7-azatridecane-1,13-diamine

Endpoint summary

Description of key information

No repeated dose toxicity data are available for the registration substance. However adequate and reliable studies performed with a surrogate substance (multi-constituent substance containing high levels of this registration substance) are at hand.

In a subchronic toxicity study the surrogate susbtance was administered orally to rats. Recalculating the effect level to the submission substance led to a NOAEL of 13 mg/kg bw. However, as explained below, the only effects seen in the study were in the upper and lower respiratory tract. Based on this study the oral toxicity of the submission substance appears to be low and the effects observed in rats seem to be consecutive to the inhalation route (false route perhaps du to the viscosity of the substance).

In a subchronic inhalation toxicity study rats were exposed to aerosol of the test material. A No observed adverse effect level could not be determined as in all concentration tested effects on the respiratory tract were observed (organs were affected; the nasal passages, trachea and lungs). The incidence and severity of the lesions was increased as a function of higher exposure levels. The LOAEC of this study is 10 mg/m³.

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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

recalculated to submission substance

Sex:

male/female

Basis for effect level:

other: 3 animals (female) with respiratory effects were noted at 50 mg/kg bw/day

Critical effects observed:

not specified

Conclusions:

The test material was subjected to test subchronic toxicity in rats. For 13 weeks (7days/week) the test substance was applied orally (gavage) to rats (15 males and 15 females/dose) in doses of 0, 20, 50, and 120 mg/kg bw/day. Based on the respiratory effects noted in 3 animals at 50 mg/kg bw/day the NOAEL in this study was conservatively set to be 20 mg/kg bw. Based on the information on the test material the NOAEL was recalculated to 13 mg submission substance/kg bw.

Executive summary:

The study used as source investigated Reaction mass of 7-azatridecane-1,13-diamine and hexamethylenediamine (EC 907 -605 -7, which contains relevant amounts of the submission substance,

7-azatridecane-1,13-diamine).

The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

13 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Reliable and adequate study with a surrogate substance of the submission study available (Klimisch 2).

System:

respiratory system: upper respiratory tract

Organ:

lungs

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Key result

Dose descriptor:

LOAEC

Effect level:

10 mg/m³ air (analytical)

Based on:

other: BHMT analysed from test material

Remarks:

)

Sex:

male/female

Basis for effect level:

other: lesions of the respiratory tract (nasal passages, trachea and lungs all showed graduated prog ression of responses from hypertrophy to squamous metaplasia hyperplasia to ulceration of the cilia ted respiratory epithelium)

Remarks on result:

other: no further recalculation requiered

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

10 mg/m³ air (analytical)

System:

respiratory system: upper respiratory tract

Organ:

lungs

nasal cavity

trachea

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

The test material was subjected to test subchronic toxicity in rats. For 13 weeks (5 days/week, 6 h/d) the rats (12 males and 12 females/group) were exposed to aerosol containing BHMT at analytical concentrations of 0, 10, 31, and 62 mg/m³/day.
Based on the fact that the lesions of the respiratory tract were seen throughout all exposure concentrations tested in this study the lowest observable adverse effect concentration is 10 mg per cubic metre (LOAEC, no recalculation necessary as the analysis of the exposure was set to analyse BHMT, the registration substance of this submission).

Executive summary:

The study used as source investigated Reaction mass of 7-azatridecane-1,13-diamine and hexamethylenediamine (EC 907 -605 -7, which contains relevant amounts of the submission substance,

7-azatridecane-1,13-diamine).

The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

10 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Reliable and adequate study with a surrogate substance of the submission study available (Klimisch 2).

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

No repeated dose toxicity data are available for the registration substance. However adequate and reliable studies performed with a surrogate substance (multi-constituent substance containing high levels of this registration substance) are at hand.

Oral exposure:

Male and female Sprague-Dawley rats were subjected to test subchronic toxicity. Doses of 0, 20, 50, and 120 mg test material/kg bw/day (corresponding to 13, 32,5, and 78 mg submission substance/kg bw/day; 15 males and 15 females /dose) were applied orally via gavage at 7days/week for 13 weeks.

One male and one female in the high-dose group died and one male at the mid-dose died during the treatment period. With the possible exception of respiratory rales seen in a few males and females at the high-dose level and mid-dose females, no clinical signs of toxicity associated with treatment were observed. The high-dose females showed a slight decrease in body weights in comparison to controls (minus 5% only). No significant weight differences were measured in males at any dose level or females at the low- and mid-dose levels. Some evidence of reduced food consumption was noted for high-dose males (on the basis of mg/kg/day). Ophthalmoscopic examination did not reveal any effects of treatment on the eye. With the exception of an increase in segmented neutrophils in high-dose males and females, there was no evidence of treatment-related changes in the hematologic, clinical chemistry or urinalysis examinations. Nevertheless the values were within the historical control range for this species in this laboratory. The incidental findings from gross necropsy did not appear to be related to treatment. Males at the high-dose level had decreased absolute adrenal weights and the liver weight relative to body weight for mid-dose females was elevated. These changes were not correlated with any microscopic findings and were considered unrelated to treatment. No other significant organ weight differences between control and treatment groups were noted. The microscopic lesions observed were generally comparable in treated and control group animals and were considered to be of spontaneous origin. Interstitial pneumonia was slightly increased in treatment groups but was considered non-specific and unrelated to treatment. Therefore, treatment did not result in histopathologic changes in any organ or tissue.

CONCLUSIONS Administration of the test material at dose levels of 20 mg/kg bw/day did not produce any toxicological signs which were attributable to treatment. At 50 and 120 mg/kg bw/day, respiratory rales were seen in males and females. At 120 mg/kg bw/day the females had slightly decreased body weights and both males and females showed increases in segmented neutrophils which may have been treatment-related but the values were in the normal range of historical control data. Overall the no-observable adverse effect level was considered to be 20 mg/kg bw/day for both sexes (corresponding to 13 mg subsmission substance/kg bw/day).

As the only organ showing macroscopic and microscopic findings related to the substance was the lung it is possible that the effects were consecutive to the inhalation route (false route perhaps du to the viscosity of the substance). Based on this study the test material oral systemic toxicity appears to be low.

Inhalation exposure:

Male and female Sprague-Dawley rats were subjected to test subchronic toxicity of the test material being given as aerosol for 13 weeks (5 d/week, 6 h/d;equivalent to OECD 413, GLP). Mean analytical values for the three expsoure levels were 10, 31 and 62 mg BHMT/m³. The nominal to analytical ratios ranged from 3.2 to 5.9 which resulted from substantial deposition of test material on chamber surfaces; however chamber distribution data indicated acceptable dispersion of the aerosol. Generally, greater than 90% of the test material particles were in the respirable size range. No animals died on study. Clinical signs of toxicity were confined to respiratory wheezing in high dose animals and discoloration of fur in females. High dose animals exhibited significantly decreased body weight in comparison to control animals. Elevated red blood cell counts with associated increases in hemoglobin and hematocrit were observed in the high dose females (maybe as compensatory response to hypoxia which was secondary to the pulmonary changes/emphysema). ALT, AST and phosphorous were elevated in high dose males; high dose females had lowered serum glucose levels. Other differences in clinical chemistry seen at the low and mid-dose level were within normal ranges and were not considered to be treatment-related. In the high-dose animals, several organs showed reduced absolute weights and increased relative weights which was attributed to overall body weight reductions. Dose related increases in the incidence of pulmonary emphysema were noted at gross necropsy. Lesions associated with treatment were restricted to the respiratory tract. Three target organs were affected; the nasal passages, trachea and lungs all showed graduated progression of responses from hypertrophy to squamous metaplasia hyperplasia to ulceration of the ciliated respiratory epithelium. The incidence and severity of the lesions was increased as a function of higher exposure levels, being most notable in the two highest dose groups and much less severe at the low dose level. Hypertrophy and eosinophilic granularity of the olfactory epithelium was noted at all levels of treatment and was considered to be an age-related change exacerbated by treatment. Hypertrophy, hyperplasia, squamous metaplasia and ulceration were found in the nasal passages, trachae and lungs with secondary inflammation of the ciliary epithelium. These responses were consistent with those expected for a corrosive substance; there was no evidence that these changes represented a pre-neoplastic condition. The pulmonary emphysema noted at gross necropsy was related to the histopathological changes and may have resulted in hypoxia and associated increases in red blood cell production.

CONCLUSION: Exposure of rats to the test material at the high dose group for thirteen weeks resulted in pathological lesions of the respiratory tract, reduced body weight, increased RBC count and pulmonary emphysema. Lesions of the respiratory tract were observed in the low and mid dose grouops, although with much lesser incidence and severity at the low-dose level. Therefore a no-effect level could not be determined for this study.The LOAEC is 10 mg/m3.

Justification for classification or non-classification

Organ-specific effects observed after repeated inhalation and oral exposure are confined to the respiratory tract. The most probable cause of the effects is the corrosive activity of the substance, which

is expected to occur even after short-terrm exposure. Therefore, classification with respect to specific target organ toxicity after short-term exposure is proposed:

STOT SE Cat 3 (H335), according to Regulation (EC) No 1272/2008.

Based on findings in the oral repeated dose study, a STOT classification for oral long-term effect is not needed. Indeed the only effects observed after oral repeated exposure appeared to be consecutive

to intake by the inhalation route.

After repeated inhalation exposure, the effects noted in rats are clearly due to the corrosivity of the substance. Accordingly, the classification of the submission substance for its corrosive properties and with regard to STOT single exposure is sufficient.