17-21 in males and 24-28 in females compared to controls. These results are regarded as incidental and not treatment related because no dose realationship could be detected.

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:

effects observed, non-treatment-related

Description (incidence and severity):

Spontaneous findings such as remainders of the pupillary membrane or corneal stippling were observed in several animals of all test groups and the control group without any concentration-response relationship.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

In male rats of test group 1 and 3 (5 and 100 mg/m³) the relative monocyte counts were lower compared to controls. This decrease was not dose-dependent and it was the only deviated parameter in hematology. Therefore, it was regarded as incidental rather than treatment-related.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

In females of all dose groups the glucose level was higher compared to controls. The increase was not dose dependent and it was not accompanied by an alteration of any other clinical pathology parameter. Therefore, this alteration was regarded as incidental and not treatment-related.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Compared to the control group (group 0), there were no significant absolute mean organ weight changes observed in both sexes with the exception of intermediate group 2 female thymus weights only. This was significantly decreased compared to the control group. However, this was considered to be a non-dose related incidental finding with no relation to treatment.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- Changes were observed in the mucosa of the nose in the high-dose group (100 mg/m³) animals of both sexes ( Acute inflammation and/or degeneration in the olfactory/respiratory epithelium and atrophy and/or necrosis (largely of olfactory epithelium)).
- Erosion/ulceration of the olfactory epithelium was observed in the high-dose animals of both sexes as well.
- Suppurative exudate was also observed in the nasal cavity of high-dose animals and in one male intermediate-dose animal.
- At the intermediate-dose level of 20 mg/m³ (test group 2), acute inflammation and degeneration were also observed as well as some occasional necrosis, however, all to a lesser severity degree compared to the high-dose group. No erosion/ulceration or atrophy of the olfactory epithelium was observed at this dose level.

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Dose descriptor:

NOAEC

Effect level:

100 mg/m³ air

Sex:

male/female

Basis for effect level:

other: for systemic toxicity

Dose descriptor:

NOAEC

Effect level:

5 mg/m³ air

Sex:

male/female

Basis for effect level:

other: for local effect in nasal cavity

Critical effects observed:

not specified

Conclusions:

Due to lack of any exposure-related systemic toxicity, the NOAEC for systemic toxicity of the test substance was 100 mg/m³ (highest dose). Due to exposure-related local effects in the nasal cavity, observed in a concentration-related manner, the NOAEC for local effects was 5.0 mg/m³ (lowest dose).

Executive summary:

To determine the potential toxicity of the test substance after inhalation exposure, a 28-day inhalation study was carried out according to OECD 412 and EC No 440/2008. Wistar rats, 5 male and 5 female animals per test group, were head-nose exposed to vapor on 6 hours per day, on 5 consecutive days per week for 4 weeks (20 exposures). The target concentrations were 5, 20 and 100 mg/m³ test substance in synthetic air. On each exposure day clinical examination was performed before, during and after exposure. Body weight was determined prior to the preflow period at the start of exposure and twice weekly (Monday + Friday) during exposure period. Food consumption of the animals was determined weekly. After the last exposure, blood was sampled from the animals, hematology and clinical chemistry parameters were determined as indicated in the guideline. The animals were then subjected to gross necropsy (including macroscopic examination of the major internal organs and collection of organ weight data). Selected tissues were processed histopathologically and were evaluated by light microscopy.

Inhalation exposure of rats to the test substance for 28 day (20 exposures) did not lead to any exposure-related systemic toxicity as indicated by clinical chemical, hematological examinations of the blood as well as histological examinations at termination of the study. Local effect in the nasal cavity comprised acute inflammation, degeneration, atrophy, erosion/ulceration, necrosis of the epithelium (olfactory/respiratory epithelium) and suppurative exudate in the lumen. These effects were observed in a concentration-related manner.

Under the current test conditions, the No Observed Adverse Effect Concentration (NOAEC) for systemic toxicity was the highest tested concentration of 100 mg/m³, the NOAEC for local effect in nasal cavity was 5.0 mg/m³.

Reference 2

Endpoint:: short-term repeated dose toxicity: inhalation
Type of information:: experimental study
Adequacy of study:: weight of evidence
Study period:: 2009/10 - 2011/03
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: comparable to guideline study
Qualifier:: equivalent or similar to guideline
Guideline:: OECD Guideline 412 (28-Day (Subacute) Inhalation Toxicity Study
Deviations:: yes
Remarks:: exposure period of only 5 days, limited parameters (range finding study)
Qualifier:: equivalent or similar to guideline
Guideline:: EU Method B.8 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:: yes
Remarks:: exposure period of only 5 days
GLP compliance:: yes (incl. QA statement)
Species:: rat
Strain:: Wistar
Sex:: male
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: 9 weeks
- Weight at study initiation: mean weight = 228g
- Fasting period before study: no
- Housing: in groups of 5
- Diet (e.g. ad libitum): ad lib. (mouse/fat laboratory diet "GLP", 10mm pellets, Provimi Kliba SA, Switzerland)
- Water (e.g. ad libitum): ad lib.
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15/h
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:: inhalation: vapour
Type of inhalation exposure:: nose/head only
Vehicle:: air
Details on inhalation exposure:: GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: continuous infusion pumps PERFUSOR (B.Braun), glass vaporizers with thermostat (BASF SE)
- Method of holding animals in test chamber: glass holding tubes
- Temperature, humidity, pressure in air chamber: 23 +/- 3°C, 5-70% humidity
- Air flow rate: 1,35m³/h

TEST ATMOSPHERE
- Brief description of analytical method used: HPLC, FID (real time measurements during exposure)
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Group 1: 100.7 mg/m³ (target: 100)
Group 2: 260 mg/m³ (target: 300)
Group 3: 967 mg/m³ (target (1000)

The concentrations of the inhalation atmospheres in test groups 1 - 3 were analyzed by calibrated total hydrocarbon analyzers (FID). Additionally, 6 gas samples (3 during exposure and 3 after exposure) were taken from each chamber by gas sampling cylinder ( 1 L) on one day of exposure for each concentration. The samples were analyzed by high pressure liquid chromatography.
• Absorption solvent: 0.05 M sulfuric acid
• Sampling site: immediately adjacent to the animals' noses
• Sampling frequency: as a rule, 4 samples per concentration and exposure.
Duration of treatment / exposure:: 6h/day for 5 days
Frequency of treatment:: daily
Dose / conc.:: 100 mg/m³ air
Remarks:: 33 ppm
Dose / conc.:: 300 mg/m³ air
Remarks:: 99 ppm
Dose / conc.:: 1 000 mg/m³ air
Remarks:: 330 ppm
No. of animals per sex per dose:: 5 male rats
Control animals:: yes, concurrent vehicle
Details on study design:: - Dose selection rationale: dose levels/concentrations were selected based on a non-GLP Inhalation Risk Test (IRT) and a repeated dose inhalation study with the structure-related ethylene diamine.
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once on non-exposure days, 3 times on exposure days (before, during, after exposure)
- Cage side observations included.: mortality, clinical condition

BODY WEIGHT: Yes
- Time schedule for examinations: pre-exposure, start of exposure, prior to necropsy

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: day -2 , day 5 (before and after the exposure period)
- Dose groups that were examined: all

HAEMATOLOGY: NO

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

BRONCHOALVEOLAR LAVAGE FLUID (BALF): No
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, nasal cavity, Larynx, Trachea, Lungs, Pharynx, all gross lesions
Other examinations:: ORGAN WEIGHTS
1. anesthetized animals
2. adrenals
3. brain
4. epididymides
5. heart
6. kidneys
7. liver
8. lungs
9. spieen
10. testes
11. thymus
12. thyroid glands
Clinical signs:: effects observed, treatment-related
Description (incidence and severity):: reddish eye discharge (all treatment groups)
moderate salivation and reduced fur care after day 2 (high dose only)
These signs are presumably associated to inflammatory changes in the respiratory tract
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: body weight change in highs dose animals was significantly lower (-15.42g vs -2.66g in control animals)
Ophthalmological findings:: effects observed, non-treatment-related
Description (incidence and severity):: Spontaneous findings such as remainders of the pupillary membrane, opacity of vitreous body or corneal stippling were observed in several animals of all test groups and the control group without any concentration-response relationship.
Organ weight findings including organ / body weight ratios:: no effects observed
Gross pathological findings:: no effects observed
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: In the nasal cavity mainly level I and II were affected and there especially the dorsal meatus. There was necrosis of the olfactory epithelium, inflammatory cell infiltrates, and where no necrosis was observed degeneration of the epithelium was present. The further caudal in the nasal cavity the examination took place, the fewer and less severe were the findings. Necrosis, degeneration and inflammation were still observed in the 100 mg/m3 concentration group.
Dose descriptor:: LOAEC
Remarks:: local effects
Effect level:: 100 mg/m³ air
Based on:: test mat.
Sex:: male
Basis for effect level:: histopathology: non-neoplastic
Dose descriptor:: NOAEC
Remarks:: systemic effects
Effect level:: 1 000 mg/m³ air
Based on:: test mat.
Sex:: male
Basis for effect level:: other: no systemic effects observed
Critical effects observed:: no

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEC
: 100 mg/m³
Study duration:: subacute
Species:: rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

air

Details on inhalation exposure:

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 h per day

Frequency of treatment:

20 exposures (5 days per week for 4 weeks)

Dose / conc.:

5 mg/m³ air (analytical)

Dose / conc.:

18.5 mg/m³ air (analytical)

Dose / conc.:

100 mg/m³ air (analytical)

No. of animals per sex per dose:

Control animals:

yes

Observations and examinations performed and frequency:

Mortality, Clinical observations, Body weight data, Food consumption, Ophtalmology

Sacrifice and pathology:

Clinical pathology (hematology, clinical chemistry), Pathology (necropsy, organ weights, histology)

Statistics:

Dunnett´s test, Kruskal-Wallis test, Wilcoxon test

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

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:

effects observed, non-treatment-related

Description (incidence and severity):

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Dose descriptor:

NOAEC

Effect level:

100 mg/m³ air

Sex:

male/female

Basis for effect level:

other: for systemic toxicity

Dose descriptor:

NOAEC

Effect level:

5 mg/m³ air

Sex:

male/female

Basis for effect level:

other: for local effect in nasal cavity

Critical effects observed:

not specified

Conclusions:

Executive summary:

Endpoint conclusion

Endpoint conclusion:: adverse effect observed
Dose descriptor:: NOAEC
: 5 mg/m³
Study duration:: subacute
Species:: rat

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

Inhalation:

In a GLP guideline study (OECD 412) male and female Wistar rats were exposed subacutely for 28 days to test substance vapour (5, 18.5, 100 mg/m³; 6 h/day, 5 days/week, 4 weeks). A concurrent control group was exposed to synthetic air as air control. No exposure-related systemic toxicity as indicated by clinical chemical, hematological examinations of the blood as well as histological examinations at termination of the study was observed. Local effects in the nasal cavity comprised acute inflammation, degeneration, atrophy, erosion/ulceration, necrosis of the epithelium (olfactory/respiratory epithelium) and suppurative exudate in the lumen. These effects were observed in a concentration-related manner. Therefore, the NOAEC for systemic toxicity of the test substance was 100 mg/m³ (highest tested dose) and the NOAEC for local effects in the nasal cavity was 5.0 mg/m³ (lowest dose).

Due to the corrosive effects observed at 100mg/m³ in all animals and still in 1 animal at app. 20mg/m³, the highest dose in a 90-day repeat toxicity study would be below 20mg/m³ in accordance with animal welfare as described in the OECD documents and ECHA guidance. Thus the animals in the 28-day study were exposed to a higher cumulative dose as would be achieved even after 90 days. The likely outcome would be no systemic toxicity, but local effects probably at approximatly the same contrations as after 28 days.

In a weight of evidence approach, data from an oral 90-day study with the structurally related diamine 104-78-9 is presented. Because of the different route of exposure, local effects were less relevant, which allowed exposure of the animals up to 750 mg/kg. In a dose range finding study lower body weights and squamous cell hyperplasia and hyperkeratosis were observed in the forestomach at 1000mg/kg. In the main study, a slight reduction in body weight was still observed in the high dose of 750 mg/kg, as well as slight hyperkeratosis in single animals at 750 and 250 mg/kg. The main systmic effect observed at the highest dose was poor general state, which included troubled breathing likely due to reflux of the corrosive chemical. One female was euthanized due to animal welfare reasons. Thus these results confirm the above theory of very low systemic toxicity. The leading health effect is corrosion, as expected based on the classification for skin corrosion. It should be noted however, that in the case of 1,2 PDA, because of its high vapour pressure and exclusively industrial handling, exposure will mainly occur via inhalation. Oral exposure is irrelevant.

A 5 -day inhalation study (used as range finder for the 28 -day exposure) further supports this weight of evidence approach. Exposure of rats to 100, 300, and 1000mg/m³ (vapor) led to histological findings in the nasal cavity in all dose groups. These consisted of inflammation, degeneration, and necrosis, which was worst at the point of first contact and worsened dose-dependently from 100 to 1000mg/m³. Consequently, no NOEAC for local effects was identified. No systemic toxicity was observed in the limited parameters examined.

Regarding potential exposure and worker safety, the low local DNEL will protect workers from all potential systemic effects at much higher concentrations. Also, Propane-1,2-diamine is a flammable liquid with a flash point not far above room temperature and high vapour pressure. In addition to the pungent, amine-typical odour and low pH (and consecutive risk of corrosion), the risk of generating a flammable atmosphere dictates handling of the substance in enclosed systems. Consequently, all processes must be automated and contained as far as possible. This includes transfer via enclosed lines, clearing of transfer line with prior to decoupling, and controlled / restricted access. Any risk of accumulation is minimized by natural ventilation, as the chemical is produced in closed systems installed in open air. Prior to repair and maintenance work, vessels, pipes and other equipment are purged to remove any residual substance. Manual tasks are limited to coupling of drums or other containers, occasional sampling and maintenance. For these tasks, workers are required to wear PPE to cover all skin surfaces and respiratory protection where no LEV is present. Regular trainings ensure correct usage of PPE. Propane-1.2-diamine is produced on only app. 60 days / year and formulated on app. 20 days per year. Personal monitoring is performed during formulation, more explicitly during transfer of the substance from the drums into the reactor, when personal exposure is most likely.

Justification for classification or non-classification

As no systemic effects of the target substance were observed in the inhalation studies and the local effects are covered by the classification for corrosivity, a classification for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the 13th time in Regulation (EU) 2018/1480, is not warranted.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Registration Dossier

Registration Dossier

Diss Factsheets

Propylenediamine

Endpoint summary

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint conclusion

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Reference 1

Reference 2

Endpoint conclusion

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint conclusion

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Additional information

Justification for classification or non-classification

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