Registration Dossier

Administrative data

Description of key information

Sustained decreased body weights, body weight gain in repeated dose oral study of the amine in rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Clariant Genamin OL 100D, CAS 112-90-3, as stated in the EU Risk Assessment Report on Primay Alkyl Amines, 2008
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Analytical verification of doses or concentrations:
yes
Remarks:
according to EU B.7/OECD 407
Duration of treatment / exposure:
28 day, with treatment-free 14 day recovery period
Frequency of treatment:
daily, 7 days per week
Dose / conc.:
3.25 mg/kg bw/day (nominal)
Dose / conc.:
12.5 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10, with 5 additiona animals per sex in the recovery groups
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Gait abnormalities in high dose (stilted and/or uncoordinated gait)
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight was significantly lower for high dose males and females; mean body weights for mid dose males were significantly lower.
Food efficiency:
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Clinical chemistry changes comprised significantly increased total bilirubin for the high dose group, slightly increased urea nitrogen for mid and high dose females and very slightly increased AST and ALT activity in the liver of high dose males.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
At the end of 28-day treatment, body weight in males was -5.3% (p > 0.05, ns) at low dose -7.5% (p ≤ 0.05) at mid dose, and -10% (p ≤ 0.05) at high dose compared to the body weight of controls. At the end of recovery, body weight in high dose males remained at the same, significantly lower level (-9.8%, p ≤ 0.05). Body weights in high dose females were -10.4% lower than the control values at the end of treatment and a clear tendency to recover was seen at the end of 4-week recovery (difference was still -5.9%, p > 0.05, ns). Food consumption remained unaffected throughout the study in all dose groups. Hematology findings in high dose groups included significantly increased hematocrit and decreased reticulocyte counts (males only) and slightly increased white blood cell counts with a shift towards increased neutrophils (both genders), all findings were reversible. Clinical chemistry changes comprised significantly increased total bilirubin for the high dose group, slightly increased urea nitrogen for mid and high dose females and very slightly increased AST and ALT activity in the liver of high dose males. Urinalysis remained unaffected in all dose groups. No anatomic pathology correlates (organ weights, macroscopy, microscopy) of toxicological significance were detected.
Key result
Dose descriptor:
NOAEL
Effect level:
3.25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
12.5 mg/kg bw/day (nominal)
System:
nervous system
Organ:
other: motor activity alteratioons
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
The test substance was administered by gavage to CD rats in a 28-day OECD 407 guideline experiment with a 14 day recovery period. Doses were 3.25, 12.5 and 50 mg/kg bw/day. Mean body weight was significantly lower for mid and high dose males and in high dose females. There were no significant clinical effects, clinical chemistry or pathology results associated with treatment. The NOAEL was 3.25 mg/kg bw/d.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
3.25 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
adquate
System:
other: body weight changes
Organ:
not specified

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Not applicable

Additional information

The draft EU Risk Assessment Report (2008) states the NOAEL for the category of primary (fatty) alkylamines is 3.25 mg/kg bw/day, based on body weight changes after 28 days oral gavage to octadec-9-enylamine. The expert committee stated that this guideline study (under GLP) is adequate for filling the data gaps of the category and no additional repeated dose toxicity is needed. The NOAEL of 3.25 mg/kg bw/d is used for determination of the DNEL of the registered substance.

A risk assessment has been undertaken for a metabolite, terephthalic acid (TPA). This risk assessment includes TPA and its esters, namely dimethyl phthalate (DMT) and diethylhexyl phthalate (DEHP) (Ball GL, McLellan CJ and Bhat VS, 2012. Toxicological review and oral risk assessment of terephalic acid (TPA) and its ester: A category approach. Crit Review Toxicol 42(1): 28-67). Experimental data from published and unpublished toxicity and toxicokinetic studies were reviewed. The critical effect of TPA was determined to be urinary bladder urolith formation with secondary transitional cell tumor development. This was confirmed by the authors as a threshold effect, and a critical concentration of 8 mM TPA in urine has been calculated as required to achieve saturation of human urine with calcium terephthalate; this corresponds to approximately 2000 mg/kg bw/d in humans (Heck, 1981). The NOAEL for TPA in a 2012 risk assessment is 142 mg/kg bw/d based on the key CIIT 1993 chronic study. The findings of studies on the other TPA esters were consistent; the BMDL10 from a 1979 NTP chronic study on DMT was 148 mg/kg bw/d based on kidney inflammation in female rats, and the BMDL10 from a chronic study on DEHP (Deyo, 2008) was 54 mg/kg bw/d based on retinal effects in female rats. The uncertainty factors (assessment factors) applied in this risk assessment were 10 for interspecies, 10 for intraspecies, 1 for dose-response (LOAEL to NOAEL), 1 for duration of study, and 3 for uncertainties associated with database deficiencies. For TPA, the point of departure (oral reference dose (RfD)) was 0.5 mg/kg bw/d; consistent with 0.5 mg/kg bw/d for DMT and 0.2 mg/kg bw/d for DEHP (appropriate considering the higher molecular weight of the larger ester).  With exposure input, the total allowable concentration (TAC) of TPA in drinking water is 3 mg/L (rounded). TPA is listed in Annex I of Food Contact Materials (EC, 2009) with a specific migration limit of 7.5 mg/kg food; it is also listed in the US 21 CFR as acceptable for food contact use in resinous and polymeric coatings.

Male and female rats were exposed to terephalic acid vapour for 6 hours per day, for 28 days.  There were no significant findings in any systemic toxicity endpoint, and only minimal local tracheal epithelial degeneration was observed at the high dose of 3.3 mg/m3.  The NOAEC for TPA was considered 3.3 mg/m3.

The oral/dermal and inhalation values for the points of departure for TPA are higher than those for the amines; therefore, the NOAEL for amines is used as the point of departure for risk assessment for the registered substance.

Justification for classification or non-classification

In repeated dose studies of the potentially bioavailable metabolites of the registered substance, there was no evidence of specific target organ toxicity after repeated dose exposure. The substance does not meet the criteria for STOT-RE according to Regulation EC No. 1272/2008.