Isooctadecanoic acid, reaction products with tetraethylenepentamine

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Executive Summary

 

EC 701-204-9 is a polyamide dispersant made from tetraethylenepentamine (TEPA, CAS RN 112-57-2) and isostearic acid (CAS RN 2724-58-5). There are multiple studies conducted in a guinea pig model (both Buehler and M&K) as well as human data. The weight of evidence demonstrates that EC 701-204-9 does not warrant classification as a skin sensitizer. This is primarily based on two well conducted Buehler studies and one M&K study that were all negative for skin sensitization. EC 701-204-9 was concluded to be a skin sensitizer in one Buehler study but this study was confounded by excessive irritation as evidenced by responses in the naïve control animals. In addition, there was a response suggestive of skin sensitization in one human subject that was challenged with EC 701-204-9 during a cumulative irritation study. However, due to lack of background information on the subject’s activities, deficient documentation and scoring of the response, and as this method is not designed to test for skin sensitization, this response is not considered as sufficient evidence to outweigh the robust guinea pig studies.  

 

Overview and Discussion of Studies

 

Table 1 contains a summary of the available skin sensitization studies.

 

 

Table 1. Skin Sensitization Data for EC 701-204-9

Study #	Protocol	Induction	Challenge	Result	Reference	Comments
1	GPMT	100%	100%	Negative	Biosearch Incorporated.   January, 1982.   81-2842A	Klimisch code 2: GLP but deviated from current guidelines as no control was used.   Lack of irritation range-finding data   Unknown test substance purity due to age of study
2	Buehler	25%	5%   Rechallenge: 5% 1%	Study director concluded sensitization response occurred at both 5% and 1%.	Hill Top Research   Jan, 1994   93-8068-21 (A)	Klimisch code 2 due to high background irritation in naïve controls.   Whether sensitization was occurring in this study cannot be determined due to the comparable response occurring in naïve control animals.
3	Human Cumulative Irritation	NA	NA	Study director concluded sensitization response occurred in 2 (out of 25) subjects	Hill Top Research.  August, 1997   95-1805-70A	Klimisch code 4 due to incomplete information to determine whether the responses observed were due to skin sensitization.
4	HRIPT	100%	100%	Negative   (0/31)	Hill Top Research.  August, 1997   95-1805-70B	Klimisch code 2 as this was only a pilot study with only 31 subjects (study stopped based on indications of sensitization in cumulative irritation study (95-1805-70A)
5	Buehler	75%	25%   Rechallenge: 25% 10%	Negative   4/20 at challenge responded and 1/20, 0/20 at rechallenge (25%, 10% respectively)	Springborn Laboratories.   Mar, 2003   SLI 3580.3   Study conducted for ACC HERTG	Klimisch code 1. Well conducted guideline study.
6	Buehler	25%	2.5%	Negative (0/20)	Charles River Laboratories   August, 2007   LMT00011	Klimisch code 2 due low induction dose; otherwise a well conducted guideline study.

 

Study 1: GPMT (81-2842A)

A preliminary irritation study on the test material did not produce irritation. Therefore, the test substance was applied undiluted for induction and challenge. This study deviates from current OECD protocol in that there does not appear to be a concurrent control group or information from a positive control group. The supplier has also indicated that they believe the test substance is as manufactured (~>90% purity), however this cannot be confirmed given the age of the study. The conclusion is that the test substance did not elicit a sensitization response in guinea pig.

 

Study 2: Buehler (93-8068-21 (A))

This study used challenge concentrations that were too irritating leading to a similar response in naïve controls as challenge/rechallenge animals; it is uncertain why the irritation response in this study appears to be greater compared to the other guinea pig studies.

 

Upon first challenge, 65% of test article induced animals responded with a score of “1” after 48 hours compared to 70% in naïve controls; 5% of test article induced animals responded with a score of “2” after 48 hours compared to 0% of naïve controls. 

 

A rechallenge was conducted, including at a lower concentration (1%) at different exposure sites. The 5% rechallenge still resulted in significant responses in naïve controls (50% with a score of “1”); however, there was a greater incidence of scores of “2” in test article induced animals (30%) compared to naïve controls (0%). 

 

Rechallenge using 1% resulted in significantly less irritation in naïve controls (10% responded with a score of “1”). In previously induced animals, 25% responded with a score of “1” and 10% with a score of “2”.

 

The conclusion by the study director that sensitization had occurred appears to be based on the higher incidences of scores of “2” in induced animals compared to naïve controls. However, the high background irritation (as evidenced by the responses in naïve controls) may be leading to an artificially greater response in induced animals related to “angry back” syndrome.

 

In addition, assuming that 1% is considered a more appropriate rechallenge dose due to less background irritation, only 10% of induced animals responded with scores of 2, which does not meet the classification criteria.

 

Following is a summary of the skin sensitization results from the study report:

 

 

 

 

Studies 3 and 4 (95-1805-70A and 95-1805-70B)

A cumulative irritation study in human subjects and HRIPT were conducted; the HRIPT was stopped at the pilot phase due to evidence of skin sensitization in the cumulative irritation study. The pilot phase of the HRIPT study was completed and 0/31 subjects had evidence of skin sensitization. Following is an overview of both methods:

 

Parameter	HRIPT	Cumulative Irritation
Induction dose/Initial treatment	3 times a week for 3 weeks (9 total)	14 days (repetitive, 14 total)
Challenge dose	After two weeks	Typically none
Dose level and application	One dose at same site	Multiple doses per subject (each dose is done at the same site)
Patch exposure period	~24 hours	~23 hours

 

 

25 subjects completed the cumulative irritation study; the study director concluded that 2 subjects had responses that were “strongly suggesting of sensitization:”

 

·       

·        A challenge of undiluted test article and mineral oil to naïve sites resulted in erythema, papules, and edema.

 

 

Regarding subject 28, this should be considered more of an irritant response than a skin sensitization response as no challenge was conducted. The cumulative irritation study is designed for different purposes than an HRIPT and this may also factor into a heightened or hypersensitive response; for example, multiple doses are administered continually for 14 days as opposed to an induction period in the HRIPT that allows for rest between doses.

 

Regarding subject 21, while a challenge was conducted, no quantitative assessment of the reaction was reported; instead a qualitative description of the reaction is provided. In addition, there is no description of the response at the patch site with mineral oil. Finally, no characterization or questionnaire of what the subject may have been exposed to after the end of the study occurred; therefore, it is unknown the state of the subject and whether there was any confounding factors or exposures that led or contributed to the response. 

 

Study 5 (SLI 3580.3)

The 2003 study was done under the direction of the ACC HERTG and used an induction dose of 75%. At primary challenge with a dose of 25%, 4/20 animals exhibited signs of skin sensitization (at 48 hour observation). No responses of “1” or greater were noted for naïve controls at any dose or time. A characteristic of skin sensitization is that the response should be replicated after a rest period (i.e., rechallenge); this characteristic is often used to confirm skin sensitization (as opposed to confounding skin irritation). At rechallenge, 1/20 animals responded to a dose of 25% and 0/20 responded to a dose of 10% (48 hours). Therefore, the conclusion of the study director was that skin sensitization did not occur under the conditions of this test.

 

This is the key study as it is a Klimisch code 1 and used the highest induction dose of the Buehler studies available.

 

Study 6 (LMT00011)

The concentration selected for induction in this study was the highest concentration to cause mild irritation based on a preliminary irritation study in which eight concentrations between 1% - undiluted were tested. However, scores of “2” were only noted in the preliminary study at a concentration of 100%. In addition, the concentration selected for the challenge dose was reported as the highest non-irritating dose, however, 5% may have been a more appropriate concentration as none of these animals scored higher than a +/- (between 0 and 1). Following challenge with 2.5%, test animals were indistinguishable from control animals with no irritation observed in either group. A rechallenge was not conducted as the results from the challenge were considered definitive. The conclusion o is that the test substance did not elicit a sensitization response in guinea pigs.

 

Conclusion

Of the 4 guinea pig studies that have been conducted on EC 701-204-9, one study resulted in the conclusion that skin sensitization had occurred; however, this study is not used for classification purposes as the naïve controls demonstrated that the challenge dose caused excessive irritation. This is confirmed in subsequent studies that were negative for skin sensitization and used higher or similar doses at both induction and challenge and did not have excessive irritation.

 

Challenge of a subject in a human cumulative irritation study indicated that sensitization may have occurred. However, human cumulative irritation studies are not designed to determine skin sensitization and there is a lack of documentation on both the response and any confounding factors. In addition, 0/31 subjects were not sensitized in the pilot phase of an HRIPT.

 

Therefore, the robust and high quality guinea pig is used as authoritative for the classification of EC 701-204-9.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

There are multiple studies conducted in a guinea pig model (both Buehler and M&K) as well as human data. The weight of evidence demonstrates that EC 701-204-9 does not warrant classification as a skin sensitizer.