Registration Dossier

Administrative data

Description of key information

Repeated dose oral toxicity: NOEL = 100 mg/kg bw

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

REPEATED DOSE TOXICITY: ORAL

No tests regarding repeated dose oral toxicity are available on the substance in itself. Nevertheless, some information are available on the structural analogous Similar Substance 01 (CAS 21850-44-2) and on the precursor/metabolite of AP 1300 S, Similar Substance 02 (CAS 79-94-7).

Similar Substance 01 has been considered in order to complete the assessment due to the great similarity with AP 1300 S. Similar Substance 01 shares with AP 1300 S the same structure, except for the fact that Similar Substance 01 presents two dibromobutane functional groups linked to the dibromophenol core, instead the dibromo-methylbutane as in the case of AP 1300 S.

As previously mentioned, the Similar Substance 02 is a precursor/metabolite of AP 1300 S, therefore the second study has been also considered for the assessment.

The justification for the Read Across approaches has been attached to the Section 13.

 

Test conducted on Similar Substance 01:

Only one short abstract is available on Similar Substance 01. The evaluation of Repeated dose toxicity by oral route (90 days) reported from Great Lakes Chemical Corporation (1987)[1] in the WHO publication[2] has been considered in order to complete the assessment. During the test no adverse effect has been observed on mice.

NOAEL(90days) > 2000 mg/kg bw/day. 

 

Test conducted on Similar Substance 02:

Five different studies are available on Similar Substance 02. One study of Subacute toxicity and the other of Subchronic toxicity:

 

Subacute test 28 days (Goldenthal & Geil)

The evaluation of Repeated dose toxicity by oral route (28 days) is reported from Goldenthal & Geil (1972)[3] in the WHO publication[2]; No effects on behaviour, appearance, food consumption, body weight gain, or mortality were observed moreover no gross or microscopic abnormalities were observed during the study.

NOAEL(28days) > 50 mg/kg bw/day.

 

Subchronic test 90 days (Quast et al.)

The evaluation of Repeated dose toxicity by oral route (90days) is reported from Quast et al. (1975)[4] in the WHO publication[2]; During the test rats have been fed with doses up to 100 mg/kg bw/day of substance. The administration of the substance in the diet at a dose as high as 100 mg/kg body weight per day for 90 days did not produce toxicological effects

NOAEL(90days) > 100 mg/kg bw/day

 

Subchronic test 3 months(Tobe et al.)

The evaluation of Repeated dose toxicity by oral route (3 months) is reported from Tobe et al. (1975)[5] in the WHO publication[2]; During the test mice have been fed with doses up to 7100 mg/kg bw/day of substance. All animals at the highest dose died during the study and other adverse effect have been observed during the study at the highest concentrations (7100 mg/kg bw/day and 2200 mg/kg bw/day).

NOAEL(3months) = 700 mg/kg bw/day

 

Subchronic test 14 weeks (From NTP Report - rats)

The evaluation of Repeated dose toxicity by oral route (14weeks) on rats reported in the NTP Technical Report on rats, conducted as a range finding for a two years study. All core study rats survived to the end of the study but some adverse effect has been observed in the rats groups administered with concentration higher and equal than 100 mg/kg bw/day

NOEL(14weeks) = 100 mg/kg bw/day

 

Subchronic test 14 weeks (From NTP Report - mice)

The evaluation of Repeated dose toxicity by oral route (14weeks) on mice reported in the NTP Technical Report, conducted as a range finding for a two years study. All core study mice survived to the end of the study but some adverse effect has been observed in the mice groups administered with concentration higher and equal than 100 mg/kg bw/day

NOEL(14weeks) = 100 mg/kg bw/day

The information on the Similar Substances derived from older studies (1972 – 1987) are lacking of many details on the histopathological results. Based on the macroscopic effects and gross pathological examinations, the No Adverse Effect Levels reported are in general higher than 700 mg/kg bw/day. The two years NTP studies (2014) on rats and mice report LOAEL at 250 mg/kg bw/day, but not NOAELs. The preliminary 90 days dose range finding studies indicate a NOEL at 100 mg/kg bw/day and this value will be take as reference for the DNEL calculation.

 

REPEATED DOSE TOXICITY: INHALATION

According to the REACH Regulation (EC n. 1907/2006) Annex VII, Column 2, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets.

Moreover, no exposure to particles is expected as the substance during the use will be included in matrix.

 

REPE ATED DOSE TOXICITY: DERMAL

According to the REACH Regulation (EC n. 1907/2006) Annex VII, Column 2, testing by the dermal route is appropriate if:

  1) inhalation of the substance is unlikely and

  2) skin contact in production and/or use is likely and

  3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.

The substance does not show any properties that suggest potential for a significant rate of absorption through the skin. No skin contact during production or use is expected. Therefore no test has been conducted by the dermal route.

 

 

[1] Great Lakes Chemical Corporation (1987) Summaries of toxicity data. PE-68, Bis(2,3-dibromopropyl ether) of tetrabromobisphenol A. West Lafayette, Indiana, Great Lakes Chemical Corporation (Unpublished   report submitted to WHO by the Brominated Flame Retardant Industry Panel).

[2]World Health Organization (WHO, Geneva, 1995); Dr. G.J. van Esch “Tetrabromobisphenol A and Derivatived” (Environmental health criteria; 172)

[3] Goldenthal EI & Geil RG (1972) Tetrabromobisphenol A. Twenty-eight day toxicity study in rats. Mattawan, Michigan, International Research and Development Corporation (Report to Great Lakes Chemical Corporation, West Lafayette, submitted to WHO by the Brominated Flame Retardant Industry Panel). 

[4]Quast JF, Humiston CG, & Schwetz BA (1975) Results of a 90-day toxicological study in rats given tetrabromobisphenol A in the diet. Midland, Michigan, Dow Chemical (Unpublished report No. HET 17.5-36-(3), submitted to WHO by the Brominated Flame Retardant Industry Panel).

[5]Tobe M, Kurokawa Y, Nakaji Y, Yoshimoto H, Takagi A, Aida Y, Monma J,Naito K, & Saito M (1986) [Subchronic toxicity study of tetrabromobisphenol-A: Report to the Ministry of Health and Welfare](in Japanese).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No selection has been done due to the Weight of Evidence approach, nevertheless for the effect level selection has been considered the NOAEL value associated to the subchronic test on Similar Substance 01.

Justification for classification or non-classification

According to the CLP Regulation (EC n. 1272/2008), 3.9 Specific target organ toxicity - repeated exposure section, substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed.

 

In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. Nevertheless, they can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration (the assessment shall be done on a case-by- case basis). For example, for 28-day study the guidance values are increased by a factor of three.

 

In the case of AP 1300 S, no statistically significant effects were recorded on Similar Substance 01 up to 2000 mg/kg bw/day in females and males rats and treated for 90 days. Taken into account the reference values indicated in the CLP Regulation, the substance effects were recorded at doses exceeding of the classification criteria.

In conclusion, the substance is expected to be not classified for repeated dose toxicity according to the CLP Regulation (EC n. 1272/2008).